December 2, 2014 Mr. John D. Hadden Assistant Attorney General Litigation Division Office of the Attorney General 313 North East 21st Street Oklahoma City, OK 73105 Re: Charles F. Warner, et al, v. Gross, et al, No CIV-14-665F Dear Mr. Hadden: I have been requested to address the pharmacological effects of the drugs used in the execution protocol for the State of Oklahoma. The following outlines the classification of the drugs in the protocol, their mechanisms of action, dosing in therapeutic use and the consequences of toxic doses as outlined in AttachmentAttachment D1, Charts A-D. Midazolam is a short acting benzodiazepine which is use as a pre-anesthetic agent for routine medical procedures to allay patient apprehension, create amnesia, and anesthesia induction. It produces different levels of central nervous system (CNS) depression through binding to gamma-aminobutyric acid (GABA) receptors. It is available in an injectable dosage form. Once the drug is administered the onset of action is 1.5-5 minutes. It is widely distributed after administration and crosses the blood brain barrier. Maximum effects are seen in 20-60 minutes with recovery occurring in 2-6 hours. Serious adverse events include cardiac arrest, agitation, apnea and respiratory depression/arrest. The drug can result in depression of the spinal reflexes and reticular activating system leading to coma and respiratory arrest. The drug will potentiate the effect of other central nervous system depressants, such as ethanol, opioids and sedative hypnotics. When given together with opioids, the dose of both drugs can be reduced. The therapeutic dose as a pre-anesthetic for adults is 1.5 – 3.5 mg for a 70kg adult less than sixty years old with a maximum recommended dose of 5mg intravenously. The maximum daily dose should not exceed 10mg. When the drug is used for induction of anesthesia no more the 40 mg. should be used. Fatalities have occurred from midazolam in doses ranging from 0.04 to 0.07mg/kg. (2.8 – 4.9mg/70Kg adult) The dose indicated in Charts C & D of Attachment D of the State of Oklahoma’s execution protocol is 500 mg IV. This dose is at least 100 times the normal therapeutic dose. When the drug is administered rapidly in this large dose it will lead to toxicity resulting in CNS depression, respiratory and cardiac arrest. Midazolam is not an analgesic however the dose administered per Chart B will render the person unconscious and ”insensate” during the remainder of the procedure. The lowest dose resulting in human deaths according the manufacturer’s “material Safety Data Sheet” is .071 mg/kg, intravenously. Over 80 deaths from the use of midazolam had occurred as of 2009. 1 Attachment D in this report refers generally to the attachment to the Oklahoma Department of Corrections execution protocol identified as OP-040301 with an effective date of 9/30/2014 that identifies specifics regarding the preparation and administration of chemicals for use in the execution of offenders sentenced to death. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPSU 1) Midazolam 2) Pentobarbital Chart A of Attachment D calls for the use of pentobarbital. This drug is a short-acting oral or parenteral barbiturate having sedative-hypnotic and anticonvulsant properties. In general, the drug has a nonselective depressant effect throughout the central nervous system due to a decrease in both preand postsynaptic excitability. The sedative-hypnotic effects of pentobarbital are related to its inhibition of ascending conduction in the reticular formation, which controls central nervous system arousal. The inhibition depresses the sensory cortex: decreases motor activity; alters cerebral function; and increases the threshold for electrical stimulation, which contributes to its anticonvulsant properties. It has been suggested that the sedative-hypnotic and anticonvulsant effects of barbiturates may be due to their ability to mimic the inhibitory synaptic action of gamma-aminobutyric acid. Historically, the drug was used to induce a coma characterized by absent brainstem reflexes and suppression of the EEG for patients with status epilepticus, acute eclampsia or poisoning. In order to use the drug this way, patients had to be mechanically ventilated first and a loading dose of 10-15 mg/kg IV for 1 hour with the maximum loading dose of 30mg/kg would be used. The onset of action of pentobarbital is about 1 minute following intravenous dosage. Therapeutically the drug should not be administered at rate higher than 50 mg/minute with at total dose 200-500mg. Chart A calls for 5,000 mg to be administered in an IV bolus (as rapidly as possible). Adverse Drug Reactions (selected): Apnea, respiratory depression, hypoventilation, bronchospasm, hypotension, sinus tachycardia, syncope and vasodilatation leading to cardio-pulmonary collapse may occur with rapid intravenous (IV) administration of pentobarbital. When the drug is administered in accordance with Chart A it will lead to toxicity resulting in cardiopulmonary collapse. Chart B of Attachment D of the State of Oklahoma’s execution protocol calls for the use of sodium thiopental. Thiopental is used to induce general anesthesia prior to administration of other anesthetic agents or as the sole anesthetic agent for short surgical procedures. It is a barbiturate which had dose related hypnotic effects ranging from light sleep to unconsciousness and anterograde amnesia but no analgesia. Thiopental works by enhancing GABA activity by altering inhibitory synaptic transmissions mediated by GABAa. Onset of activity occurs in 10-40 seconds with maximal effects occurring in about one minute. The duration of action is 5-8 minutes after a single dose. This can be extended with continuous IV administration. Doses required to induce and maintain anesthesia are 50-75mg (2-3 m Lof a 2.5% solution) administered every 20-40 seconds with additional drug administered should the patient’s anesthesia lighten. Alternatively, anesthesia could be rapidly inducted with a bolus dose of 210-280 mg (3-4 mg/kg) given in 2-4 divided doses in an average 70 kg adult. Thiopental could induce respiratory depression leading to decreased ventilator response to carbon dioxide. Myocardial depression could occur resulting in arrhythmias, increased heart rate, circulatory depression and death. Oklahoma’s execution protocol Attachment D Chart B calls for 5 grams to be injected all at once which is over 20 times the dose for rapid induction which is given in divided doses. At this dose and rate of injection cardio-pulmonary arrest will occur. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPSV 3) Sodium Thiopental (Pentothal®) 4) Hydromorphone Chart C of Oklahoma’s execution protocol calls for the use of Hydromorphone Hydrochloride (Dilaudid®). The drug is an opioid agonist. It is a semisynthetic analog of morphine used to relieve severe pain in in cancer, surgery, trauma, burn, and cardiac patients. Fatal cases of respiratory arrest have occurred even when the drug was used as recommended and not misused or abused. The FDA has required a “black box warning” concerning the dangers of the drug regarding fatalities secondary to the drug’s use to be included in the manufacturer’s package insert. It is a potent mu (OP3) receptor agonist. Mu receptors couple with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Analgesia is mediated through changes in the perception of pain at the spinal cord and in the central nervous system. Opioids close N-type voltage-operated calcium channels and open calcium dependent inwardly rectifying potassium channels resulting in hyperpolarization and reducing neuronal excitability. Opiates do not alter afferent nerve stimulation secondary to noxious stimuli. They do however blunt the emotional response to pain. Clinically, stimulation of mu receptors produces analgesia, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Respiratory depression is caused by direct action on the respiratory centers of in the brain stem. A reduction in the responsiveness of the brain stem to carbon dioxide and electrical stimulation occurs. Since the respiratory center is severely depressed at high doses of hydromorphone, it does not respond to increasing levels of carbon dioxide and therefore, there is no urge to breathe (no “air hunger”). Intravenous administration drug distribution has two half-lives with the initial half-life being 1.27 minutes followed by 14.7 minutes. The first half-life is the time to reach equilibrium in the plasma and the second half represents the distribution to other tissues. Drug elimination is through hepatic and renal mechanism; therefore the dose would be reduced for patients with diminished hepatic or kidney function. The primary metabolite of hydromorphone is hydromorphone-3-glucuronide which has 35-40 times greater exposure than parent compound. The time it takes to eliminate half of an administered dose is 2.3 hours. These properties indicate that the drug has a very quick onset of action with its peak pharmacological effect occurring within 15 minutes. The majority of the drugs effect is seen quickly after administration via the intravenous route. At therapeutic doses, cardiovascular adverse effects include: sinus bradycardia (<2%), sinus tachycardia (<2%), palpitations (<2%), hypertension, hypotension, orthostatic hypotension, faintness, flushing, extrasystoles (<2%), and syncope. In cases of severe respiratory and/or circulatory depression, shock and cardiac arrest may occur. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTM In clinical use, 0.2 to 1 mg IV may be administered over at least 2-3 minutes every 2-3 hours as needed for pain. In the opiate naïve patient, the dose is initiated at the lowest possible amount and titrated upwards to obtain pain control. With appropriate titration there is no maximum dose. Duration of action is 4-5 hours. An overdose causes respiratory depression, extreme somnolence, stupor or coma, skeletal muscle flaccidity, cold and clammy skin, bradycardia, hypotension apnea, circulatory collapse, cardiac arrest and death. Chart C of Oklahoma’s execution protocol calls for 500mg of hydromorphone (500 times the IV dose) administered IV in a bolus. This dose and speed of administration in combination with the hydromorphone administered will lead to cardio-pulmonary collapse. 5) Paralytic Agents Chart D of Oklahoma’s execution protocol calls for the use of a paralytic such as vecuronium bromide, pancuronium bromide or rocuronium bromide. These agents are neuro muscular blocking agents that are clinically used to as adjuncts to general anesthesia providing skeletal muscle relaxation during surgery or mechanical ventilation. They work by binding to acetylcholine receptors but do not activate them. All three of these paralytics have the same mechanism of action and may be used interchangeably taking into differences in dosing, length of action and some differences in side effects. Drug Dose Onset Duration Recovery Vagal Block Pancuronium 0.05 mg/kg 2-3 min 120-180 min Modest to marked Vecuronium 0.05mg/kg 1-1.5 min 90-100 min 35-45 min 45-60 min No Rocuronium 0.3 mg/kg 2 min 30 min 20-30 min Some at higher doses 6) Potassium Chloride Injection Potassium is the major cation of body cells (160 mEq/liter of intracellular water) and is concerned with the maintenance of body fluid composition and electrolyte balance. Potassium participates in carbohydrate utilization, protein synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in the heart. Recommended administration rates should not usually exceed 10 mEq/hour or 200 mEq for a 24 hour period if the serum potassium level is greater than 2.5 mEq/liter. The signs and symptoms of intoxication include, paresthesia of the extremities, are flexia, muscular or respiratory paralysis, mental confusion, weakness, hypotension, cardiac arrhythmia, heart block, electrographic abnormalities and cardiac arrest. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTN The typical initial dose of vecuronium bromide for a 70 Kg individual to achieve skeletal muscle relaxation would range from 5.6to 7 mg in adults. Chart D of Oklahoma’s execution protocol calls for 100 mg of vecuronium bromide or equivalent dose of either of the other agents. This dose is approximately 20 times the normal dose in skeletal muscle relaxation and will achieve the desired effect at a very high confidence level. Chart D calls for 240 mEq of potassium chloride to be administered intravenously as rapidly as possible. The dose is 24 times that is recommended over a one hour period. This dose will induce a cardiac arrest. 7) Involuntary Movements Some involuntary motor movements may be observed during normal anesthesia and have been observed during execution by injection. It is also postulated that when the brain is deprived of oxygen, movements are a result of hypoxemia. “Most of the movements described in brain-dead patients are considered spinal reflexes. The pathophysiologic basis of these reflexes is not known. However, hypoxic stimulation of neurons in the cervical spinal cord, isolated from the control of rostral areas, can elicit spinal reflexes. This hypothesis is supported by the appearance of spinal movements after a ventilator is turned off or during apnea testing. Other triggering factors—such as mechanical or painful stimuli, hypotension, and acidosis— have also been associated with spinal reflexes. Movements with muscular origin, such as eye opening or facial myokymia, have also been described.” (Saposnik, G. Spontaneous and reflex movements in 107 patients with brain death. The American Journal of Medicine (2005) 118, 311-314). 8) Can the subject feel pain? Excluding potassium chloride, none of the drugs in question causes pain upon injection. When high dose pentobarbital, thiopental, hydromorphone or midazolam are used in the amounts specified in Attachment D, the subject quickly reaches an unconscious and unresponsive state and would not react to painful stimuli. As specified in Attachment D, a consciousness check is conducted after 5 minutes have elapsed following the administration of the first chemical. Even so, the proper administration of of 500 mg of midazolam as specified in Chart D, make it a virtual certainty that any individual will be at a sufficient level of unconsciousness to resist the noxious stimuli which could occur from application of the 2nd and 3rd drugs in that Chart . The addition of benzyl alcohol to pharmaceutical preparations is for its bacteriostatic properties. In midazolam solution for injection, there is 1% benzyl alcohol. By volume the amount of benzyl alcohol would be 1 ml contained in 100ml of midazolam for injection. Most complications reported with benzyl alcohol have been in premature infants and a few cases in adults who have serious medical conditions. A 4.5 mg/kg dose is considered safe for health adults. Respectfully Submitted, R. Lee Evans, Pharm.D., FASHP, FCCP, BCPP Dean and Professor t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTO 9) Benzyl Alcohol Selected References: WWW. Drugs.Com (for health professionals) for Thiopental, Pentobarbital, Hydromorphone, Potassium Chloride, Midazolam, Vecuronium Bromide, Pancuronium Bromide or Rocuronium Bromide Material Safety Data Sheet for Midazolam Injection, Bedford Laboratories, 2007. Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. ASHP Therapeutic Guidelines. American Society of Health System Pharmacists, 2001 Final Report on the Safety Assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate. International Journal of Toxicology 2001:20;23. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTP Benzyl Alcohol. PubChem.ncbi.nlm.gov/compound/benzyl_alcohol. 12/2/2014 NIH benzyl alcohol ­ PubChem   U.S. National Library of Medicine     National Center for Biotechnology Information OPEN Search Compounds CHEMISTRY  D A T A B A S E  Compound Summary for CID 244 Benzyl Alcohol       Vendors Drug Information Pharmacology Literature Patents Bioactivities Also known as: benzenemethanol, phenylmethanol, phenylcarbinol, 100­51­6, alpha­Toluenol, Benzoyl alcohol Molecular Formula: C7H8O Molecular Weight: 108.13782 g/mol InChI Key: FDA UNII: WVDDGKGOMKODPV­UHFFFAOYSA­NLKG8494WBH A colorless liquid with a sharp burning taste and slight odor. It is used as a local anesthetic and to reduce pain associated with LIDOCAINE injection. Also, it is used in the manufacture of other benzyl compounds, as a from MeSH [18] pharmaceutic aid, and in perfumery and flavoring. http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol from FDA Pharm Classes [13] 1/75 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTQ Benzyl alcohol is a Pediculicide. 12/2/2014 benzyl alcohol ­ PubChem  Contents 1 2D Structure 2 3D Conformer 3 Identification 4 Chemical and Physical Properties 5 Related Records 6 Chemical Vendors 7 Drug and Medication Information 8 Pharmacology and Biochemistry 9 Use and Manufacturing 10 Safety and Hazards 11 Toxicity 12 Literature 13 Patents 14 Biomolecular Interactions and Pathways 15 Biological Test Results 16 Classification http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTR 17 Information Sources 2/75 12/2/2014 benzyl alcohol ­ PubChem 1 2D Structure  Search  Download  Get Image  http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTS from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 3/75 12/2/2014 benzyl alcohol ­ PubChem 2 3D Conformer  Download  Get Image                              Search                         Show Hydrogens  Show Atoms  Animate http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTT from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 4/75 12/2/2014 benzyl alcohol ­ PubChem 3 Identification 3.1 Computed Descriptors 3.1.1 IUPAC Name phenylmethanol from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 3.1.2 InChI InChI=1S/C7H8O/c8­6­7­4­2­1­3­5­7/h1­5,8H,6H2 from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 3.1.3 InChI Key WVDDGKGOMKODPV­UHFFFAOYSA­N from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 3.1.4 Canonical SMILES C1=CC=C(C=C1)CO from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 3.2 Other Identifiers 100­51­6 from DrugBank [2] http://drugbank.ca/drugs/DB06770 100­51­6 from EPA Chemical Data Report [11] http://www.epa.gov/cdr/ 3.2.2 EC Number 202­859­9 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 3.2.3 ICSC Number 0833 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 3.2.4 RTECS Number DN3150000 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 3.2.5 UNII LKG8494WBH  http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTU 3.2.1 CAS 5/75 12/2/2014 benzyl alcohol ­ PubChem from FDA/SPL Indexing data [16] http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm377913.htm 3.2.6 Wikipedia Benzyl alcohol  from Wikipedia [14] http://en.wikipedia.org/wiki/Benzyl_alcohol 3.3 Synonyms 3.3.1 MeSH Synonyms 1.  Alcohol, Benzyl 2.  Benzenemethanol 3.  Benzyl Alcohol from MeSH [18] http://www.ncbi.nlm.nih.gov/mesh/68019905 3.3.2 Depositor­Supplied Synonyms 11.  (Hydroxymethyl)benzene 21.  BENZYL­ALCOHOL 31.  Benzyl alcohol (nat 2.  benzenemethanol 12.  Phenolcarbinol 22.  Phenyl­Methanol 32.  Benzene Carbinol 3.  phenylmethanol 13.  alpha­hydroxytoluene 23.  Euxyl K 100 33.  Alcool benzilico [DC 4.  phenylcarbinol 14.  Benzal alcohol 24.  Itch­X 34.  .alpha.­Toluenol 5.  100­51­6 15.  Alcool benzylique 25.  Caswell No. 081F 35.  alcoholum benzylic 6.  alpha­Toluenol 16.  Benzylicum 26.  Bentalol 36.  aplha­Hydroxytolue 7.  Benzoyl alcohol 17.  Phenylcarbinolum 27.  Ulesfia 37.  Alcool benzylique [I 8.  Phenylmethyl alcohol 18.  hydroxymethylbenzene 28.  Aromatic primary alcohol 38.  .alpha.­Hydroxytolu 9.  Benzenecarbinol 19.  Methanol, phenyl­ 29.  benzylic alcohol 39.  Alcohol bencilico [IN 20.  benzylalcohol 30.  Phenyl Methanol 40.  Alcoholum benzylic 10.  Hydroxytoluene from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 3.4 Create Date 2004­09­16 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol from PubChem [17] http://pubchem.ncbi.nlm.nih.gov t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTV 1.  benzyl alcohol 6/75 12/2/2014 benzyl alcohol ­ PubChem 4 Chemical and Physical Properties 4.1 Computed Properties Molecular Weight 108.13782 g/mol Molecular Formula C7H8O XLogP3 1.1 Hydrogen Bond Donor Count 1 Hydrogen Bond Acceptor Count 1 Rotatable Bond Count 1 Exact Mass 108.057515 g/mol Monoisotopic Mass 108.057515 g/mol Topological Polar Surface Area 20.2 A^2 Heavy Atom Count 8 Formal Charge 0 Complexity 55.4 Isotope Atom Count 0 Defined Atom Stereocenter Count 0 Undefined Atom Stereocenter Count 0 Defined Bond Stereocenter Count 0 Undefined Bond Stereocenter Count 0 Covalently­Bonded Unit Count 1 4.2 Experimental Properties 4.2.1 Physical Description PelletsLargeCrystals; Liquid from EPA Chemical Data Report [11] http://www.epa.gov/cdr/ COLOURLESS LIQUID WITH CHARACTERISTIC ODOUR. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.2 Color Water­white liquid Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 128 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUM from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 7/75 12/2/2014 benzyl alcohol ­ PubChem 4.2.3 Odor Faint aromatic odor O'Neil, M.J. (ed.). The Merck Index ­ An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 186 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.4 Taste Sharp burning taste Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons, Inc. 1997., p. 129 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.5 Boiling Point 205.3 deg C Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 205.3 °C, 478 K, 402 °F http://sitem.herts.ac.uk/aeru/footprint/en/Reports/953.htm. from DrugBank [2] http://drugbank.ca/drugs/DB06770 205 °C from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.6 Melting Point ­15.2 deg C from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 ­15..2 °C, 258 K, 5 °F http://sitem.herts.ac.uk/aeru/footprint/en/Reports/953.htm. from DrugBank [2] http://drugbank.ca/drugs/DB06770 ­15 °C from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.7 Flash Point 213 DEG F (CLOSED CUP); 220 DEG F (OPEN CUP) The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983., p. 161 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 213 deg F (open cup) Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985., p. 264 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUN Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 8/75 12/2/2014 benzyl alcohol ­ PubChem 200 deg F (93 deg C) (closed cup) Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325­18 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 93 °C from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.8 Solubility Soluble in benzene, methanol, chloroform, ethanol, ether, and acetone Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 In water, 35,000 mg/L at 20 deg C Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 310 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 In water, 42,900 mg/L at 25 deg C Yalkowsky, S.H., He, Yan., Handbook of Aqueous Solubility Data: An Extensive Compilation of Aqueous Solubility Data for Organic Compounds Extracted from the AQUASOL dATAbASE. CRC Press LLC, Boca Raton, FL. 2003., p. 397 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Water Solubility (33 mg/mL, clear, colorless) http://www.chemicalbook.com/ProductChemicalPropertiesCB3852587_EN.htm from DrugBank [2] http://drugbank.ca/drugs/DB06770 Solubility in water, g/100ml: 4 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.9 Density 1.0419 at 20 deg C/4 deg C from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Relative density (water = 1): 1.04 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.10 Vapor Density 3.72 (Air = 1.00) Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 10th ed. Volumes 1­3 New York, NY: John Wiley & Sons Inc., 1999., p. V2: 407 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Relative vapour density (air = 1): 3.7 ; Relative density of the vapour/air­mixture at 20°C (air = 1): 1.0 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.11 Vapor Pressure 0.094 mm Hg at 25 deg C http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUO Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 9/75 12/2/2014 benzyl alcohol ­ PubChem Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Vapour pressure, Pa at 20°C: 13.2 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.12 LogP log Kow = 1.10 Hansch, C., Leo, A., D. Hoekman. Exploring QSAR ­ Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 31 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 1.1 http://sitem.herts.ac.uk/aeru/footprint/en/Reports/953.htm. from DrugBank [2] http://drugbank.ca/drugs/DB06770 1.1 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.13 Stability OXIDIZES SLOWLY, THEREFORE REMAINS STABLE FOR LONG TIME Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 393 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 It is slowly oxidized to benzaldehyde and benzoic acid on exposure to air ... . Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale­The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 39 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 817 deg F (436 deg C) Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325­18 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 436 °C from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 4.2.15 Decomposition When heated to decomposition it emits acrid smoke and fumes. Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley­Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 399 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.16 Viscosity 5.474 cP at 25 deg C; 2.760 cP at 50 deg C; 1.618 cP at 75 deg C; 1.055 cP at 100 deg C Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 6­178 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUP 4.2.14 Auto­Ignition 10/75 12/2/2014 benzyl alcohol ­ PubChem from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.17 Corrosivity Will attack some plastics U.S. Coast Guard, Department of Transportation. CHRIS ­ Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984­5. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.18 Heat of Combustion 894.3 kg cal/g mol wt at 20 deg C Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988­1989., p. D­274 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.19 Heat of Vaporization 50.48 kJ/mol at 205.31 deg C Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 6­104 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.20 pH A soln in water is neutral to litmus Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale­The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 39 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 39.0 dynes/cm = 0.0390 N/M at 20 deg C Kirk­Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991­ Present., p. V4: 117 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.22 Polymerization Benzyl alcohol contaminated with 1.4% of hydrogen bromide and 1.2% of dissolved iron(II) polymerizes exothermally above 100 deg C. Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth­Heinemann Ltd., 1990, p. 718 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.23 Odor Threshold 5.5 ppm U.S. Coast Guard, Department of Transportation. CHRIS ­ Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUQ 4.2.21 Surface Tension 11/75 12/2/2014 benzyl alcohol ­ PubChem Government Printing Office, 1984­5. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.24 pKa 15.4 http://sitem.herts.ac.uk/aeru/footprint/en/Reports/953.htm. from DrugBank [2] http://drugbank.ca/drugs/DB06770 4.2.25 Dissociation Constants pKa = 15.40 Serjeant, E.P., Dempsey B.; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23, 1979. New York, New York: Pergamon Press, Inc. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.2.26 Other Experimental Properties PERCENT IN SATURATED AIR AT 20 DEG C: 0.02; DENSITY OF SATURATED AIR: 1.0005 (AIR= 1) Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993­1994., p. 2590 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 CONVERSION FACTORS: 1 MG/L= 226.1 PPM & 1 PPM= 4.42 MG/CU M @ 25 DEG C, 760 MM HG Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993­1994., p. 2591 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Dielectric constant: 1.66; specific heat: 0.5402 cal/g at 15­20 deg C; wt/gal: 9.78 lb at 20 deg C Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985., p. 264 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 6­114 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Specific heat capacity: 2.015 J/g­K at constant pressure Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 15­13 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Liquid heat capacity = 0.520 BTU/lb­F at 68 deg F; Liquid thermal conductivity = 1.088 BTU­in/hr­sq ft­F at 70 deg F; Saturated vapor density = 0.00161 lb/cu ft at 180 deg F; Ideal gas heat capacity = 0.276 BTU/lb­F at 60 deg F; Ratio of specific heats of vapor: 1.070 U.S. Coast Guard, Department of Transportation. CHRIS ­ Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984­5. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Wt/mL: 1.043 to 1.046 g Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale­The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 39 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUR Heat of fusion: 8.97 kJ/mol at ­15.4 deg C 12/75 12/2/2014 benzyl alcohol ­ PubChem Forms a large number of azeotropes Mookerjee BD, Wilson RA; Kirk­Othmer Encyclopedia of Chemical Technology. (2001). NY, NY: John Wiley & Sons; Benzyl Alcohol and beta­Phenethyl Alcohol. Online Posting Date: Dec 4, 2000. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Enthalpies of formation at 298.15 K: ­160.7 kJ/mole (liquid); ­100.4 kJ/mol (gas). Standard molar entropy at 298.15 K: 217.9 J/mol K Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 5­34 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Dielectric constant: 13.0 at 20 deg C & 9.5 at 70 deg C; dipole moment: 1.67 in benzene at 25 deg C Dean, J.A. Handbook of Organic Chemistry. New York, NY: McGraw­Hill Book Co., 1987., p. 4­47 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Henry's Law constant = 3.37X10­7 atm­cu m/mole at 25 deg C  Abraham MH et al; J Pharm Sci 83: 1085­100 (1994) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Hydroxyl radical rate constant= 2.29X10­11 cu cm/molec­sec Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 4.3 Spectral Properties SADTLER REF NUMBER: 157 (IR, PRISM); 985 (IR, GRATING); MAX ABSORPTION (ALCOHOL): 243 NM (LOG E= 1.91); 258.5 NM (LOG E= 2.26); 268 NM (LOG E= 1.95) Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979., p. C­525 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Index of refraction: 1.5396 at 20 deg C/D Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 3­42 IR: 5219 (Coblentz Society Spectral Collection) Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 UV: 62 (Sadtler Research Laboratories Spectral Collection) Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 1H NMR: 161 (Varian Associates NMR Spectra Catalogue) Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 MASS: 61913 (NIST/EPA/MSDC Mass Spectral Database, 1990 version); 204 (National Bureau of Standards) Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 1029 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUS from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 13/75 12/2/2014 benzyl alcohol ­ PubChem 5 Related Records 5.1 Related Compounds with Annotation  Download Literature (95) 3D Structure (37) acetophenone Bioactivities (384) Phenylethyl Alcohol Patents (4597) phenylhydrazine from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Same Connectivity (14) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Same Parent, Connectivity (109) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Same Parent, Exact (96) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Mixtures, Components, and Neutralized Forms (510) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Similar Compounds (954) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Similar Conformers (9361) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 5.3 Related Substances All (1218) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Same (262) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Mixture (956) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 5.4 Entrez Crosslinks PubMed (456) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Protein Structures (3) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov Taxonomy (4) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov OMIM (1) from PubChem [17] http://pubchem.ncbi.nlm.nih.gov http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUT 5.2 Related Compounds 14/75 Gene (5) http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem from PubChem [17] http://pubchem.ncbi.nlm.nih.gov t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUU 12/2/2014 15/75 12/2/2014 benzyl alcohol ­ PubChem 6 Chemical Vendors  Download Vendor/Supplier Purchasable Chemical PubChem SID Mcule MCULE­6011707909 169537728 108006_ALDRICH 24846793 108006_SIAL 57646818 13160_FLUKA 24848025 13160_SIAL 57647066 24122_RIEDEL 24854469 24122_SIAL 57648059 305197_ALDRICH 24858412 305197_SIAL 57648443 34460_FLUKA 57649227 34460_RIEDEL 24861264 402834_SIAL 24865125 442481_SUPELCO 24867866 W213705_ALDRICH 24900875 W213713_ALDRICH 24900876 AG­C­84906 136393913 AGN­PC­00UN6S 223070959 AGN­PC­0BT00W 195279921 AGN­PC­0BT0GO 195280489 AGN­PC­0BT4T2 195286120 AGN­PC­0NYNLY 222077802 ZINC00895302 61013394 FT­0622812 164806891 FT­0673838 164764357 AKOS000119907 104668330 AC1L18SY 104294271 AC1Q7C20 117619147 Angene International AG­D­05803 124366324 Achemica ACMC­1BQPG 162271656 TCI (Tokyo Chemical Industry) B2378 87565187 Sigma­Aldrich Angene Chemical ZINC Finetech Industry Limited AKos Consulting & Solutions ABI Chem http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPUV  Refine/Analyze 16/75 RennoTech Co., Ltd. benzyl alcohol ­ PubChem RP18893 174550070 193822 85084106 193882 85084107 199632 85084108 225214 56370468 SBB058558 143433014 ST51028320 143840407 Chemical Synthesis Database 100­51­6 126533561 Jamson Pharmachem Technology Jsp000133 93616672 105712 162092393 134487 162228763 Amadis Chemical A800221 131292812 Boerchem BC222892 196109775 Ambinter BB_SC­7027 102852041 3B_SCI 3B4­3118 184609630 MolPort MolPort­001­783­216 88826200 King Scientific KSC176G5N 163802951 BBL011938 125326598 STL163453 125292518 ChemMol 98000450 135699375 IS Chemical Technology I01­4406 87241542 RTR­033774 204379505 TR­033774 204940131 ChemExper Chemical Directory HaDH@@RVU[j@@@@ 3132108 Ark Pharm, Inc. AK146334 176251804 Chembo KB­200532 172851291 ChemFrog 888­884­348 125336423 MP Biomedicals TimTec Chembase.cn Vitas­M Laboratory Tractus from PubChem [17] http://pubchem.ncbi.nlm.nih.gov http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVM 12/2/2014 17/75 12/2/2014 benzyl alcohol ­ PubChem 7 Drug and Medication Information 7.1 Drug Information 1 of 1 Drug Name Ulesfia (from Drugs@FDA) Drug Label ULESFIA(benzyl alcohol) Lotion is supplied as a white topical lotion containing benzyl alcohol, 5%. Inactive ingredients in this formulation are water, mineral oil, sorbitan monooleate, polysorbate 80, carbomer 934P and trolamine.... Click here to see drug label(s) from DailyMed Active Ingredient Benzyl alcohol Dosage Form Lotion Route Topical Strength 5% Market Status Prescription Company Shionogi Patent 6793931; 7294342; 6139859; 5858383 (from FDA Orange Book) from FDA Drugs, DailyMed, and PubMed Health [15] 7.2 Therapeutic Uses /On April 9, 2009, the U.S. Food and Drug Administration approved a new prescription medication for the treatment of head lice ( Pediculosis capitis ) infestation. Benzyl Alcohol Lotion, 5%, received full market approval as a prescription medication, for use in patients 6 months of age and older. Benzyl Alcohol Lotion, 5%, is the first head lice product approved by the FDA with benzyl alcohol as the active pharmaceutical ingredient. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 The safety and effectiveness of Benzyl Alcohol Lotion, 5%, was demonstrated in two studies of 628 people, 6 months of age and older, with active head lice infestation. The subjects received two, 10­minute treatments of either Benzyl Alcohol Lotion or a topical placebo, one week apart. Fourteen days after the final treatment, more than 75 percent of the subjects treated with Benzyl Alcohol Lotion, 5%, were lice free. FDA; FDA Approves Benzyl Alcohol Lotion for the Treatment of Head Lice, FDA News (April 9, 2009) Available from, as of April 20, 2009: http://www.fda.gov/bbs/topics/NEWS/2009/NEW01993.html from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 In each of two double­blind studies, 25 patients suffering from early progressive idiopathic cataracts, subcapsular or cortical in site, received one drop of saline containing 0.07% benzyl alcohol every 8 hours. The eyelid was held open for at least 2 minutes. Treatment continued for 22 months. In one study, a control group received placebo, whereas in the other study, the control group received an anticataract medication. Clinical findings were recorded every 30 days for the first 14 months, then patients were followed for up to 18 and 22 months. A significant (p < .01) increase in visual acuity (VA) was observed in patients treated with benzyl alcohol after 30 and 60 days as compared to those receiving either placebo or the medication. Compared to those placebo or medication treated, a significant (p < .01) decrease in lens opacity was noted in 19 and 17 patients treated with benzyl alcohol, respectively. In the course of the studies, a significant increase in the number of surgeries for cataracts was noted in patients not receiving benzyl alcohol. One patient treated with benzyl alcohol required surgery after 22 months compared to 38 total who had http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVN FDA; FDA Approves Benzyl Alcohol Lotion for the Treatment of Head Lice, FDA News (April 9, 2009) Available from, as of April 20, 2009: http://www.fda.gov/bbs/topics/NEWS/2009/NEW01993.html 18/75 12/2/2014 benzyl alcohol ­ PubChem received either placebo or medication. benzyl alcohol was well tolerated except in two patients (4%) where tolerance was fair in one and poor in the other.  Benzyl Alcohol. Cosmetic Ingredient Review; International Journal of Toxicology; 20(suppl 3):23­50 (2001) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 /EXP THER/ In 2 long­term double blind studies on humans comparing benzyl alcohol, placebo and Catalin in the topical treatment of progressive cataract, rapid (2­3 weeks treatment) reversal of incipient cataract was obtained accompanied by a marked improvement of vision and by a significantly lower percentage of eyes requiring surgery after 22 months of treatment with benzyl alcohol than with placebo and Catalin. Organization for Economic Cooperation and Development; Screening Information Data Set for Benzoates, CAS #s 65­85­0, 532­32­1, 582­25­2, 100­51­6 p.295 (2001). Available from, as of July 9 2008: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Anesthetics, Local; Pharmaceutic Aids National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol has been widely used in human medicine as a antimicrobial preservative and as a local anesthetic and antipruritic. European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, Committee for Veterinary Medicinal Products; Benzyl Alcohol, Summary Report (1997). Available from, as of July 8, 2008: http://www.emea.europa.eu/pdfs/vet/mrls/Benzylalcohol.pdf from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 It has been used for toothache, a few drops being applied to the cavity or exposed nerve. Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale­The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 39 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 MEDICATION (VET): Benzyl alcohol is active against Gram positive bacteria and has some weak activity against gram negative bacteria, yeasts and molds. Benzyl alcohol also has some mild local anesthetic and anti­spasmodic properties. European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, Committee for Veterinary Medicinal Products; Benzyl Alcohol, Summary Report (1997). Available from, as of July 8, 2008: http://www.emea.europa.eu/pdfs/vet/mrls/Benzylalcohol.pdf MEDICATION (VET): In veterinary medicine it is widely used as an antimicrobial preservative and as a solubilizer. Benzyl alcohol is also used as an active ingredient in some teat dip and spray formulations where it is present at a concentration of approximately 4%, for the prevention of mastitis. European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, Committee for Veterinary Medicinal Products; Benzyl Alcohol, Summary Report (1997). Available from, as of July 8, 2008: http://www.emea.europa.eu/pdfs/vet/mrls/Benzylalcohol.pdf from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 In leukemic patients indwelling cardiac catheters with a non­return slit valve inserted into a tributary of the subclavian vein had been kept free of infection for up to 3 months by filling with benzyl alcohol 0.9% in water for injections when not in use. Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale­The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 39 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 A randomized, prospective, double­blind study comparing benzyl alcohol with epinephrine, 1:100,000 (BA), and lidocaine with epinephrine, 1:100,000 (LID), as local anesthetics was carried out on adult patients with simple lacerations. The two study groups were compared for pain of infiltration (100 mm visual analog scale) and need for additional anesthesia. Pain scores were compared by a Mann Whitney Independent Rank Sum test and need for additional anesthesia by a Fishers Exact test. A total of 52 subjects (26 per group) were analyzed. The groups were similar in demographics and wound characteristics. The median pain score for BA, 7.5 mm, was less than for LID, http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVO from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 19/75 12/2/2014 benzyl alcohol ­ PubChem 19.5 mm (p = 0.049). Although more patients receiving BA required additional anesthesia as compared to LID (8/26 versus 2/26), this difference did not reach statistical significance. BA is a reasonable alternative local anesthetic to LID for patients who are allergic to LID.  Bartfield JM et al; J Emerg Med 21 (4): 375­9 (2001) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol ... usually used in a concentration of 0.9% as a bacteriostatic preservative in multiple­dose vials of solutions or drugs for parenteral therapy. Bacteriostatic sodium chloride, USP, is frequently used in the management of critically ill patients to flush intravascular catheters after the addition of medications or the withdrawal of blood; and sterile bacteriostatic water for injection, USP, is used to dilute or reconstitute medications for intravenous use. In addition, medications, such as some formulations of sodium heparin, USP, that are frequently used for infants and other critically ill patients may be preserved with benzyl alcohol. CDC/MMWR; Neonatal Deaths Associated With Use Of Benzyl Alcohol ­­ United States. Morbidity and Mortality Weekly Repost 31(22);290­1 (June 11, 1982). Available from, as of July 23, 2008: http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 7.3 Drug Warning Common side effects of /Benzyl Alcohol Lotion, 5%/ include irritations of the skin, scalp, and eyes, and numbness at the site of application. As with all medications, it is important to use benzyl alcohol, 5%, as labeled to maximize benefits and minimize risks. The product should be applied only to the scalp or the hair attached to the scalp. It is not approved for use in children younger than six months. Use in premature infants could lead to serious respiratory, heart­ or brain­related adverse events such as seizure, coma, or death. FDA; FDA Approves Benzyl Alcohol Lotion for the Treatment of Head Lice, FDA News (April 9, 2009) Available from, as of April 20, 2009: http://www.fda.gov/bbs/topics/NEWS/2009/NEW01993.html from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 It also seems prudent to avoid the use of products containing benzyl alcohol to pregnant patients within whom the benzyl alcohol molecule, given its small size, presumably crosses the placental barrier into immature fetal tissues as readily as it crosses the blood­brain barrier. Organization for Economic Cooperation and Development; Screening Information Data Set for Benzoates, CAS #s 65­85­0, 532­32­1, 582­25­2, 100­51­6 p.294 (2001). Available from, as of July 9 2008: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html Premature neonates may receive multiple drugs in the neonatal intensive care unit, some of which may contain benzyl alcohol. As there may be no safe lower dose of benzyl alcohol in these patients, it would seem prudent to avoid the use of multiple dose vials containing benzyl alcohol whenever alternatives exist. Organization for Economic Cooperation and Development; Screening Information Data Set for Benzoates, CAS #s 65­85­0, 532­32­1, 582­25­2, 100­51­6 p.294 (2001). Available from, as of July 9, 2008: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol is believe to have a role in the increased frequency of cerebral intraventricular hemorrhages and mortality reported in very­low­birth­weight (VLBW) infants (weight < 1000 g) who received flush solutions preserved with benzyl alcohol. An increased incidence of developmental delay and cerebral palsy is also noted in the same VLBW patient population, suggesting a secondary damaging effect of benzyl alcohol. Goldfrank, L.R., Goldfrank's Toxicologic Emergencies 8th Ed. 2006., McGraw­Hill, New York, N.Y., p. 831 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol, which is used as a preservative in intravascular flush solutions, caused neurological deterioration and deaths in very low birth weight infants. Preterm infants who received large volumes of fluids containing 0.9% benzyl alcohol via catheter developed "gasping baby syndrome." Estimated intakes of 99 to 405 mg benzyl alcohol/kg body weight for 2 to 28 days caused effects including severe metabolic acidosis, gasping, neurological deterioration, blood abnormalities, skin breakdown, liver and kidney failure, lowered blood pressure, heart failure, and death. No effects were seen for intakes of 27 to 99 mg/kg body weight over similar periods, although there is one report of 32 to 105 mg/kg body weight for 7 days causing breathing difficulty. http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVP from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 20/75 12/2/2014 benzyl alcohol ­ PubChem Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1­9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V6 500 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. However, this metabolic pathway may not be well developed in premature infants. The benzyl alcohol may therefore have been metabolized to benzoic acid, which could not be conjugated by the immature liver but accumulated, causing metabolic acidosis ... . CDC/MMWR; Neonatal Deaths Associated With Use Of Benzyl Alcohol ­­ United States. Morbidity and Mortality Weekly Repost 31(22);290­1 (June 11, 1982). Available from, as of July 23, 2008: http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 7.4 Drug Indication http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVQ Ulesfia (benzyl alcohol) lotion is indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Ulesfia Lotion does not have ovicidal activity. from DrugBank [2] http://drugbank.ca/drugs/DB06770 21/75 12/2/2014 benzyl alcohol ­ PubChem 8 Pharmacology and Biochemistry 8.1 MeSH Pharmacological Classification Anesthetics, Local Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage­dependent sodium channels to activate.  from MeSH [26] http://www.ncbi.nlm.nih.gov/mesh/68000779 8.2 FDA Pharmacological Classification 8.2.1 Active Moiety Benzyl alcohol from FDA Pharm Classes [13] http://www.accessdata.fda.gov/spl/data/559bd7e4­b52e­44a0­99f0­ 408ed89eb1bf/559bd7e4­b52e­44a0­99f0­408ed89eb1bf.xml 8.2.2 FDA UNII LKG8494WBH from FDA Pharm Classes [13] http://www.accessdata.fda.gov/spl/data/559bd7e4­b52e­44a0­99f0­ 408ed89eb1bf/559bd7e4­b52e­44a0­99f0­408ed89eb1bf.xml 8.2.3 Pharmacological Classes Pediculicide from FDA Pharm Classes [13] http://www.accessdata.fda.gov/spl/data/559bd7e4­b52e­44a0­99f0­ 408ed89eb1bf/559bd7e4­b52e­44a0­99f0­408ed89eb1bf.xml 8.3 Absorption, Distribution and Excretion The percutaneous absorption was determined in vivo in rhesus monkeys. Absorption through occluded skin was high (56­80 %) in 24 hr. No correlation was seen between skin penetration and the octanol­water partition coefficient. Under unoccluded conditions skin penetration was reduced (32 %), because of evaporation of the compound. Organization for Economic Cooperation and Development; Screening Information Data Set for Benzoates, CAS #s 65­85­0, 532­32­1, 582­25­2, 100­51­6 p.298 (2001). Available from, as of July 9, 2008: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 High levels of benzyl alcohol (5­500 ug/10 mL plasma) were found in uremic patients on hemodialysis; benzyl alcohol was not detected in normal controls. Organization for Economic Cooperation and Development; Screening Information Data Set for Benzoates, CAS #s 65­85­0, 532­32­1, 582­25­2, 100­51­6 p.294 (2001). Available from, as of July 9, 2008: http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVR Established Pharmacologic Class [EPC] 22/75 12/2/2014 benzyl alcohol ­ PubChem http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Rabbits given 1 g of benzyl alcohol sc eliminated 300­400 mg of hippuric acid within the following 24 hr. Within 6 hr after oral administration of 0.40 g benzyl alcohol/kg bw, rabbits eliminated 65.7% of dose as hippuric acid in the urine. Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993­1994., p. 2704 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 In humans and animals, benzyl alcohol was readily absorbed from the gastrointestinal tract. Percutaneous absorption was high following topical use. Rhesus monkeys absorbed 56­80% of a topical dose administered under occlusive conditions in 24 hours; absorption was less under unoccluded conditions due to evaporation. Benzyl alcohol rapidly disappeared from the injection site following intramuscular administration in rats; the disappearance half­life was estimated to be less than 10 minutes. ... European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, Committee for Veterinary Medicinal Products; Benzyl Alcohol, Summary Report (1997). Available from, as of July 8, 2008: http://www.emea.europa.eu/pdfs/vet/mrls/Benzylalcohol.pdf from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 ... VAPORS CAN PENETRATE THE INTACT SKIN ... Opdyke, D.L.J. (ed.). Monographs on Fragrance Raw Materials. New York: Pergamon Press, 1979., p. 128 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 The dermal flux for benzyl alcohol across human skin in vitro was reported at 0.073 mg/sq cm/hr, indicating a low rate of dermal uptake. The percentage of the applied dose that penetrated through human skin in vitro in 6 hr was 1.42% for adult skin and 0.73% for full term infant skin. Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1­9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V6 499 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 8.4 Metabolism/Metabolites CDC/MMWR; Neonatal Deaths Associated With Use Of Benzyl Alcohol ­­ United States. Morbidity and Mortality Weekly Repost 31(22);290­1 (June 11, 1982). Available from, as of July 23, 2008: http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 When metabolized, benzyl alcohol is converted to benzoic acid by simple oxidation. The relevant data, therefore, relate to benzoic acid and sodium benzoate.  Benzyl Alcohol. Cosmetic Ingredient Review; International Journal of Toxicology; 20(suppl 3):23­50 (2001) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol was an intermediate product in the metabolic pathway of benzyl acetate; the subsequent metabolism was identical to that of benzyl alcohol. European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, Committee for Veterinary Medicinal Products; Benzyl Alcohol, Summary Report (1997). Available from, as of July 8, 2008: http://www.emea.europa.eu/pdfs/vet/mrls/Benzylalcohol.pdf from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 In adults, benzyl alcohol is oxidized to benzoic acid, conjugated in the liver with glycine, and excreted in the urine as hippuric acid. The immature metabolic capacities of infants diminish their ability to metabolize and excrete benzyl alcohol. Preterm babies have a greater ability to metabolize benzyl alcohol to benzoic acid than do term babies, but http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVS Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. However, this metabolic pathway may not be well developed in premature infants. The benzyl alcohol may therefore have been metabolized to benzoic acid, which could not be conjugated by the immature liver but accumulated, causing metabolic acidosis ... . 23/75 12/2/2014 benzyl alcohol ­ PubChem are unable to convert benzoic acid to hippuric acid, possibly because of glycine deficiency. This results in the accumulation of benzoic acid. Goldfrank, L.R., Goldfrank's Toxicologic Emergencies 8th Ed. 2006., McGraw­Hill, New York, N.Y., p. 831 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol is readily absorbed from the gastrointestinal tract and rapidly oxidized to benzoic acid, which is conjugated with glycine and excreted as hippuric acid in the urine. ...Human subjects eliminated 75 to 85% of the dose in the urine as hippuric acid within 6 hr after taking 1.5 g of benzyl alcohol orally. Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1­9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V6 498 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 /BENZYL ALCOHOL IS/ ... OXIDIZED BY LIVER ALCOHOL DEHYDROGENASE. Testa, B. and P. Jenner. Drug Metabolism: Chemical & Biochemical Aspects. New York: Marcel Dekker, Inc., 1976., p. 4 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 YIELDS BENZALDEHYDE IN RABBITS: BRAY ET AL, BIOCHEM J, 70, 570 (1958). YIELDS PHENOL IN GUINEA PIGS: SLOANE, NH, BIOCHEM BIOPHYS ACTA, 107, 573 (1971). /FROM TABLE/ Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. B­13 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 8.5 Biological Half­Life The plasma half­life of benzyl alcohol administered as 2.5% solution in saline was found to be approximately 1.5 hr in dogs injected iv at doses of 52 and 105 mg/kg. Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981­1982., p. 4640 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 8.6 Mechanism of Action http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVT Benzyl alcohol inhibits lice from closing their respiratory spiracles, allowing the vehicle to obstruct the spiracles and causing the lice to asphyxiate. from DrugBank [2] http://drugbank.ca/drugs/DB06770 24/75 12/2/2014 benzyl alcohol ­ PubChem 9 Use and Manufacturing 9.1 Methods of Manufacturing (a) By hydrolysis of benzyl chloride; (b) from benzaldehyde by catalytic reduction or Cannizzaro reaction. Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 140 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol can be produced /by/ ... 1) the hydrolysis of benzyl chloride and 2) the hydrogenation of benzaldehyde. Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley­VCH Verlag GmbH & Co. 2003 to Present, p. V5 85 (2003) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 The hydrogenation of methyl benzoate in the presence of a copper­chromium catalyst is a feature of a three­step process for the production of benzyl alcohol from toluene. The first step is the oxidation of toluene to form benzoic acid. The acid is esterified with methanol in the second step. The hydrogenation of methyl benzoate to form benzyl alcohol is performed in the final step. Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley­VCH Verlag GmbH & Co. 2003 to Present, p. V5 87 (2003) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Other processes for the production of benzyl alcohol include the hydrogenation of benzoic acid, the electrochemical reduction of benzoic acid, the hydrolysis of benzylsulfonic acid, and the decarboxylation of benzyl formate. These processes have no importance in the industrial production of benzyl alcohol, but they may be used to produce derivatives substituted on the aromatic nucleus. Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley­VCH Verlag GmbH & Co. 2003 to Present, p. V5 87 (2003) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol is manufactured on a commercial scale from benzyl chloride and sodium carbonate. Kirk­Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991­ Present., p. V4 116 Originally prepd by Cannizzaro reaction from benzaldehyde and potassium hydroxide ... Produced on large scale by action of ... potassium carbonate on benzyl chloride: German patent 484,662; Chem Zentr 1930, I, 1052; FRDL 16, 426 ... Budavari, S. (ed.). The Merck Index ­ An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 189 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Synthesis: By saponification of the ester present in Tolu and Pery balsams; synthetically, it is obtained from benzyl chloride by the action of sodium or potassium carbonate. Burdock, G.A. (ed.). Fenaroli's Handbook of Flavor Ingredients. 5th ed.Boca Raton, FL 2005, p. 143 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 9.2 Formulations/Preparations Grades: free from chlorine (FFC); technical; NF (National Formulary); textile; photographic reagent; FCC Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons, Inc. 1997., p. 129 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVU from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 25/75 12/2/2014 benzyl alcohol ­ PubChem from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Euxyl K 100 Estrin, N.F., Crosley, P.A. and Haynes, C.R. (eds.) CTFA Cosmetic Ingredient Dictionary. 3rd ed. Washington, D.C.: The Cosmetic, Toiletry and Fragrance Association, Inc. 1982., p. 6 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Pure, photo, pharmaceutical, and perfume grades, 99% min purity, liquid form Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988., p. 272 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Bacteriostatic Water for Injection, USP is a sterile, nonpyrogenic preparation of water for injection containing 0.9% (9 mg/mL) of benzyl alcohol added as a bacteriostatic preservative. /Bacteriostatic Water for Injection/ US Natl Inst Health; DailyMed. Current Medication Information. Bacteriostatic Water (water) Injection, Solution. December 2005. Available from, as of July 8, 2008: http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?id=1165&type=display from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 9.3 Consumption 60% IS USED IN THE TEXTILE INDUSTRY AS A DYE ASSISTANT (MOSTLY FOR DYEING NYLON CARPETING); AND 40% IS USED IN OTHER APPLICATIONS (1972) SRI from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 9.4 U.S. Production (1971) 4.22X10+9 G SRI from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 (1975) 5.84X10+9 G SRI Production volumes for non­confidential chemicals reported under the Inventory Update Rule. Year Production Range (pounds) 1986 >10 million ­ 50 million 1990 >1 million ­ 10 million 1994 >10 million ­ 50 million 1998 >10 million ­ 50 million 2002 >10 million ­ 50 million US EPA; Non­confidential Production Volume Information Submitted by Companies for Chemicals Under the 1986­2002 Inventory Update Rule (IUR). Benzenemethanol (100­51­6). Available from, as of July 1, 2008: http://www.epa.gov/oppt/iur/tools/data/2002­vol.html from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438). EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program. Available from the http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPVV from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 26/75 12/2/2014 benzyl alcohol ­ PubChem Database Query page at: http://www.epa.gov/hpv/pubs/general/opptsrch.htm on Benzyl Alcohol (100­51­6) as of July 1, 2008 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 9.5 U.S. Imports (1971) NEGLIGIBLE SRI from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 (1975) 3.53X10+6 (PRINCPL CUSTMS DISTS) SRI from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 (1983) 8.25X10+8 g USITC. IMPORTS OF BENZENOID CHEM & PROD 1983 p.11 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 9.6 Analytic Laboratory Methods Method: EPA­EAD 1625; Procedure: gas chromatography/mass spectrometry; Analyte: benzyl alcohol; Matrix: water; Detection Limit: not provided. National Environmental Methods Index; Analytical, Test and Sampling Methods. Available from http://www.nemi.gov on Benzyl Alcohol (100­51­6) as of July 1, 2008 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Method: EPA­OSW 8270D; Procedure: gas chromatography/mass spectrometry; Analyte: benzyl alcohol; Matrix: solid waste matrices, soils, air sampling media and water samples; Detection Limit: 20 ug/L. National Environmental Methods Index; Analytical, Test and Sampling Methods. Available from http://www.nemi.gov on Benzyl Alcohol (100­51­6) as of July 1, 2008 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 National Environmental Methods Index; Analytical, Test and Sampling Methods. Available from http://www.nemi.gov on Benzyl Alcohol (100­51­6) as of July 1, 2008 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Method: OSHA PV2009; Procedure: gas chromatography with flame ionization detector; Analyte: benzyl alcohol; Matrix: air; Detection Limit: 1 ug. U.S. Department of Labor/Occupational Safety and Health Administration's Index of Sampling and Analytical Methods. Available from: http://www.osha.gov/dts/sltc/methods/toc.html on Benzyl Alcohol (100­51­6) as of July 3, 2008 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Method: OSHA 49; Procedure: gas chromatography using electron capture detection; Analyte: ethylene oxide; Matrix: air; Detection Limit: 0.7 ppb. U.S. Department of Labor/Occupational Safety and Health Administration's Index of Sampling and Analytical Methods. Available from: http://www.osha.gov/dts/sltc/methods/toc.html on Ethylene Oxide (75­21­8) as of July 3, 2008 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Method: OSHA 50; Procedure: gas chromatography using electron capture detection; Analyte: ethylene oxide; Matrix: air; Detection Limit: 3.0 ppb. U.S. Department of Labor/Occupational Safety and Health Administration's Index of Sampling and Analytical Methods. Available from: http://www.osha.gov/dts/sltc/methods/toc.html on Ethylene Oxide (75­21­8) as of July 3, 2008 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMM Method: DOE OM100R; Procedure: gas chromatography with mass spectrometer ion trap detector; Analyte: benzyl alcohol; Matrix: solid waste matrices, soils, and groundwater; Detection Limit: 40 ug/L. 27/75 12/2/2014 benzyl alcohol ­ PubChem http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMN from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 28/75 12/2/2014 benzyl alcohol ­ PubChem 10 Safety and Hazards 10.1 Hazards Identification 10.1.1 Exposure Routes The substance can be absorbed into the body by inhalation of its vapour and by ingestion. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.1.2 Fire Hazard Combustible. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.1.3 Skin Hazard Redness. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.1.4 Inhalation Hazard Cough. Dizziness. Headache. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.1.5 Eye Hazard Redness. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 Abdominal pain. Diarrhoea. Drowsiness. Nausea. Vomiting. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.1.7 Fire Potential Slight, when exposed to heat or flame ... Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley­Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 399 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 THE LIQ IS FLAMMABLE & A MODERATE FIRE HAZARD. International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 111 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.1.8 Skin, Eye, and Respiratory Irritations It is slightly irritating to the skin ... . http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMO 10.1.6 Ingestion Hazard 29/75 12/2/2014 benzyl alcohol ­ PubChem International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 111 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Vapor: Irritating to eyes, nose and throat. Liquid: Irritating to skin & eyes. U.S. Coast Guard, Department of Transportation. CHRIS ­ Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984­5. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.2 Safety and Hazard Properties 10.2.1 Critical Temperature Critical temperature: 715 K; Critical pressure: 4.3X10+6 Pa Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 6­46 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.2.2 Critical Pressure Critical temperature: 715 K; Critical pressure: 4.3X10+6 Pa Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005­2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 6­46 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.2.3 NFPA Hazard Classification Health: 1. 1= Materials that, on exposure, would cause significant irritation, but only minor residual injury, including those requiring the use of an approved air­purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325­18 Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi­solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325­18 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Instability: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325­18 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.2.4 Chemical Danger Reacts with strong oxidants. Attacks some forms of plastic. On combustion, forms toxic gases including carbon monoxide. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMP from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 30/75 12/2/2014 benzyl alcohol ­ PubChem 10.2.5 Occupational Exposure Limits TLV (NOT­ESTABLISHED):. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.2.6 Inhalation Risk No indication can be given about the rate at which a harmful concentration of this substance in the air is reached on evaporation at 20°C. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.2.7 Effects of Short Term Exposure The aerosol is irritating to the eyes and skin. The substance may cause effects on the nervous system. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.2.8 Effects of Long Term Exposure Repeated or prolonged contact may cause skin sensitization. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.2.9 Explosive Limits and Potential Explosive limits, vol% in air: 1.3­13 from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.2.10 Other Occupational Permissible Levels Workplace Environmental Exposure Level (WEEL): 8­hr Time­weighted Average (TWA) 10 ppm. American Industrial Hygiene Association. AIHA 2007 Emergency Response Planning Guidelines & Workplace Environmental Exposure Levels. American Industrial Hygiene Association, Fairfax, Virginia 2007., p. 38 10.3 First Aid Measures 10.3.1 Fire First Aid Use powder, AFFF, foam, carbon dioxide. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.3.2 Inhalation First Aid Fresh air, rest. Refer for medical attention. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.3.3 Skin First Aid Remove contaminated clothes. First rinse with plenty of water for at least 15 minutes, then remove contaminated http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMQ from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 31/75 12/2/2014 benzyl alcohol ­ PubChem clothes and rinse again. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.3.4 Eye First Aid First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.3.5 Ingestion First Aid Rinse mouth. Refer for medical attention . from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.4 Fire Fighting Measures FOAM, CARBON DIOXIDE, DRY CHEM ... Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley­Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 399 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Alcohol foam. Water or foam may cause frothing. Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 325­18 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 If material on fire or involved in fire: Use water in flooding quantities as fog. Use "alcohol" foam, dry chemical or carbon dioxide. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Keep run­off water out of sewers and water sources. /Benzyl alcohol (Combustible liquid, NOS)/ Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation. Association of American Railroads, Pueblo, CO. 2005, p. 118 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.5.1 Spillage Disposal Collect leaking and spilled liquid in sealable containers as far as possible. Absorb remaining liquid in sand or inert absorbent. Then store and dispose of according to local regulations. Personal protection: filter respirator for organic gases and vapours adapted to the airborne concentration of the substance. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.5.2 Cleanup Methods Environmental considerations: Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ /Benzyl alcohol (Combustible liquid, NOS)/ Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation. Association of American Railroads, Pueblo, CO. 2005, p. 118 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Environmental considerations: Water spill: Use natural barriers or oil spill control booms to limit spill travel. Remove http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMR 10.5 Accidental Release Measures 32/75 12/2/2014 benzyl alcohol ­ PubChem trapped material with suction hoses. /Benzyl alcohol (Combustible liquid, NOS)/ Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation. Association of American Railroads, Pueblo, CO. 2005, p. 118 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Environmental considerations: Air spill: Apply water spray or mist to knock down vapors. /Benzyl alcohol (Combustible liquid, NOS)/ Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation. Association of American Railroads, Pueblo, CO. 2005, p. 118 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.5.3 Disposal Methods SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.5.4 Other Preventative Measures VENTILATION CONTROL: THE BASIC VENTILATION METHODS ARE LOCAL EXHAUST VENTILATION & DILUTION OR GENERAL VENTILATION. Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984., p. 17 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975., p. 446 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. /Benzyl alcohol (Combustible liquid, NOS)/ Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation. Association of American Railroads, Pueblo, CO. 2005, p. 118 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Personnel protection: Keep upwind. Avoid breathing vapors. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Avoid bodily contact with the material. /Benzyl alcohol (Combustible http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMS ... SUBSTITUTION OF LESS IRRITATING SUBSTANCES ... REDESIGN OF OPERATIONS ... PREVENT CONTACT, PROVISION OF A PHYSICAL BARRIER AGAINST CONTACT, PROPER WASHING FACILITIES, WORK CLOTHING & STORAGE FACILITIES, PROTECTIVE CLOTHING, & BARRIER CREAMS. MEDICAL CONTROL ... . 33/75 12/2/2014 benzyl alcohol ­ PubChem liquid, NOS)/ Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation. Association of American Railroads, Pueblo, CO. 2005, p. 118 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.6 Handling and Storage 10.6.1 Safety Storage Separated from strong oxidants. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.6.2 Storage Conditions Benzyl alcohol is stored in stainless steel tanks. Because benzyl alcohol oxidizes readily, it is advisable to cover the surface of the liquid with nitrogen. Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley­VCH Verlag GmbH & Co. 2003 to Present, p. V5 88 (2003) from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 ... STORE IN PLACES THAT ARE COOL ... PROVIDE ADEQUATE VENTILATION ... LOCATE THE STORAGE AREA ... AWAY FROM AREAS OF FIRE HAZARD. HIGHLY FLAMMABLE MATERIALS MUST BE KEPT APART FROM POWERFUL OXIDIZING AGENTS, MATERIALS SUSCEPTIBLE TO SPONTANEOUS HEATING, EXPLOSIVES ... Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975., p. 446 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Store at a temp not exceeding 40 deg C in airtight containers. Protect from light. Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale­The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 39 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.7.1 Fire Prevention NO open flames. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.7.2 Inhalation Prevention Use ventilation. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.7.3 Skin Prevention Protective gloves. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.7.4 Eye Prevention Wear safety spectacles. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMT 10.7 Exposure Control and Personal Protection 34/75 12/2/2014 benzyl alcohol ­ PubChem 10.7.5 Ingestion Prevention Do not eat, drink, or smoke during work. from ILO­ICSC [12] http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=0833 10.7.6 Protective Equipment and Clothing RUBBER GLOVES; CHEMICAL SAFETY GOGGLES U.S. Coast Guard, Department of Transportation. CHRIS ­ Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984­5. from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Personnel protection: ... Wear appropriate chemical protective gloves, boots and goggles. /Benzyl alcohol (Combustible liquid, NOS)/ Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation. Association of American Railroads, Pueblo, CO. 2005, p. 118 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.8 Stability and Reactivity 10.8.1 Reactivities and Incompatibilities A mixture of /benzyl/ alcohol with 58% sulfuric acid decomp expliosively at about 180 deg C. Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth­Heinemann Ltd., 1990, p. 1216 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 ... Incompatible with oxidizing agents. Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale­The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 39 POSSIBLE PROBLEMS ... MAY OCCUR WHEN POLYSTYRENE SYRINGES ARE USED WITH CERTAIN TYPES OF DRUG PRODUCTS THAT CONTAIN PARAALDEHYDE, BENZALDEHYDE, & BENZYL ALCOHOL SINCE THESE AGENTS CAN EXTRACT & DISSOLVE THE PLASTIC. AT TIMES THE RUBBER TIP OF THE PLUNGER MAY RELEASE A CONSTITUENT TO THE DRUG PRODUCT. Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 545 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 Benzyl alcohol containing acidic constituents and dissolved iron was found to polymerize with a rapid temperature increase when heated in excess of 100 deg C. Amines, pyridene, and alkali hydroxides act as inhibitors and prevent polymerization. Fire Protection Guide to Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002., p. 491­9 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.9 Transport Information 10.9.1 Shipment Methods and Regulations Benzyl alcohol can be transported in drums protected by stoving finishes and in tank wagons of aluminum or http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMU from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 35/75 12/2/2014 10.10 Regulatory Information benzyl alcohol ­ PubChem 10.10.1 State Drinking Water Guidelines (FL) FLORIDA 2,100 ug/L USEPA/Office of Water; Federal­State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) To Present from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.10.2 FIFRA Requirements As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA '88 were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Benzyl alcohol is found on List D. Case No: 4013; Pesticide type: insecticide, fungicide; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the RED document.; Active ingredient (AI): benzyl alcohol; AI Status: The active ingredient is no longer contained in any registered products ... "cancelled." United States Environmental Protection Agency/ Prevention, Pesticides and Toxic Substances; Status of Pesticides in Registration, Reregistration, and Special Review. (1998) EPA 738­R­98­002, p. 297 from HSDB [1] http://toxnet.nlm.nih.gov/cgi­bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+100­51­6 10.10.3 FDA Requirements 21 CFR 172.515 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of June 26, 2008: http://www.gpoaccess.gov/ecfr http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQMV Benzyl alcohol is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: a) they are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice, and 2) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior­sanctioned for such use, or regulated by an appropriate section in this part. 36/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNM 12/2/2014 37/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNN 12/2/2014 38/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNO 12/2/2014 39/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNP 12/2/2014 40/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNQ 12/2/2014 41/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNR 12/2/2014 42/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNS 12/2/2014 43/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNT 12/2/2014 44/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNU 12/2/2014 45/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQNV 12/2/2014 46/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOM 12/2/2014 47/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQON 12/2/2014 48/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOO 12/2/2014 49/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOP 12/2/2014 50/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOQ 12/2/2014 51/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOR 12/2/2014 52/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOS 12/2/2014 53/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOT 12/2/2014 54/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOU 12/2/2014 55/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQOV 12/2/2014 56/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPM 12/2/2014 57/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPN 12/2/2014 58/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPO 12/2/2014 59/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPP 12/2/2014 60/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPQ 12/2/2014 61/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPR 12/2/2014 62/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPS 12/2/2014 63/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPT 12/2/2014 64/75 12/2/2014 benzyl alcohol ­ PubChem 13.1 Depositor­Supplied Patent Identifiers 1 2   3 ... 5,446  Download Relevance  Patent Submitted Granted ENGINEERING PLASTIC COMPOSITION AND ARTICLES MADE OF THE SAME [EP0420619] 1991­04­03 1993­09­29 Composition and method for coloring and moisturizing the skin. [EP0420713] 1991­04­03 1993­11­18 6­SUBSTITUTED ACYCLOPYRIMIDINE NUCLEOSIDE DERIVATIVES AND ANTIVIRAL AGENT CONTAINING THE SAME AS ACTIVE INGREDIENT THEREOF [EP0420763] 1991­04­03 1999­07­28 Addition products of alkylene and styrene oxide on arylalkanols. [EP0420807] 1991­04­03 Pyran­containing phthalides. [EP0420808] 1991­04­03 1995­03­01 THERAPEUTIC USES OF 2',5'­OLIGOADENYLATE DERIVATIVES [EP0420872] 1991­04­10 1996­08­28 COMPOUNDS CONTAINING AT LEAST THREE FUNCTIONAL ESTER GROUPS AND PROCESS FOR PRODUCING THEM. [EP0420884] 1991­04­10 MACROCYCLIC BIFUNCTIONAL CHELANTS, COMPLEXES THEREOF AND THEIR ANTIBODY CONJUGATES. [EP0420942] 1991­04­10 Pharmacologically active peptides and pharmaceutical preparations containing them. [EP0421074] 1991­04­10 1995­04­26 Substituted acrylic acid esters. [EP0421102] 1991­04­10 1995­03­29 from PubChem [17] http://pubchem.ncbi.nlm.nih.gov http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPU  Refine/Analyze 65/75 12/2/2014 benzyl alcohol ­ PubChem  Refine/Analyze MMDB ID: 116233 MMDB ID: 73807  Download MMDB ID: 49809 14.2 Biosystems and Pathways  Download 1 2 3 ... 663 BioSystem Toluene degradation [376] Toluene degradation [118059] Toluene degradation [120721] Toluene degradation [121981] Toluene degradation [122147] Toluene degradation [127482] Toluene degradation [129272] Toluene degradation [129577] Toluene degradation [130545] from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 14.3 DrugBank Interactions 1 of 8 Enzyme Cytochrome P450 2C8 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQPV Toluene degradation [120147] 66/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQM 12/2/2014 67/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQN 12/2/2014 68/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQO 12/2/2014 69/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQP 12/2/2014 70/75 12/2/2014 benzyl alcohol ­ PubChem 15.1 BioAssay Results  Refine/Analyze 1 2 3 ... 68    Download Relevance  Activity Substance BioAssay inactive Potency 17390015 qHTS Assay for Inhibitors of 12­hLO (12­human lipoxygenase) [AID: 1452] inactive Potency 17390015 qHTS Assay for Inhibitors Targeting the Menin­MLL Interaction in MLL Related Leukemias: Competition With Fluorescein Labeled MLL­derived Peptide [AID: 1766] inactive Potency 17390015 qHTS Assay for Inhibitors of Tyrosyl­DNA Phosphodiesterase (TDP1) [AID: 485290] inactive Potency 124891475 A Quantitative High throughput Screen to Identify Chemical Modulators of PINK1 Expression [AID: 624263] inconclusive 17390015 qHTS profiling for inhibitors of Plasmodium falciparum proliferation [AID: 504749] inconclusive 17390015 qHTS profiling for inhibitors of Plasmodium falciparum proliferation [AID: 504749] inconclusive 17390015 qHTS profiling for inhibitors of Plasmodium falciparum proliferation [AID: 504749] active 17390015 qHTS profiling for inhibitors of Plasmodium falciparum proliferation [AID: 504749] inconclusive 17390015 qHTS profiling for inhibitors of Plasmodium falciparum proliferation [AID: 504749] inactive 17390015 qHTS profiling for inhibitors of Plasmodium falciparum proliferation [AID: 504749] http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQQ from PubChem [17] http://pubchem.ncbi.nlm.nih.gov 71/75 12/2/2014 benzyl alcohol ­ PubChem 16.1.1 MeSH Tree  Refine/Analyze  List View  Download  Tree View Benzyl Alcohol from MeSH [19] http://www.nlm.nih.gov/mesh/meshhome.html 16.1.2 ChEBI Ontology  Refine/Analyze  List View  Download  Tree View benzyl alcohol from ChEBI [20] http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology  Refine/Analyze  List View  Download  Tree View Benzyl alcohol (JP16/NF/INN) from KEGG [21] http://www.genome.jp/dbget­bin/www_bget?brite:br08302  Refine/Analyze  List View http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol  Download  Tree View t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQR 16.1.3 KEGG: USP 72/75 12/2/2014 benzyl alcohol ­ PubChem Benzyl alcohol 16.1.5 KEGG: Risk Category of Japanese OTC Drugs  Refine/Analyze  List View  Download  Tree View Benzyl alcohol (JP16/NF/INN) from KEGG [23] http://www.genome.jp/dbget­bin/www_bget?brite:br08312 16.1.6 KEGG: Additive  Refine/Analyze  List View  Download  Tree View [001574] Benzyl alcohol from KEGG [25] http://www.genome.jp/dbget­bin/www_bget?brite:br08316 1 2 3 ... 1,265 A61P11/04 ­ for throat disorders A61P11/06 ­ Antiasthmatics A61P11/08 ­ Bronchodilators A61P11/10 ­ Expectorants A61P11/12 ­ Mucolytics A61P11/14 ­ Antitussive agents A61P11/16 ­ Central respiratory analeptics http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol  List View  Download  Tree View t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQS  Refine/Analyze 73/75 12/2/2014 benzyl alcohol ­ PubChem A61P13/00 ­ Drugs for disorders of the urinary system A61P13/02 ­ of urine or of the urinary tract, e.g. urine acidifiers A61P13/04 ­ for urolithiasis  Download  Bioassay Screening Results (5)  Biological Properties (20)  Chemical Reactions (8)  Database Vendor (2)  Journal Publishers (5)  Metabolic Pathways (6)  NIH Molecular Libraries (4)  Patents (144)  Protein 3D Structures (3)  Substance Vendors (57)  Theoretical Properties (10)  Toxicology (10) http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQT  Physical Properties (17) 74/75 http://pubchem.ncbi.nlm.nih.gov/compound/benzyl_alcohol benzyl alcohol ­ PubChem t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQU 12/2/2014 75/75 Drugs.com Prescription Drug Information, Interactions & Side Effects Browse all medications  A B C D E F G H I J K L M N O P Q R S T U V W X Y Z    Advanced Search   Phonetic Search Enter a search term Drugs A-Z Pill Identifier Interactions Checker News Health Professionals Search Q&A Mednotes Apps Sign In or Register Recommended Content Check Now •••• Drugs.com is the most popular, comprehensive and up-to-date source of drug information online. Providing free, peer-reviewed, accurate and independent data on more than 24,000 prescription drugs, over-thecounter medicines & natural products. Featured Tools Pill Identifier Identify your medication Check for drug interactions Medical Transcription Phonetic search assistant Drug Information Infants Remember a Good Time, Study Finds When it comes to remembering things, infants appear to focus on the good times, recent research suggests. The new study included 5-month-old babies who watched a person on a computer screen talking to them in either a happy, neutral or angry voice, followed immediately by a geometric shape. In follow-up tests -- one conducted just five minutes later... A to Z Drug List OTC Database Drugs by Condition Inactive Ingredients Drugs by Class Veterinary Drugs POSTED TODAY IN MEDICAL Dosage International Drugs Side Effects Info en Español Pregnancy Warnings Pricing & Coupon Guide Statins Won't Help Protect Bones, Study Finds Mayo Clinic Disease Reference Tools Interactions Checker Medication Record Pill Identifier Mobile Apps Symptom Checker Drug Imprint Codes News & Alerts Medical News Clinical Trial Results FDA Drug Alerts FDA Consumer Updates New FDA Approvals The cholesterol-lowering drugs known as statins have been touted by some as capable of reducing the risk for broken bones. But, it appears that's not the case, a new study finds. In the study, almost 18,000 older adults were selected to take either the statin Crestor (rosuvastatin) or an inactive placebo. Of the 431 fractures during the study, 221... Featured Topic Centers Bipolar Disorder: Learn about treatment options New Drug Applications Video Center Popular Articles Health & Medication Slideshows Multiple Sclerosis Assessment Personal Stories:Treating Osteoarthritis Knee Pain Treatments for Severe Allergies Video: Important Facts About Afib Medications Treating Advanced Rheumatoid Arthritis Manage Severe Allergies http://www.drugs.com/[12/2/2014 2:44:04 PM] Irritable Bowel Syndrome Treatments Aren't One-Size-FitsAll Fighting Diabetes' Deadly Impact on Minorities More FDA updates... t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQQV Interactions Checker Generic Drugs Fighting Allergy Season with Medications Medications for High Blood Pressure POSTED TODAY IN MEDICAL Harvard Health Guide Updates Drugs.com Prescription Drug Information, Interactions & Side Effects High Cholesterol Center Professionals Resource Center Medical Conferences Treatment for Hepatitis C Medical Dictionary Patient Care Notes Epileptic Seizure Symptoms and Treatments Managing Type 2 Diabetes Medical Encyclopedia POSTED 2 DAYS AGO IN PHARMA INDUSTRY NEWS Top 100 by sales Abilify Fenofibrate Penicillin Accutane Flexeril Percocet Acetaminophen Fluoxetine Phentermine Acyclovir Gabapentin Pradaxa Adderall HydrochlorothiazidePravastatin Advair Hydroxyzine Prednisone Alprazolam Ibuprofen Promethazine Amitriptyline Januvia Propranolol Amlodipine Klonopin Prozac Amoxicillin Lantus Qsymia Androgel Levofloxacin Risperdal Aspirin Levothyroxine Ritalin Ativan Lexapro Seroquel Atorvastatin Lipitor Sertraline Azithromycin Lisinopril Simvastatin Baclofen Loratadine Spironolactone Belviq Lorazepam Suboxone Benadryl Losartan Symbicort Carvedilol Lyrica Synthroid Celebrex Meloxicam Tamiflu Celexa Metformin Tamsulosin Cephalexin Methadone Tramadol Cialis Methylphenidate Trazodone Ciprofloxacin Metoprolol Valium Citalopram Metronidazole Venlafaxine Clindamycin Mirena Verapamil Clonazepam Morphine Viagra Clonidine Mucinex Vicodin Codeine Naproxen Vyvanse CyclobenzaprineNeurontin Warfarin Cymbalta Nexium Wellbutrin Diazepam Norco Xanax Diclofenac Omeprazole Xarelto Doxycycline Opana Zoloft Effexor Oxycodone Zolpidem Elavil Pantoprazole Zolpidem Eliquis Paroxetine Zyrtec More A-K · More L-Z · By Class · UK Medicines Monthly News Roundup - November 2014 Purdue Pharma’s Abuse-Deterrent Hysingla ER Approved for Pain The U.S. Food and Drug Administration (FDA) has approved Hysingla ER (hydrocodone bitartrate), an acetaminophen-free, extended-release (ER) opioid for severe pain requiring daily, long-term treatment and for which no alternatives exist. Hysingla ER abuse-deterrent properties may reduce,... Cerner Multum Drug Information Micromedex® Advanced Consumer MedFacts Natural Products For Professionals FDA Professional Information A-Z Drug Facts (Facts & Comparisons) ASHP Monographs (AHFS DI) Micromedex® Carenotes FDA Medwatch Alerts News Roundup Daily Daily 'Trouble in Toyland' Report Targets Hazardous Gifts for Kids Enter your email here Submit This holiday season, all kids on Santa's list are vulnerable to toys that can pose real health risks, a new report finds. There are toys with toxic chemicals, small toys that are choking hazards, toys that are so loud they can damage hearing, and toy magnets that can cause serious injury if swallowed, says the annual "Trouble in Toyland" report from... POSTED TODAY IN MEDICAL Poorest Seniors at Risk for Repeat Hospital Stays Seniors from the poorest U.S. neighborhoods are at increased risk for repeat trips to the hospital for heart disease or pneumonia, a new study finds. The research, published in the Dec. 2 issue of the Annals of Internal Medicine, looked at records from nearly 256,000 Medicare patients who were discharged from a hospital after being treated for heart... POSTED TODAY IN MEDICAL Is HIV Becoming Less Contagious? New research in Africa suggests that the AIDS virus is getting smarter about evading the immune system while evolving into a less contagious and less lethal infection overall. In the country of Botswana, at least, "anyone who is newly infected now with HIV is less likely to suffer disease than if they had been infected 20 or 30 years ago," said study... POSTED TODAY IN MEDICAL Study Questions Safety of Adrenaline Shots for Cardiac Arrest A shot of adrenaline can jumpstart a heart that's stopped beating and save a life -- think of Uma Thurman in "Pulp Fiction," near death from overdose and rescued by a hypodermic needle to the chest. But adrenaline might also harm those it helps, says a new study from France. Four out of five people who receive adrenaline to restart their heart end... MedFacts Natural Products POSTED TODAY IN MEDICAL http://www.drugs.com/[12/2/2014 2:44:04 PM] Email me: POSTED TODAY IN MEDICAL For Consumers MedFacts Drug Information Updates by Email t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRM Top 100 Drugs Drugs.com Prescription Drug Information, Interactions & Side Effects U.S. Pharmaceutical Sales Statistics Pharmaceutical Company Directory Announcements Physician's Desk Reference (PDR) Latest FDA New Drug Approvals Onexton Onexton (benzoyl peroxide and clindamycin phosphate) is an antimicrobial and lincosamide antibacterial combination for the once-daily... Hysingla ER Hysingla ER (hydrocodone) is a single-entity (without acetaminophen) extended-release opioid analgesic for around-the-clock management of... Lemtrada Lemtrada (alemtuzumab) is a CD52-directed cytolytic monoclonal antibody indicated for the treatment of relapsing forms of multiple... More... Drugs in Development (Not yet approved) Toddlers Hurt in Falls Often Not Warned About Climbing on Furniture Toddlers who wound up in the emergency room after falls at home were more likely to have parents who did not use safety gates or teach their kids not to climb onto kitchen counters or furniture, a new study finds. In the United States, 1 million children are treated in the ER each year for injuries related to falls in the home, the researchers noted. Most... POSTED TODAY IN MEDICAL Midlife Diabetes Linked to Memory Problems Later A midlife diagnosis of diabetes or prediabetes may raise the risk of memory and thinking problems over the next 20 years, new research suggests. Having diabetes in midlife was linked with a 19 percent greater decline in memory and thinking (cognitive) skills over 20 years, according to the new study. "What we saw was, people with prediabetes, diabetes... POSTED TODAY IN MEDICAL Health Tip: Be a Safe Patient AVP-825 AVP-825 (sumatriptan) is an investigational fastacting, dry-powder intranasal form of sumatriptan in development for the treatment of... -- When you're scheduled for a procedure at the doctor's office or hospital, make sure you play an active role in preserving your health. The American Academy of Orthopaedic Surgeons offers these suggestions for becoming a smarter patient: Don't be afraid to ask questions or tell your doctor you need more information. Share with your doctor your complete... Opdivo Opdivo (nivolumab) is an investigational PD-1 immune checkpoint inhibitor in development for the treatment of advanced melanoma. Read more news... brincidofovir Brincidofovir is a nucleotide analog broad-spectrum antiviral under FDA review to assess the safety and efficacy in patients with confirmed... More... 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Verify here Terms of Use · Privacy Policy +1 Like Tweet Email t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRO Hide http://www.drugs.com/[12/2/2014 2:44:04 PM] Drugs.com Print Version Print   Close Pentobarbital Sodium Class: Barbiturates VA Class: CN301 CAS Number: 76-74-4 Brands: Nembutal Introduction Barbiturate; anxiolytic, sedative, hypnotic, and anticonvulsant.a b Uses for Pentobarbital Sodium Insomnia Short-term treatment of insomnia (i.e., ≤2 weeks duration); decreased effectiveness for sleep induction and maintenance after 2 weeks.a b Has been used for routine sedation.a b However, barbiturates used infrequently for this indication since there are few clinical situations in which oral barbiturates provide a safety or efficacy advantage over nonbarbiturate sedatives/hypnotics.e Surgery and Preanesthesia Provide basal hypnosis for general, spinal, or regional anesthesia, or to facilitate intubation procedures.a b Seizure Disorders Alternate therapy to control status epilepticus or acute seizure episodes resulting from meningitis, poisons, eclampsia, alcohol withdrawal, tetanus, or chorea.a b IV diazepam generally considered drug of choice for termination of status epilepticus.g Drug Withdrawal Withdrawal of barbiturate or nonbarbiturate hypnotics in physically dependent patients.b Agitated Behavior Has been used to control acute episodes of agitated behavior in psychoses†; however, little value in long-term management of psychoses.b http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRP Preoperatively, to produce sedation and relieve anxiety.b Drugs.com Print Version Coma Induction Has been used in high doses to induce coma in the management of cerebral ischemia† and increased intracranial pressure† associated with head trauma, stroke, Reye’s syndrome, cardiac arrest, asphyxiation, or drowning. b Has been used to ameliorate or prevent sequelae associated with cerebral ischemia during neurosurgical procedures† that require long periods of cerebral hypoxia.b Pentobarbital Sodium Dosage and Administration General Adjust dosage carefully and slowly according to individual requirements and response.b Following chronic administration, withdraw pentobarbital slowly to avoid the possibility of precipitating withdrawal symptoms if the patient is physically dependent on the drug.b To prevent rebound in rapid eye movement (REM) sleep, withdrawal of a single therapeutic dose over 5 or 6 days (e.g., reducing dosage from 3 to 2 doses daily for 1 week) has been recommended when barbiturates are discontinued following prolonged use.a Insomnia Do not administer for periods >2 weeks.a b e Administration Administer by IM or slow IV injection.a b IV Administration For solution and drug compatibility information, see Compatibility under Stability. Usually administered in a concentration of 50 mg/mL. Must be administered by slow IV injection and in fractional doses to allow for adequate time for pentobarbital to distribute into CNS.a A time interval of ≥1 minute is required to determine the full effect of an IV dose.a b Administer under close supervision and in a setting where vital signs can be monitored; BP, respiration, and cardiac function maintained; and equipment for resuscitation and artificial ventilation are readily available.a b (See Respiratory and Cardiovascular Effects under Cautions.) Avoid intra-arterial and extravascular injection.a (See Intra-arterial Injection under Cautions.) Rate of Administration Do not exceed 50 mg/minute.a b (See Respiratory and Cardiovascular Effects under Cautions.) IM Administration Administer by deep IM injection into a large muscle.a b http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRQ Reserve IV administration for inducing anesthesia or emergency treatment of acute seizure episodes or acute episodes of agitated behavior in psychoses.b (See Seizure Disordersand also Agitated Behavior under Uses.) Drugs.com Print Version Administer a maximum volume of 5 mL at any one site to avoid tissue irritation.a b After administration of large hypnotic doses, observe patient closely for 20–30 minutes and monitor vital signs to ensure narcosis will not be excessive.a b Dosage Available as pentobarbital sodium; dosage expressed in terms of the salt.a IV dosage generally determined by patient’s reaction to slow administration of the drug.b A time interval of >1 minute required to determine the full effect of an IV dose.a b Pediatric Patients Insomnia IM 2–6 mg/kg a b or 125 mg/m2 as a single dose (maximum 100 mg).a b Surgery and Preanesthesia IM Usually, approximately 5 mg/kg. b IV Initially, usually 50 mg.b If necessary, administer subsequent doses after >1 minute.b Seizure Disorders IV Initially, usually 50 mg.b If necessary, administer subsequent doses after >1 minute.b Agitated Behavior† Initially, usually 50 mg.b If necessary, administer subsequent doses after >1 minute.b Adults Insomnia IM 150–200 mg as a single dose.a b IV Initially, usually 100 mg for an adult weighing 70 kg.a b After >1 minute, if necessary, administer additional small doses up to a total of 200–500 mg.a b Surgery and Preanesthesia IM 150–200 mg as a single dose.a b http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRR IV Drugs.com Print Version Seizures IV Initially, usually 100 mg.a b After >1 minute, if necessary, administer additional small doses up to a total of 200–500 mg.a b Administer minimum dosage to avoid compounding the CNS and respiratory depression which may follow seizures.a b (See CNS Depression and also Respiratory and Cardiovascular Effects, under Cautions.) Drug Withdrawal IM Establish a stabilizing dose (generally adminstered at 6-hour intervals), then decrease the daily dose by no more than 100 mg per day.b Severely dependent patients can usually be withdrawn from barbiturates in 14–21 days.b Agitated Behavior† IV Initially, usually 100 mg.a b After >1 minute, if necessary, administer additional small doses up to a total of 200–500 mg.a b Prescribing Limits Pediatric Patients Insomnia IM Maximum 100 mg daily.a b IV Maximum 200–500 mg.a b Special Populations Hepatic Impairment Dosage reduction recommended. a b e Renal Impairment Dosage reduction recommended.a Geriatric Patients Dosage reduction recommended.a b e Debilitated Patients http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRS Adults Drugs.com Print Version Dosage reduction recommended.a b e Cautions for Pentobarbital Sodium Contraindications Known hypersensitivity to any barbiturates.a History of manifest or latent porphyria.a e (See Porphyria under Cautions.) Bronchopneumonia or other severe pulmonary insufficiency.e Warnings/Precautions Warnings Pain Reaction Potential for paradoxical excitement and/or euphoria, restlessness, or delirium in patients with severe pain. a e Barbiturates could mask important symptoms in patients with acute or chronic pain.a e Use with caution in such patients. a e Should not be used in the presence of uncontrolled pain.e Abuse Potential Possible tolerance, psychological dependence, and physical dependence following prolonged administration.a Withdrawal Effects Abrupt cessation after prolonged use in dependent individuals may result in withdrawal symptoms (e.g., delirium, convulsions) and potentially be fatal.a Drug must be withdrawn gradually in patients receiving excessive dosages over extended periods of time.a CNS Depression Concurrent use of other CNS depressants may potentiate CNS depression.a (See Specific Drugs under Interactions.) Respiratory and Cardiovascular Effects Possible respiratory depression, apnea, laryngospasm, or vasodilation and hypotension, particularly if pentobarbital is administered IV too rapidly. a e Administer slowly; personnel and equipment should be readily available for administration of artificial respiration.a b Fetal/Neonatal Morbidity May cause fetal harm.a e If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.a e Retrospective, case-controlled studies indicate an association between maternal ingestion of barbiturates and a higher than expected incidence of fetal abnormalities.a e Barbiturates have caused postpartum hemorrhage and hemorrhagic disease in neonates; readily reversible with vitamin K therapy.e Possible withdrawal symptoms in neonates born to women who received barbiturates throughout the http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRT Performance of activities requiring mental alertness or physical coordination may be impaired.a e Drugs.com Print Version last trimester of pregnancy.a e Premature neonates are particularly susceptible to the depressant effects of barbiturates.e Porphyria Potential exacerbation of acute intermittent porphyria or porphyria variegata.e (See Contraindications under Cautions.) Complex Sleep-related Behaviors Potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food, while asleep.h Sensitivity Reactions Potential risk of anaphylaxis and angioedema; may occur as early as with the first dose of drug.h Dermatologic Effects and Hypersensitivity Reactions Exfoliative dermatitis (e.g., Stevens-Johnson syndrome), sometimes fatal, reported rarely. a e Because skin eruptions can precede potentially fatal reactions, discontinue pentobarbital whenever dermatologic reactions occur.e General Precautions Intra-arterial Injection Inadvertent intra-arterial administration can cause local reactions varying in severity from transient pain to gangrene.a Inadvertent extravascular injection may cause local tissue damage and result in necrosis.a e Discontinue injection if the patient complains of pain in limb.a Suicide Concomitant Diseases Use parenterally with caution in patients with hypertension, hypotension, pulmonary or cardiovascular disease, or shock.e Specific Populations Pregnancy Category D.a (See Fetal/Neonatal Morbidity under Cautions.) Lactation Distributed into milk;a e use with caution.a Geriatric Use Possible increased sensitivity to barbiturates.a Geriatric patients may frequently react to barbiturates with excitement, confusion, or depression.a e Debilitated Patients http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRU Use with caution, if at all, in patients with depression or suicidal tendencies.a e Drugs.com Print Version Possible increased sensitivity to barbiturates.a Debilitated patients may frequently react to barbiturates with excitement, confusion, or depression.a Hepatic Impairment Use with caution;a e should not be used in patients with marked hepatic impairment, including patients with premonitory signs of hepatic coma.a Common Adverse Effects Residual sedation,e drowsiness,a e lethargy,e vertigo,a e nausea,a e vomiting,a e headache.a e Interactions for Pentobarbital Sodium Metabolized by hepatic microsomal enzymes.a Induces hepatic microsomal enzymes.a Specific Drugs Drug Interaction Comments Anticoagulants, oral (e.g., warfarin) Possible decreased plasma warfarin concentrationsa e Adjust anticoagulant dosage as necessary, especially upon initiation or discontinuance of pentobarbitala e Contraceptives, oral Possible enhanced metabolism of estrogenic and progestinic components; potential for decreased oral contraceptive effectiveness and increased risk of pregnancy with pentobarbital pretreatment or concurrent therapya e Consider alternate methods of contraceptiona e Corticosteroids Possible increased corticosteroid metabolisma Dosage adjustment of corticosteroid may be required; closely monitor patients (especially asthmatics) receiving corticosteroids when pentobarbital is initiateda e Doxycycline Possible decreased half-life of doxycycline; effect may persist up to 2 weeks after discontinuance of pentobarbitala If possible, avoid concomitant administration; if administered concomitantly, monitor clinical response to doxycyclinea e Griseofulvin Possible decreased griseofulvin absorption, resulting in decreased blood concentrationsa e Avoid concomitant administration; if concomitant http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQRV CNS Possible additive depressant effectsa e depressants (e.g., sedatives, hypnotics, antihistamines, tranquilizers, alcohol) Drugs.com Print Version therapy is necessary, administration of griseofulvin in 3 divided doses daily may improve absorptiona e Monitor blood griseofulvin concentrations and increase dosage, if necessarye MAO inhibitors Possible prolongation of pentobarbital effectsa e Dose adjustment of pentobarbital may be requirede Phenytoin Increased, decreased, or no change in plasma phenytoin concentrations reported a Monitor plasma concentrations of phenytoin and pentobarbital; a adjust dosages as necessarya Valproic acid Possible increased plasma pentobarbital concentrationsa Monitor plasma pentobarbital concentrations and adjust dosage as neededa Pentobarbital Sodium Pharmacokinetics Absorption Onset Following IV administration, onset occurs within 1 minute.a b e Following IM administration, onset occurs within 10–25 minutes.b Duration Variable;a patient-dependent and may vary occasionally within same patient.a About 15 minutes following IV administration.b Plasma concentrations of 1–5 mcg/mL generally produce sedation and plasma concentrations of 5–15 mcg/mL generally produce sleep; however, plasma concentrations >10 mcg/mL may produce deep coma and those >30 mcg/mL are potentially lethal.b Distribution Extent Rapidly distributed to all tissues and fluids,a e with high concentrations in the brain, liver, and kidneys.a e Crosses the placenta and is distributed into milk.a e Plasma Protein Binding Approximately 35–45%.b Elimination http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSM Plasma Concentrations Drugs.com Print Version Metabolism Metabolized primarily by hepatic microsomal enzymes.a b e Elimination Route Excreted principally in urine, mostly as metabolites; excreted less commonly in the feces.a Half-life Biphasic; terminal half-life is 35–50 hours.b Stability Storage Parenteral Solution for Injection 30°C (brief exposure up to 40°C permitted).a Protect from freezing and avoid excessive heat.a Do not use if discoloration or precipitation occurs.a Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Solution CompatibilityHID Compatible Dextran 6% in dextrose 5% Dextrose–Ringer’s injection combinations Dextrose–Ringer’s injection, lactated, combinations Dextrose–saline combinations Dextrose 2½ or 10% in water Fructose 10% in sodium chloride 0.9% Fructose 10% in water Invert sugar 5 and 10% in sodium chloride 0.9% Invert sugar 5 and 10% in water Ionosol products Ringer’s injection http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSN Dextran 6% in sodium chloride 0.9% Drugs.com Print Version Ringer’s injection, lactated Sodium chloride 0.45% Sodium lactate (1/6) M Variable Dextrose 5% in water (depends on pentobarbital concentration) Sodium chloride 0.9% (depends on pentobarbital concentration) Drug Compatibility Admixture CompatibilityHID Compatible Amikacin sulfate Aminophylline Calcium chloride Chloramphenicol sodium succinate Dimenhydrinate Erythromycin lactobionate Lidocaine HCl Thiopental sodium Verapamil HCl Incompatible Ephedrine sulfate Hydrocortisone sodium succinate Hydroxyzine HCl Norepinephrine bitartrate Penicillin G potassium Pentazocine lactate Phenytoin sodium Promazine HCl Promethazine HCl Sodium bicarbonate Streptomycin sulfate http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSO Chlorpheniramine maleate Drugs.com Print Version Succinylcholine chloride Vancomycin HCl Y-Site CompatibilityHID Compatible Acyclovir sodium Gatifloxacin Linezolid Propofol Incompatible Amphotericin B cholesteryl sulfate complex Fenoldopam mesylate Lansoprazole Actions CNS effects appear to be related, at least partially, to the drug's ability to enhance activity of GABA, the principal inhibitory neurotransmitter in the CNS, by altering inhibitory synaptic transmissions that are mediated by GABAA receptors.e Capable of producing all levels of CNS depression—from mild sedation to hypnosis to deep coma to death.a e Barbiturates lower serum bilirubin concentrations in neonates and patients with congenital nonhemolytic unconjugated hyperbilirubinemia, presumably by induction of glucuronyl transferase, the enzyme that conjugates bilirubin.e Advice to Patients Potential for pentobarbital to impair mental alertness or physical coordination; do not drive or operate machinery until effects on individual are known.a e Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption.a Importance of avoiding alcohol while taking the drug.a Importance of women informing clinicians if they are or plan to become pregnant or plan to breastfeed.a Importance of informing patients of other important precautionary information.a (See Cautions.) Preparations http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSP Anticonvulsant effects of barbiturates are multiple and rather nonselective.g Principal mechanism of action appears to be reduction of monosynaptic and polysynaptic transmission resulting in decreased excitability of the entire nerve cell; barbiturates also increase the threshold for electrical stimulation of the motor cortex.g Drugs.com Print Version Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.b * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Pentobarbital Sodium Routes Dosage Forms Bulk Powder Parenteral Injection Strengths Brand Names Manufacturer 50 mg/mL* Ovation Nembutal Sodium Solution (C-II; with alcohol 10% and propylene glycol 40% v/v) AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. † Use is not currently included in the labeling approved by the US Food and Drug Administration. References a. Ovation Pharmaceuticals, Inc. Nembutal (pentobarbital sodium) injection prescribing information. Deerfield, IL; 2006 Nov. b. AHFS Drug Information 2007. McEvoy GK, ed. Pentobarbital. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2505-2506. c. Sirven JI, Waterhouse E. Management of Status Epilepticus. American Family Physician.. 2003; 68:469-76. [PubMed 12924830] e. AHFS Drug Information 2007. McEvoy GK, ed. Barbiturates General Statement. Bethesda, MD: American Society of HealthSystem Pharmacists; 2007: 2500-2503. g. AHFS Drug Information 2007. McEvoy GK, ed. Anticonvulsant General Statement. Bethesda, MD: American Society of HealthSystem Pharmacists; 2007: 2201-2206. h. Food and Drug Administration. Pentobarbital injection. and HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1319-25. http://www.drugs.com/monograph/pentobarbital-sodium.html?printable=1[12/2/2014 2:50:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSQ d. Fick DM, Cooper JW, Wade WE et al. Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults: results of a US consensus panel of experts. Arch Intern Med. 2003; 163:2716-2724. [PubMed 14662625] Drugs.com Print Version Print   Close Hydromorphone Hydrochloride Class: Opiate Agonists VA Class: CN101 CAS Number: 71-68-1 Brands: Dilaudid, Dilaudid-HP, Exalgo Warning(s) Abuse Potential Abuse potential similar to that of other opiate agonists.n o v Consider abuse potential when prescribing or dispensing hydromorphone in situations where the clinician or pharmacist is concerned about increased risk of misuse, abuse, or diversion.n o v Respiratory Depression Risk of respiratory depression.n o v Concomitant use of CNS depressants, including alcohol, increases risk of fatal respiratory depression.n o Overdose Risk with Improper Administration of Extended-release Tablets or 10-mg/mL Injection Use extended-release tablets only in patients who are tolerant to opiate agonists; fatal respiratory depression may result if used in patients who are not opiate tolerant.n Extendedrelease tablets are not indicated for management of acute or postoperative pain or for asneeded (“prn”) use.v Patients are considered opiate tolerant if they have been receiving at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone hydrochloride daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for ≥1 week.o v Breaking, chewing, crushing, or dissolving the extended-release tablets can result in rapid release of hydromorphone and absorption of a potentially fatal dose.v Accidental ingestion of extended-release tablets can result in fatal overdosage, particularly in children.v REMS: FDA approved a REMS for hydromorphone to ensure that the benefits outweigh the risks. (See REMS Program under Dosage and Administration.) The REMS may apply to one or more preparations of hydromorphone and consists of the following: medication guide and elements to http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSR Use highly concentrated injection (10 mg/mL) only in patients who are tolerant to opiate agonists; overdosage and/or death may result if confused with less concentrated formulations and used in patients who are not opiate tolerant.a o Drugs.com Print Version assure safe use. See the FDA REMS page () or the ASHP REMS Resource Center (). Introduction Opiate agonist; semisynthetic phenanthrene derivative.a Uses for Hydromorphone Hydrochloride Acute Pain A strong analgesic used in the relief of moderate to severe pain.a f Usually, temporary relief of moderate to severe pain such as that associated with acute and some chronic medical disorders including renal or biliary colic, acute trauma, postoperative pain, and cancer.f Used to provide analgesia during diagnostic and orthopedic procedures.f Highly concentrated (10-mg/mL) injection is used for relief of moderate to severe pain in opiate-tolerant patients requiring large doses for adequate pain relief (see Boxed Warning); smaller volume may be injected IM or sub-Q, and discomfort of larger volumes avoided.o IV route (including patient-controlled administration) is preferred for administration of opiate agonists after major surgery since repeated IM injections may cause pain and trauma.f Consider around-the-clock dosing of analgesics in the initial stages of acute pain to avoid wide swings in pain and sedation often associated with as-needed dosing regimens.f Chronic Pain For relief of malignant (cancer) pain and chronic nonmalignant pain.f In the management of severe, chronic pain associated with a terminal illness such as cancer, the principal goal of analgesic therapy is to make the patient relatively pain-free while maintaining as good a quality of life as possible.f Analgesic therapy must be individualized and titrated according to patient response and tolerance.f Although consideration of the dependence potential of opiate agonists has often limited their effective use by many clinicians in terminally ill patients with severe, chronic pain, such consideration is irrelevant in the context of terminal illness.f As tolerance to initial dosage develops, larger doses may be given as necessary.f Alternative analgesic adjuncts such as tricyclic antidepressants or anticonvulsants also should be considered in the treatment of chronic nonmalignant pain (e.g., neurogenic pain).f During prolonged use, especially when opiate agonists are self-administered, precautions should be taken to prevent unnecessary increases in dosage.f Hydromorphone Hydrochloride Dosage and Administration http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSS Extended-release tablets are used orally for management of moderate to severe pain in opiate-tolerant patients who require a continuous, around-the-clock analgesic for an extended period of time; do not use on an as-needed (“prn”) basis.v (See Boxed Warning.) Drugs.com Print Version General REMS Program FDA required and approved a REMS for hydromorphone hydrochloride extended-release tablets.w Goals are to minimize potential for abuse, misuse, overdose, and addiction and to ensure safe use.w Medication guide must be distributed to all patients with every prescription; clinicians who prescribe the extended-release tablets must complete special training on appropriate and safe use of the drug.w Administration Administer orally or by sub-Q, IM, or slow IV injection or infusion.a o n v Has been administered epidurally†.i p t Oral Administration Administer orally as conventional (immediate-release) or extended-release tablets or as an oral solution.n v Use caution when prescribing or dispensing hydromorphone to avoid inadvertent interchange of 8-mg extended-release tablets and 8-mg conventional tablets.v Conventional Tablets and Oral Solution Conventional tablets and oral solution are bioequivalent.n Food may decrease rate and extent of absorption of conventional tablets (see Food under Pharmacokinetics), but effects may not be clinically important.n Extended-release Tablets Discontinue all other extended-release opiates when initiating therapy with extended-release hydromorphone.v Swallow tablets intact; do not break, crush, dissolve, or chew.v Ingestion of broken, crushed, chewed, or dissolved tablets may result in rapid drug release and absorption of a potentially fatal dose.v Administer without regard to food.v Do not administer with alcohol.v x (See Specific Drugs under Interactions.) Parenteral Administration For solution and drug compatibility information, see Compatibility under Stability. Administer by sub-Q, IM, or slow (over at least 2–3 minutes) IV injection.o Has been administered by continuous IV or sub-Q infusion in selected opiate-tolerant patients with chronic pain; use extreme caution when administering continuous infusions of opiates to patients with no prior exposure to opiate analgesics.i p r s t Also administered IV via controlled-delivery device for patient-controlled analgesia (PCA).i i http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQST Do not administer more frequently than once every 24 hours.v Drugs.com Print Version IM injection is discouraged for any analgesic (e.g., the injection itself is painful, delayed onset). Highly Concentrated (10-mg/mL) Injection Injection is commercially available in various concentrations (1, 2, 4, and 10 mg/mL).o Use the 10mg/mL injection only in patients who are tolerant to and already receiving high dosages of opiate agonists.o (See Boxed Warning.) Confusion between the different concentrations or between mg and mL can result in accidental overdosage and death.o Take care to ensure that correct dosages are prescribed and dispensed.o When writing prescriptions, specify the intended total dose (in mg) along with the corresponding total volume (in mL).o Use the 10-mg/mL injection only when required volume can be accurately measured.a o Reserve for patients who require the reduced total volume and higher concentration of this formulation.o Reconstitution Reconstitute lyophilized powder immediately prior to use by adding 25 mL of sterile water for injection to a vial containing 250 mg of the drug to provide 10-mg/mL solution.o Dilution If the 500-mg single-use (10-mg/mL) vial is used for preparation of an IV infusion solution, remove container seal and rubber stopper in a laminar flow hood or equivalent clean air compounding area; do not penetrate with a syringe.o Withdraw appropriate amount and then discard any unused portion in an appropriate manner.o Has been diluted to a concentration of 1 mg/mL in 5% dextrose or 0.9% sodium chloride injection for continuous IV infusion in critically ill adult patients.r Rate of IV Administration IV injection for PCA: Self-administered intermittently as needed (“prn”) via controlled-delivery device, with usual lockout intervals (minimum time between self-administered doses programmed into device) of 5–10 minutes.i Dosage Available as hydromorphone hydrochloride; dosage expressed in terms of the salt.n o Give the smallest effective dose as infrequently as possible to minimize the development of tolerance and physical dependence.a Reduce dosage in geriatric or debilitated patients and in patients with renal or hepatic impairment.a n o v When administered concomitantly with another CNS depressant (e.g., sedatives, tranquilizers, general anesthetics, phenothiazines), reduce dosage of one or both agents.n o v (See Specific Drugs under Interactions.) Individualize dosage to provide adequate analgesia and minimize adverse effects.n o i v When selecting initial dosage, consider type, severity, and frequency of pain; age, general condition, http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSU If rapid onset and shorter duration of analgesia are required, may give IV at slow rate (over at least 2–3 minutes), with special attention to the possibility of respiratory depression and hypotension.a o Drugs.com Print Version and medical status of patient; concurrent drug therapy; patient’s risk for abuse or addiction; prior use of opiates; and the acceptable balance between pain relief and adverse effects.n o v In patients being transferred from other opiate therapy, also consider daily dosage, potency, and specific characteristics (e.g., elimination half-life) of the previously administered opiate and reliability of the relative potency estimate used to calculate equivalent hydromorphone dosage.n o v Avoid abrupt discontinuance to avoid precipitation of withdrawal symptoms.a n o v Pediatric Patients Pain† (Treatment with Conventional [Immediate-release] Preparations) Oral Children 6–12 years of age: 0.03–0.08 mg/kg every 4–6 hours as needed.h Children >12 years of age: 1–4 mg every 4–6 hours as needed.h IV, IM, or Sub-Q Children 6–12 years of age: 0.015 mg/kg every 4–6 hours as needed.h Children >12 years of age: 1–4 mg every 4–6 hours as needed.h Adults Pain (Oral Treatment with Conventional [Immediate-release] Preparations) Oral Usual initial dosage in non-opiate-tolerant adults is 2–4 mg every 4–6 hours.n p For severe pain, initial doses of 4–8 mg have been used.i Adjust dose and/or frequency of administration gradually based on response.n For chronic pain, administer at regularly scheduled intervals (“around the clock”); may give supplemental doses of 5–15% of the total daily dosage every 2 hours as needed for breakthrough pain.n Switching from Other Opiates to Conventional Hydromorphone Preparations Oral Convert total daily dosage of current opiate to equivalent daily dosage of hydromorphone hydrochloride and then administer in divided doses.n Calculate an equianalgesic dosage of oral hydromorphone hydrochloride using manufacturer’s suggested dosage conversions (see Table 1).n o For opiates not in Table 1, convert total daily dosage of current opiate to equivalent morphine sulfate dosage; then use estimated daily morphine sulfate dosage to determine equianalgesic dosage of hydromorphone hydrochloride.n o To account for individual variation in response to different opiate agonists, reduce first few doses of hydromorphone hydrochloride to one-half to two-thirds of the estimated equianalgesic dose.n Adjust dose and/or frequency of administration based on response.n Table 1. Equianalgesic Potency Conversion http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQSV Manufacturer states that usual dosage is 2.5–10 mg every 3–6 hours, although some patients may require higher dosages.n Drugs.com Print Version   Equianalgesic Dose (in mg) Opiate Agonist or Partial Agonist Oral Parenteral Morphine sulfate 40–60 10 Hydromorphone hydrochloride 6.5–7.5 1.3–2 Oxymorphone hydrochloride 6.6 1–1.1 Levorphanol tartrate 4 2–2.3 Meperidine hydrochloride 300–400 75–100 Methadone hydrochloride 10–20 10 Nalbuphine hydrochloride – 10–12 Butorphanol tartrate – 1.5–2.5 Pain (Oral Treatment with Extended-release Tablets) Carefully individualize dosage; overestimation of initial dose may result in fatal overdosage.v Manufacturer considers the following dosage recommendations to be suggested approaches to the individual management of each patient.v Switching from Conventional Hydromorphone to Extended-release Hydromorphone Oral Administer same total daily dosage once every 24 hours.v May titrate dose every 3–4 days based on response.v In clinical trials, dosage range was 8–64 mg daily.v Switching from Other Oral Opiates to Extended-release Hydromorphone Consult published dosage conversion tables (see Table 2), keeping in mind that such conversion ratios are only approximate.v For transdermal fentanyl, estimated equianalgesic dosage of extended-release hydromorphone hydrochloride is 12 mg every 24 hours for each 25-mcg/hour increment in fentanyl transdermal dosage.v Generally initiate at 50% of the calculated total daily dosage, then titrate upward (by suggested increments of 25–50% of the current daily dosage) based on response.v Do not increase more frequently than once every 3–4 days.v Table 2. Approximate Equianalgesic Doses for Conversion from Oral Opiate Agonists to Extendedrelease Hydromorphone Opiate Agonist Equianalgesic Oral Dose (in mg) Hydromorphone hydrochloride 12 Codeine phosphate 200 http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTM Oral Drugs.com Print Version Hydrocodone bitartrate 30 Methadone hydrochloride 20 Morphine sulfate 60 Oxycodone hydrochloride 30 Oxymorphone hydrochloride 20 Conversion from transdermal fentanyl: Initiate extended-release tablets ≥18 hours following removal of fentanyl transdermal system.v Conversion from methadone: Particularly close monitoring required; equianalgesic conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure.v Consider increasing dosage if >2 doses of supplemental (rescue) analgesic are required for breakthrough pain within a 24-hour period on 2 consecutive days.v Administer extended-release tablets no more frequently than every 24 hours.v In clinical trials, dosage range was 8–64 mg daily.v Discontinuance of Therapy with Extended-release Hydromorphone Oral Discontinue therapy by reducing dose by 25–50% every 2–3 days until 8 mg is reached.v Pain (Parenteral Treatment) Treatment of Opiate-naive Adults IM or Sub-Q Initially 1–2 mg every 2–3 hours as needed.o Some patients may require lower initial dosages.o Adjust dose and/or frequency of administration based on response.o Initially 0.2–1 mg by slow injection every 2–3 hours.o Some patients may require lower initial dosages.o Adjust dose and/or frequency of administration gradually based on response.o Treatment of Critically Ill Adults IV In ICU setting, loading dose of 0.2–0.6 mg followed by continuous infusion of 0.5–3 mg/hour has been used.r Has been administered in intermittent IV doses of 10–30 mcg/kg every 1–2 hours or as continuous IV infusion of 7–15 mcg/kg per hour.s Switching from Other Opiates to Parenteral Hydromorphone IV, IM, or Sub-Q Convert total daily dosage of current opiate to equivalent daily dosage of hydromorphone hydrochloride and then administer in divided doses.o Calculate an equianalgesic dosage of parenteral hydromorphone hydrochloride using manufacturer’s no http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTN IV Drugs.com Print Version suggested dosage conversions (see Table 1). For opiates not in Table 1, convert total daily dosage of current opiate to equivalent morphine sulfate dosage; then use estimated daily morphine sulfate dosage to determine equianalgesic dosage of hydromorphone hydrochloride.n o Reduce estimated parenteral hydromorphone hydrochloride dosage by one-half because of possible incomplete cross-tolerance.o Adjust dosage based on response.o Special Populations Hepatic Impairment Pain Oral Reduce initial dosage in patients with moderate hepatic impairment (Child-Pugh class B); use even more conservative dosages in patients with severe hepatic impairment (Child-Pugh class C).n v Closely monitor during dosage titrations.n v Use oral solution rather than conventional tablets to facilitate dosage titration.n IV, IM, or Sub-Q Reduce initial dosage to one-fourth to one-half the usual recommended dosage in patients with moderate hepatic impairment; consider possibility that systemic exposure may be further increased when selecting initial dosage in patients with severe hepatic impairment.o Closely monitor during dosage titrations.o Renal Impairment Pain Oral Closely monitor during dosage titrations.n v Because extended-release tablets are intended for once-daily administration, consider an alternative analgesic regimen with flexible dosing interval in patients with severe renal impairment.v Use oral solution rather than conventional tablets to facilitate dosage titration.n IV, IM, or Sub-Q Depending on degree of impairment, reduce initial dosage to one-fourth to one-half the usual recommended dosage.o Closely monitor during dosage titrations.o Geriatric and Debilitated Patients Select dosage with caution, and use lower than usual initial dosages.a n o v Cautions for Hydromorphone Hydrochloride http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTO Reduce initial dosage in patients with moderate renal impairment (Clcr 40–60 mL/minute); further reduce dosage in those with severe renal impairment (Clcr <30 mL/minute).n v Drugs.com Print Version Contraindications Known hypersensitivity to hydromorphone or any ingredient in the formulation.n o v Respiratory depression in unmonitored settings or in the absence of resuscitative equipment.n o v Acute or severe asthma or hypercarbia.n o v GI obstruction, especially paralytic ileus (see Acute Abdominal Conditions under Cautions).o v Because extended-release tablets are nondeformable, contraindications for this formulation also include blind loops in GI tract and prior surgery or underlying disease that would cause narrowing of GI tract.v Conventional (immediate-release) oral preparations contraindicated for use in obstetrical analgesia.n (See Pregnancy under Cautions.) Extended-release tablets and 10-mg/mL injection are contraindicated in patients not already tolerant to opiate agonists.o v Warnings/Precautions Warnings Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.a Dependence and Abuse Physical and psychological dependence and tolerance may develop with repeated administration, and abuse potential exists; use with caution.a n o v Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.n o v After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.n o v Increased risk of tolerance, dependence, or addiction in patients with alcoholism or other drug dependency.n o Use with caution.n o Hydromorphone abuse in combination with other CNS depressants may result in serious risk.n o v (See Specific Drugs under Interactions.) Use of Highly Concentrated Injection Use 10-mg/mL injection only in patients who are tolerant to opiate agonists; overdosage and/or death may result if confused with less concentrated formulations and used in patients who are not tolerant to opiate agonists.o (See Boxed Warning.) Use extreme caution to avoid confusing the highly concentrated injection with the less concentrated injections.o Opiate Conversions To avoid errors that may result in overdosage or death when switching patients from other opiate therapy to hydromorphone therapy, use opiate conversion tables to calculate an equianalgesic dosage.o (See Dosage under Dosage and Administration.) Morphine sulfate and hydromorphone o http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTP Sudden, marked shortening of GI transit time in patients receiving hydromorphone extended-release tablets may result in decreased absorption of the drug and precipitation of withdrawal symptoms.v Drugs.com Print Version hydrochloride are not equianalgesic on a mg per mg basis. Use of Extended-release Tablets Use the extended-release tablets only in patients who are tolerant to opiate agonists; fatal respiratory depression may result if used in patients who are not tolerant to opiate agonists.v (See Boxed Warning.) Do not break, chew, crush, inject, or dissolve extended-release tablets as rapid release of drug and absorption of a potentially fatal dose may occur.v Respiratory Depression The major toxicity associated with hydromorphone.d n o v Occurs most frequently in geriatric or debilitated patients, in those with conditions accompanied by hypoxia or hypercapnia, following large initial doses in patients who are not opiate tolerant, or in patients receiving other agents with respiratory depressant effects.n o v Use with extreme caution in patients with COPD or cor pulmonale, and in patients with substantially decreased respiratory reserve (e.g., asthma, severe obesity, sleep apnea), hypoxia, hypercapnia, or preexisting respiratory depression.n o In such patients, even therapeutic hydromorphone doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.n o v Consider use of nonopiate analgesics and use hydromorphone under close medical supervision at lowest effective dosage.o v Head Injury and Increased Intracranial Pressure Respiratory depressant effects and ability of opiates to increase CSF pressure may be markedly exaggerated in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure.n o v Hydromorphone produces effects (e.g., pupillary changes, altered consciousness) that may obscure clinical course and neurologic signs of further increase in CSF pressure in patients with head injuries.n ov Hypotension Possible severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs that compromise vascular tone (e.g., phenothiazines, general anesthetics).n o v (See Specific Drugs under Interactions.) May produce orthostatic hypotension in ambulatory patients.n o Use with caution in patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.n o v Acute Abdominal Conditions May obscure diagnosis or clinical course of patients with acute abdominal conditions.n o v Use with caution, if at all, in patients at risk for ileus.o Extended-release tablets are nondeformable and may cause obstructive symptoms in patients with or at risk for GI strictures.v Do not administer to patients with conditions that can cause narrowing of GI http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTQ Use with extreme caution, if at all, in comatose patients and those with head injury, brain tumor, or elevated CSF pressure.f Drugs.com Print Version tract (e.g., prior GI surgery, GI obstruction, blind loop syndrome, esophageal motility disorders, small bowel inflammatory disease, short-gut syndrome due to adhesions or decreased transit time, history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, Meckel’s diverticulum).v Sensitivity Reactions Sulfite Sensitivity Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.a n o v Latex Sensitivity Packaging components for some formulations (e.g., 250- and 500-mg vials) contain natural latex proteins in the form of dry natural rubber and/or natural rubber latex; take appropriate precautions for patients with a history of natural latex sensitivity.a o General Precautions CNS Effects May impair mental alertness or physical coordination; warn patient to use caution when driving or operating machinery.n o v Concomitant use of another CNS depressant may have additive effects; decrease dosage of one or both drugs.n o v (See Specific Drugs under Interactions.) Seizures May aggravate preexisting seizures in patients with seizure disorders.n o v May induce seizures in some clinical settings.o v Mild to severe seizures and myoclonus reported in critically ill patients receiving high parenteral doses of hydromorphone.a n o Use with caution in debilitated patients, patients with myxedema or hypothyroidism, Addison’s disease, prostatic hypertrophy, urethral stricture, gall bladder disease, CNS depression or coma, toxic psychosis, acute alcoholism, delirium tremens, kyphoscoliosis, or following GI surgery.n o v Biliary Disease Use with caution in patients with biliary disease, including acute pancreatitis, and immediately before biliary tract surgery; may cause sphincter of Oddi spasm and decrease biliary and pancreatic secretions.n o v Local Effects of Concentrated Injection Consider possibility of local irritation and induration with IM or sub-Q use of 10-mg/mL injection.a Specific Populations Pregnancy Category C.n o v Administration during labor may cause neonatal respiratory depression and sinusoidal fetal heart rate patterns.a n o v Use hydromorphone injection with caution; an opiate antagonist for reversal of http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTR Debilitated and Special-risk Patients Drugs.com Print Version respiratory depression should be readily available.o Manufacturers of oral formulations recommend against use during labor.n v Infants born to women regularly taking opiates during pregnancy will be physically dependent; intensity of withdrawal syndrome does not always correlate with maternal opiate dosage or duration of use.n o v Lactation Distributed into milk in low concentrations.n o v Women receiving hydromorphone generally should not nurse.n o v Pediatric Use Safety and efficacy not established in children;n o v however, conventional preparations of hydromorphone have been used in children.b h (See Pediatric Patients under Dosage and Administration.) Geriatric Use Use with caution.n o v Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults;n o experience with extended-release tablets suggests geriatric patients may be more susceptible to adverse effects.v Select dosage with caution, and use lower than usual initial dosages.a n o v Hepatic Impairment Exposure to drug may be increased.n o v (See Absorption: Special Populations, under Pharmacokinetics.) Use with caution and in reduced dosages.n o v Renal Impairment Exposure to drug may be increased.n o v (See Absorption: Special Populations, under Pharmacokinetics.) Use with caution and in reduced dosages.n o v Light-headedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, pruritus.n o With extended-release tablets for chronic pain: Constipation, nausea, vomiting, somnolence, headache, dizziness.v Interactions for Hydromorphone Hydrochloride Not known whether hydromorphone is metabolized by CYP isoenzymes.j Minimal potential to inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.v Specific Drugs Drug Interaction Amphetamine Dextroamphetamine may enhance opiate agonist analgesiaf Comments http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTS Common Adverse Effects Anticholinergics Possible increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileuso v Antidepressants, tricyclics Potentiation of the effects of the antidepressantf Use concomitantly with caution; dosage adjustment may be necessaryf CNS depressants (e.g., other opiate agonists, general anesthetics, tranquilizers, sedatives and hypnotics, alcohol) Additive CNS and respiratory depressant effects; possible hypotension and profound sedation or comaf n o v Alcohol intake with extendedrelease tablets: Increased peak plasma hydromorphone concentrations, possible ingestion of toxic dosev x Reduce dosage of one or both agentsf n o v Avoid use of alcoholn v x Diuretics Opiate agonists may decrease effects of diuretics used in CHFf MAO inhibitors Severe, unpredictable potentiation of opiates reported; possible CNS excitation or depression, hypotension or hypertensiono v Some manufacturers recommend allowing 14 days to elapse following discontinuance of MAO inhibitor and initiation of hydromorphoneo v Opiate partial agonists (butorphanol, buprenorphine, nalbuphine, pentazocine) Possible reduced analgesic effect and/or withdrawal symptomsf n o v Caution advised;f n o some manufacturers state that combined use is not recommendedv Phenothiazines Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesiaf Possible severe hypotensionn o v Skeletal muscle relaxants May enhance the neuromuscular blocking action of skeletal muscle relaxants and increase respiratory depressant effectsf n o v Hydromorphone Hydrochloride Pharmacokinetics Absorption Bioavailability Well absorbed following oral, rectal, or parenteral administration.a Peak plasma concentrations attained within 0.5–1 hour or 12–16 hours after oral administration of conventional (immediate-release) preparations or extended-release tablets, respectively.n v http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTT Drugs.com Print Version Drugs.com Print Version Conventional tablets and oral solution are bioequivalent.n Following oral administration as conventional tablets given 4 times daily or as extended-release tablets given once daily at same total daily dosage, steady-state plasma concentrations are maintained within same concentration range; extended-release tablets produce less fluctuation in concentrations.v Onset Usually 15–30 minutes; more rapid than morphine.a d Duration Maintained for 4–5 hours following administration as conventional preparation, depending on the route; may have shorter duration of action than morphine.a Food Conventional tablets: Food decreases peak plasma concentrations and increases systemic exposure by 25 and 35%, respectively, and delays peak plasma concentrations by 0.8 hour.n Extended-release tablets: Food does not alter pharmacokinetics.v Special Populations Hepatic impairment: Systemic exposure after single oral dose is increased fourfold in individuals with moderate impairment (Child-Pugh class B).n o Further increase expected in severe hepatic impairment.n o Renal impairment: Systemic exposure after single oral dose is increased twofold in individuals with moderate impairment (Clcr 40–60 mL/minute) and threefold to fourfold in those with severe impairment (Clcr <30 mL/minute).n o Distribution Extent Plasma Protein Binding 8–27%.n o v Elimination Metabolism Principally in the liver via glucuronic acid conjugation to hydromorphone-3-glucuronide (95%); minor amounts of 6-hydroxy reduction metabolites.a n o v Elimination Route Excreted principally in the urine as hydromorphone-3-glucuronide.a n o Half-life Conventional preparations: Approximately 2.3–2.8 hours.n o http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTU Crosses the placenta.n o v Distributes into breast milk.n o Drugs.com Print Version Extended-release tablets: Approximately 11 hours (range: 8–15 hours).v Special Populations In severe renal impairment, half-life prolonged to 40 hours.n Stability Storage Oral Conventional Tablets Tight, light-resistant container at 25°C (may be exposed to 15–30°C).n Extended-release Tablets 25°C (may be exposed to 15–30°C).v Solution Tight, light-resistant container at 25°C (may be exposed to 15–30°C).n Parenteral Affected by light and injection may develop a slight yellowish discoloration; this change apparently does not indicate loss of potency.a o Powder for Injection, for IV Infusion 20–25°C (may be exposed to 15–30°C).o Protect from light.o Injection Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Injection reported physically and chemically stable for at least 24 hours in most common IV infusion solutions when protected from light at 25°C.a Solution CompatibilityHID Compatible Dextrose 5% in Ringer’s injection Dextrose 5% in Ringer’s injection, lactated Dextrose 5% in water Dextrose 5% in sodium chloride 0.45 or 0.9% http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQTV 20–25°C (may be exposed to 15–30°C).o Protect from light.o Drugs.com Print Version Ringer’s injection Ringer’s injection, lactated Sodium chloride 0.45 or 0.9% Sodium lactate (1/6) M Drug Compatibility Admixture CompatibilityHID Compatible Bupivacaine HCl Clonidine HCI Fluorouracil Heparin sodium Ketamine HCl Midazolam HCl Ondansetron HCl Potassium chloride Promethazine HCl Verapamil HCl Ziconotide acetate Y-Site CompatibilityHID Acyclovir sodium Allopurinol sodium Amifostine Amikacin sulfate Atropine sulfate Aztreonam Bivalirudin Caspofungin acetate Cefotaxime sodium Cefoxitin sodium http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUM Compatible Drugs.com Print Version Ceftaroline fosamil Ceftazidime Cefuroxime sodium Chloramphenicol sodium succinate Cisatracurium besylate Cladribine Clindamycin phosphate Co-trimoxazole Dexamethasone sodium phosphate Dexmedetomidine HCl Diltiazem HCl Diphenhydramine HCl Dobutamine HCl Docetaxel Dopamine HCl Doripenem Doxorubicin HCl liposome injection Doxycycline hyclate Epinephrine HCl Erythromycin lactobionate Famotidine Fenoldopam mesylate Fentanyl citrate Filgrastim Fludarabine phosphate Foscarnet sodium Furosemide Gemcitabine HCl Gentamicin sulfate Granisetron HCl http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUN Etoposide phosphate Drugs.com Print Version Haloperidol lactate Heparin sodium Hetastarch in lactated electrolyte injection (Hextend) Hydroxyethyl starch 130/0.4 in sodium chloride 0.9% Hydroxyzine HCl Ketorolac tromethamine Labetalol HCl Levofloxacin Linezolid Lorazepam Magnesium sulfate Melphalan HCl Metoclopramide HCI Metronidazole Micafungin sodium Midazolam HCl Milrinone lactate Morphine sulfate Nafcillin sodium Nicardipine HCl Norepinephrine bitartrate Ondansetron HCl Oxacillin sodium Oxaliplatin Paclitaxel Palonosetron HCl Pemetrexed disodium Penicillin G potassium Piperacillin sodium–tazobactam sodium Propofol http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUO Nitroglycerin Drugs.com Print Version Ranitidine HCl Remifentanil HCl Scopolamine HBr Tacrolimus Teniposide Thiotepa Tobramycin sulfate Vancomycin HCl Vecuronium bromide Vinorelbine tartrate Incompatible Amphotericin B cholesteryl sulfate complex Gallium nitrate Phenytoin sodium Sargramostim Variable Ampicillin sodium Cefazolin sodium Diazepam Actions A potent analgesic; shares actions of the opiate agonists.a n o v Opiate agonists alter perception of and emotional response to pain.f Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.f n o v Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).f Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.f Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.f Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUP Phenobarbital sodium Drugs.com Print Version temperature.f Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).f Respiratory depression may be mediated by μ-receptors, possibly μ2-receptors (which may be distinct from μ1-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.f May depress the cough reflex by a direct effect on the cough centers in the medulla; coughsuppressant opiate receptors have also been suggested.f Nausea, vomiting, constipation, and euphoria may be less marked with hydromorphone than with morphine.f Advice to Patients Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.f n o v Importance of informing patients that hydromorphone should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers).n o v Importance of informing patients that this is a drug of potential abuse and should also be protected from theft.n o v Risk of severe or fatal respiratory depression if misused or if used in individuals for whom drug was not prescribed.n v Importance of informing patients to keep the drug in a secure location and out of the reach of children.n v Importance of informing patients that hydromorphone dosage should not be adjusted without consulting with a clinician.n v Importance of not abruptly discontinuing hydromorphone following prolonged opiate therapy.n v Importance of informing clinician of any breakthrough pain or adverse effects (e.g., constipation) that occur during therapy, so that therapy may be adjusted based on individual patient requirements.n v Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.f n o v Importance of women informing clinicians if they are or plan to become pregnant or plan to breastfeed.a n o v Importance of informing patients of other important precautionary information. (See Cautions.) Hydromorphone Extended-release Tablets Medication guide must be dispensed with every prescription for the extended-release tablets.w Importance of patients reading the medication guide before initiating therapy and each time the extended-release tablets are dispensed.v Importance of not breaking, crushing, chewing, or dissolving extended-release tablets; potentially fatal overdose can occur.v Importance of using extended-release tablets exactly as prescribed and only if opiate tolerant.v If hydromorphone therapy has been interrupted for 3 or more days, importance of contacting clinician prior to reinitiating treatment.v Risk of GI obstruction in patients with preexisting severe narrowing of GI tract.v Importance of http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUQ Potential for severe constipation to occur.v Importance of considering use of appropriate laxative therapy upon initiation of therapy for chronic pain.v Drugs.com Print Version informing clinician of prior GI surgeries and GI conditions that may cause narrowing.v Importance of promptly reporting symptoms of GI obstruction (e.g., abdominal pain or distension, severe constipation, vomiting).v Importance of informing patients that shell of extended-release tablet is nonabsorbable and may be passed in the stool.v Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs. * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Hydromorphone Hydrochloride Routes Dosage Forms Bulk Powder* Oral Solution Strengths Brand Names Manufacturer Hydromorphone Hydrochloride Powder for Prescription Compounding (C-II) 5 mg/5 mL Dilaudid (C-II) Purdue Pharma Hydromorphone Hydrochloride Solution (C-II) Tablets 2 mg* Dilaudid (C-II) Purdue Pharma Hydromorphone Hydrochloride Tablets (C-II) Dilaudid (C-II) Purdue Pharma Hydromorphone Hydrochloride Tablets (C-II) 8 mg* Dilaudid (C-II; scored) Purdue Pharma Hydromorphone Hydrochloride Tablets (C-II) Tablets, extendedrelease Parenteral For injection, for preparation of IV 8 mg Exalgo (C-II) Mallinckrodt 12 mg Exalgo (C-II) Mallinckrodt 16 mg Exalgo (C-II) Mallinckrodt 250 mg Dilaudid-HP Lyophilized (C-II) Purdue Pharma http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUR 4 mg* Drugs.com Print Version infusion Injection 1 mg/mL* Dilaudid (C-II) Purdue Pharma Hydromorphone Hydrochloride Injection (C-II) 2 mg/mL* Dilaudid (C-II) Purdue Pharma Hydromorphone Hydrochloride Injection (C-II) 4 mg/mL* Dilaudid (C-II) Purdue Pharma Hydromorphone Hydrochloride Injection (C-II) 10 mg/mL (10, 50, or 500 mg)* Dilaudid-HP (C-II) Purdue Pharma Hydromorphone Hydrochloride Injection (C-II) Comparative Pricing This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays. Dilaudid 2MG Tablets (PURDUE PHARMA L.P.): 20/$23.99 or 30/$35.99 Dilaudid 4MG Tablets (PURDUE PHARMA L.P.): 20/$36.99 or 30/$49.97 Dilaudid-5 1MG/ML Liquid (PURDUE PHARMA L.P.): 473/$192.60 or 1419/$577.81 HYDROmorphone HCl 2MG Tablets (MALLINCKRODT PHARM): 20/$15.33 or 30/$22.99 HYDROmorphone HCl 4MG/ML Solution (HOSPIRA): 20/$39.83 or 30/$60.19 HYDROmorphone HCl 4MG Tablets (ROXANE): 20/$16.01 or 30/$24.01 HYDROmorphone HCl 8MG Tablets (MALLINCKRODT PHARM): 20/$29.51 or 30/$44.27 AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 9, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. † Use is not currently included in the labeling approved by the US Food and Drug Administration. References a. AHFS Drug Information 2006. McEvoy GK, ed. Hydromorphone. Bethesda, MD: American Society of Health-System Pharmacists; 2006:2108-10. http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUS Dilaudid 8MG Tablets (PURDUE PHARMA L.P.): 20/$57.77 or 30/$86.66 Drugs.com Print Version b. Endo Pharmaceuticals Inc. Hydromorphone hydrochloride tablets prescribing information. Chadds Ford, PA; 2003 May. d. Abbott Laboratories. Dilaudid (hydromorphone hydrochloride) injection, tablets, and suppositories prescribing information. North Chicago, IL; 2005 Mar. f. AHFS Drug Information 2006. McEvoy GK, ed. Opiate agonists general statement. Bethesda, MD: American Society of HealthSystem Pharmacists; 2006:2096-101. g. Bailey PL. Clinical Pharmacology and Applications of Opioid Agonists. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:105-7. h. In: Kliegman RM, Behrman RE, Jenson HB et al, eds. Nelson textbook of pediatrics. 18th ed. Philadelphia: Saunders; 2007:2978. i. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th ed. Glenview, IL: American Pain Society; 2004:1341. j. Purdue Pharma. Palladone (hydromorphone hydrochloride) extended-release capsules prescribing information. Stamford, CT; 2004 Nov 16. k. Srinivasan A, Budnitz D, Shehab N et al. Infant deaths associated with cough and cold medications—two states, 2005. MMWR Morb Mortal Wkly Rep. 2007; 56:1-4. [PubMed 17218934] l. Food and Drug Administration. Cough and cold medications in children less than two years of age. Rockville, MD; 2007 Jan 12. From FDA website. n. Purdue Pharma. Dilaudid (hydromorphone hydrochloride) oral liquid and tablets prescribing information. Stamford, CT; 2009 Oct 21. p. Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD003447. DOI: 10.1002/14651858.CD003447. r. Sessler CN, Varney K. Patient-focused sedation and analgesia in the ICU. Chest. 2008; 133:552-65. [PubMed 18252923] s. Jacobi J, Fraser GL, Coursin DB et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002; 30:119-41. [PubMed 11902253] t. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Manage. 2005; 29(5 Suppl):S57-66. v. Mallinckrodt. Exalgo (hydromorphone hydrochloride) extended-release tablets prescribing information. Hazelwood, MO; 2010 Nov. w. Food and Drug Administration. Exalgo (hydromorphone hydrochloride) extended-release tablets. Risk Evaluation and Mitigation http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUT o. Purdue Pharma. Dilaudid and Dilaudid-HP (hydromorphone hydrochloride) injection prescribing information. Stamford, CT; 2011 Jul . Drugs.com Print Version Strategy (REMS) document. Rockville, MD; 2010 Mar 24. From FDA website. x. Mallinckrodt. Exalgo (hydromorphone hydrochloride) extended-release tablets medication guide. Hazelwood, MO; 2010 Nov. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUU HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:630-9. http://www.drugs.com/monograph/hydromorphone-hydrochloride.html?printable=1[12/2/2014 2:53:33 PM] International Journal of Toxicology http://ijt.sagepub.com/ Final Report on the Safety Assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate International Journal of Toxicology 2001 20: 23 DOI: 10.1080/10915810152630729 The online version of this article can be found at: http://ijt.sagepub.com/content/20/3_suppl/23 Published by: http://www.sagepublications.com On behalf of: Additional services and information for International Journal of Toxicology can be found at: Email Alerts: http://ijt.sagepub.com/cgi/alerts Subscriptions: http://ijt.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://ijt.sagepub.com/content/20/3_suppl/23.refs.html >> Version of Record - Jan 1, 2001 What is This? Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQUV American College of Toxicology Final Report on the Safety Assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate1 munologic reactions would not be a concern. Because of the wide variety of product types in which these ingredients may be used, it is likely that inhalation may be a route of exposure. The available safety tests are not considered sufŽ cient to support the safety of these ingredients in formulations where inhalation is a route of exposure. Inhalation toxicity data are needed to complete the safety assessment of these ingredients where inhalation can occur. INTRODUCTION This report is a compilation of data concerning Benzyl Alcohol (CAS No. 100-51-6), Benzoic Acid (CAS No. 65-85-0), and Sodium Benzoate (CAS No. 532-32-1). Reviews of early literature (1920 – 1977) were prepared for the Food and Drug Administration (FDA) on Benzyl Alcohol and Benzoic Acid (Flavor and Extract Manufacturers’ Association 1984) and on Benzoic Acid and Sodium Benzoate (Informatics, Inc. 1972; Federation of American Societies for Experimental Biology [FASEB] 1973). This Cosmetic Ingredient Review (CIR) report includes relevant studies cited in the earlier reviews as well as recent animal and clinical studies. CHEMISTRY DeŽnition and Structure Benzyl Alcohol is an aromatic alcohol that conforms to the following formula (Wenninger, Canterbery, and McEwen 2000): Synonyms for Benzyl Alcohol include Benzenemethanol (Wenninger, Canterbery, and McEwen 2000), Phenyl-methanol, Phenylcarbinol, Phenylmethyl Alcohol (Food and Agricultural Organization of the United Nations/World Health Organization [FAO/WHO] 1994); Hydroxytoluene , ®-Hydroxytoluene, (Lewis 1993). Benzoic Acid is an aromatic acid that conforms to the following formula (Wenninger, Canterbery, and McEwen 2000): Received 15 May 2001; accepted 12 July 2001. Reviewed by the Cosmetic Ingredient Review Expert Panel. Bindu Nair, former CIR ScientiŽ c Analyst and Writer, prepared this report. Address correspondence to Director, Cosmetic Ingredient Review, 1101 17th Street, NW, Suite 310, Washington, DC 20036, USA. 1 International Journal of Toxicology, 20(Suppl. 3):23 – 50, 2001 c 2001 Cosmetic Ingredient Review Copyright ° 1091-5818 /01 $12.00 + .00 Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 23 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVM Benzyl Alcohol is an aromatic alcohol used in a wide variety of cosmetic formulations as a fragrance component, preservative, solvent, and viscosity-decreasing agent. Benzoic Acid is an aromatic acid used in a wide variety of cosmetics as a pH adjuster and preservative. Sodium Benzoate is the sodium salt of Benzoic Acid used as a preservative, also in a wide range of cosmetic product types. Benzyl Alcohol is metabolized to Benzoic Acid, which reacts with glycine and excreted as hippuric acid in the human body. Acceptable daily intakes were established by the World Health Organization at 5 mg/kg for Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate. Benzoic Acid and Sodium Benzoate are generally recognized as safe in foods according to the U.S. Food and Drug Administration. No adverse effects of Benzyl Alcohol were seen in chronic exposure animal studies using rats and mice. Effects of Benzoic Acid and Sodium Benzoate in chronic exposure animal studies were limited to reduced feed intake and reduced growth. Some differences between control and Benzyl Alcohol– treated populations were noted in one reproductive toxicity study using mice, but these were limited to lower maternal body weights and decreased mean litter weights. Another study also noted that fetal weight was decreased compared to controls, but a third study showed no differences between control and Benzyl Alcohol – treated groups. Benzoic Acid was associated with an increased number of resorptions and malformations in hamsters, but there were no reproductive or developmental toxicty Ž ndings in studies using mice and rats exposed to Sodium Benzoate, and, likewise, Benzoic Acid was negative in two rat studies. Genotoxicity tests for these ingredients were mostly negative, but there were some assays that were positive. Carcinogenicity studies, however, were negative. Clinical data indicated that these ingredients can produce nonimmunologic contact urticaria and nonimmuno logic immediate contact reactions, characterized by the appearance of wheals, erythema, and pruritis. In one study, 5% Benzyl Alcohol elicited a reaction, and in another study, 2% Benzoic Acid did likewise. Benzyl Alcohol, however, was not a sensitizer at 10%, nor was Benzoic Acid a sensitizer at 2%. Recognizing that the nonimmuno logic reactions are strictly cutaneous, likely involving a cholinergic mechanism, it was concluded that these ingredients could be used safely at concentrations up to 5%, but that manufacturers should consider the nonimmunologic phenomena when using these ingredients in cosmetic formulations designed for infants and children. Additionally, Benzyl Alcohol was considered safe up to 10% for use in hair dyes. The limited body exposure, the duration of use, and the frequency of use were considered in concluding that the nonim- 24 COSMETIC INGREDIENT REVIEW Synonyms for Sodium Benzoate include sodium salt of benzenecarboxylic acid, sodium salt of phenylcarboxylic acid (FAO/WHO 1994). Physical and Chemical Properties Table 1 lists physical properties of Benzyl Alcohol and Benzoic Acid. Benzyl Alcohol is a combustible liquid. When heated to decomposition it emits acrid smoke and fumes (Lewis 1993). Benzoic Acid burns rapidly in oxygen and is combustible when exposed to heat or  ame. It can react with oxidizing materials. When heated to decomposition it emits acrid smoke and fumes (Lewis 1993). When Sodium Benzoate is heated to decomposition it emits toxic fumes of Na2 O. It is cautioned that oral doses of 8 to 10 g can cause nausea and vomiting; small doses have little or no effect (Lewis 1993). Method of Manufacture Benzyl Alcohol is found naturally in many foods such as apricots, snap beans, cocoa, cranberries, mushrooms, and honey (Flavor and Extract Manufacturers’ Association 1984). Benzyl Alcohol is also found in the essential oil of many plants including jasmine, hyacinth, and ylang-ylang (Lewis 1993). Large scale production of Benzyl Alcohol is achieved by the action of sodium or potassium carbonate on benzyl chloride (Budavari 1989). Benzoic Acid is also found naturally in many foods such as apricots, snap beans, cocoa, cranberries, mushrooms, and honey (Flavor and Extract Manufacturers’ Association 1984). Analytical Methods The Benzoic Acid content of cosmetic formulations can be determined by high-performanc e liquid chromatography (Gagliardi et al. 1984). Impurities The Cosmetic, Toiletry, and Fragrance Association (CTFA) lists the following speciŽ cations for Benzyl Alcohol, 0.2% maximum aldehyde (as benzaldehyde) and 0.005% maximum sulfated ash. Other characteristics such as chlorinated compounds, speciŽ c gravity, refractive index, and distilling range must match the standards of the National Formulary (NF) or United States Pharmacopeia (USP) (Nikitakis and McEwen 1990). CTFA speciŽ cations for Benzoic Acid and Sodium Benzoate with regard to congealing range, equivalent weight, water content, and alkalinity follow standards set by the USP and NF (Nikitakis and McEwen 1990). USE Cosmetic Benzyl Alcohol Benzyl Alcohol is used in cosmetics as a fragrance component, preservative, solvent, and viscosity-decreasing agent (Wenninger, Canterbery, and McEwen 2000). In January 1998, Benzyl Alcohol was reported to be used in 322 cosmetic formulations (FDA 1998). (See Table 2.) Concentration of use data TABLE 1 Physical properties of Benzyl Alcohol and Benzoic Acid Property Appearance Odor/taste Molecular weight Boiling point (± C) Melting point (± C) Density Solubility Flash point (± F) Refractive index Benzyl alcohol Benzoic acid Liquid — Faint aromatic odor, sharp burning taste 108.14 Da 205.3 ¡15.3 1.0419 Water; alcohol; ether; acetone; benzene 213 (CC) ¡0.002 White crystalline powder — 122.12 Da 249 122.13 1.0749, 1.2659 Alcohol; ether; acetone; chloroform; benzene 250 (CC) — Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 Reference Budavari 1989 Lewis 1993 Budavari 1989 Lide 1993 Lide 1993 Lide 1993 Lide 1993 Lide 1993 Lewis 1993 Nikitakis and McEwen 1990 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVN Synonyms for Benzoic Acid include Benzeneformic acid, Benzenemethanoic Acid, Benzoate, Carboxybenzene, Dracylic Acid, Phenylformic Acid, Benzenecarboxylic Acid, Phenylcarboxylic Acid (Budavari 1989; Lewis 1993). The sodium salt of Benzoic Acid, Sodium Benzoate conforms to the following formula (Wenninger, Canterbery, and McEwen 2000): 25 BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE TABLE 2 Frequency of use of Benzyl Alcohol (FDA 1998) Baby shampoos Baby lotions, oils, powders, creams Other baby products Bath oils, tablets, and salts Other bath preparations Eyeliner Eye shadow Eye makeup remover Mascara Other eye makeup preparations Colognes and toilet waters Other fragrance preparations Hair conditioners Hair sprays (aerosol Ž xatives) Rinses (noncoloring) Shampoos (noncoloring) Tonics, dressings, and other hair grooming aids Hair dyes and colors Hair rinses (coloring) Hair color sprays (aerosol) Other hair-coloring preparations Face powders Foundations Lipstick Makeup bases Other makeup preparations Deodorants (underarm) Feminine hygiene deodorants Other personal cleanliness products Aftershave lotion Preshave lotions (all types) Shaving cream Cleansing Face and neck skin care (excluding shaving) Body and hand skin care (excluding shaving) Foot powders and sprays Moisturizing Night skin care Paste masks (mud packs) Skin fresheners Other skin care preparations Suntan gels, creams, and liquids Other suntan preparations 1998 total for Benzyl Alcohol No. of formulations in category 21 53 29 124 159 514 506 84 167 120 656 148 636 261 40 860 549 1572 33 4 59 250 287 790 132 135 250 4 291 216 14 139 653 263 796 35 769 188 255 184 692 136 38 Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 No. containing ingredient 5 3 2 2 3 3 4 10 5 4 1 2 7 4 1 7 14 130 18 1 2 1 2 1 1 2 1 2 1 4 1 3 10 12 16 2 8 3 4 4 11 2 3 322 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVO Product category COSMETIC INGREDIENT REVIEW are no longer reported to the FDA (FDA 1992). Data from FDA (1984) indicated that Benzyl Alcohol was used at concentrations ·25%. Studies cited in the Clinical Assessment of Safety section of this report tested mascara formulations containing 0.65% Benzyl Alcohol (Hill Top Research 1997a, 1997b). Benzoic Acid and Sodium Benzoate Benzoic Acid is used as a pH adjustor and preservative and Sodium Benzoate is used as a preservative (Wenninger, Canterbery, and McEwen 2000). In January 1998, Benzoic Acid and Sodium Benzoate were reported to be used in 223 and 156 cosmetic formulations, respectively (FDA 1998) (See Table 3). Data from 1984 indicated that although Benzoic Acid and Sodium Benzoate were used at up to 5% and 25%, respectively, the majority of use of both ingredients was at ·1% (FDA 1984). Studies cited in the Clinical Assessment of Safety section of this report tested eye shadow formulations containing 0.1% Benzoic Acid (Biosearch Inc. 1991; TKL Research 1991) and liquid/powder foundation formulations containing 0.2% Benzoic Acid (Biosearch Inc. 1992a, 1992b, 1992c, 1992d; Education and Research Foundation 1992). International Benzyl Alcohol The European Union (EU) has stipulated that when used as a preservative, Benzyl Alcohol is restricted to a maximum concentration of 1% (EU 1995). Benzyl Alcohol is listed in the Japanese Comprehensive Licensing Standards of Cosmetics by Category (CLS). Benzyl Alcohol, which conforms to the speciŽ cations of the Japanese Standards of Cosmetic Ingredients, has precedent for use without restriction in the following CLS categories: soaps, face cleansing products, shampoos, hair rinses, hair coloring preparations, and eye creams, eyeshadows, and mascaras. There has been precedent for use of Benzyl Alcohol at concentrations up to 5% in the following categories: hair care products, creams and milky lotions, shaving creams and lotions, suntan and sun cream, lotion and oil formulations, shaving lotions, cosmetic oils, powders, foundations, perfumes, packs, nail creams, nail enamels, nail makeup removers, cheek color products, eyebrow products, and bath preparations. There has been no precedent regarding its use in eyeliners, lipsticks, lip creams, and dentifrices (Santucci 1999). According to NotiŽ cation 990 of the Pharmaceutical and Medical Safety Bureau of the Japan Ministry of Health and Welfare, issued September 29, 2000, Benzyl Alcohol is not prohibited or restricted (beyond the limits in the CLS discussed above) in its use beyond a basic obligation of manufacturers to use all ingredients in a manner which guarantees safety (Japan Ministry of Health and Welfare 2000). Benzoic Acid and Sodium Benzoate The EU has stipulated that when used as preservatives, Benzoic Acid, its salts and esters are restricted to a maximum concentration of 0.5% (acid) (EU 1995). Benzoic Acid and Sodium Benzoate are listed in the CLS and must conform to the speciŽ cations of the Japanese Standards of Cosmetic Ingredients. Precedent to use Benzoic Acid at concentrations up to 0.2% has been established in all CLS cosmetic categories except eyeliners. Precedent to use Sodium Benzoate at concentrations up to 1% has been established in all CLS categories (Santucci 1999). According to NotiŽ cation 990 of the Pharmaceutical and Medical Safety Bureau of the Japan Ministry of Health and Welfare, issued September 29, 2000, use of Benzoic Acid is restricted to 0.2 g per 100 g of any cosmetic formulation (Japan Ministry of Health and Welfare 2000). Noncosmetic Benzyl Alcohol Benzyl Alcohol is approved for use as a food additive (Rothschild 1990). In 1979, the Joint Expert Committee on Food Additives (JECFA) of the World Health Organization (WHO) established an acceptable daily intake (ADI) level of 0 to 5 mg/kg body weight. This ADI concerned Benzyl Alcohol and benzyl benzoate and “applies to the benzyl/benzoic moiety related to benzoic acid representing total benzoate from all food additive sources” (FAO/WHO 1994). Benzyl Alcohol can be used as an active ingredient in overthe-counter (OTC) drug preparations (Wenninger, Canterbery, and McEwen 2000). In 1982, the FDA Panel on OTC Dentifrices and Dental Care Products recommended that Benzyl Alcohol not be used in the treatment of dental pain in children younger than 2 years of age (Grad and Grushka 1986). In human pain studies, Benzyl Alcohol was an effective local anesthetic. Subjects complained of less pain after receiving intramuscular (IM) injections of various medications that contained Benzyl Alcohol (Wightman and Vaughan 1976; Gouyette et al. 1982; Rasmussen, Zachmann, and Nilsson 1989; Frenken, van Lier, and Koene 1994; Jørgensen 1994; Williams and Howe 1994). Benzoic Acid and Sodium Benzoate Benzoic Acid and Sodium Benzoate both have the status “generally recognized as safe” (GRAS) (Rothschild 1990). In 1983, the JECFA established an ADI of 0 to 5 mg/kg body weight for Benzoic Acid, its salts, benzyl acetate, alcohol and benzoate (FAO/WHO 1994). Benzoic Acid (USP) is a component of benzoic and salicylic acid ointments (USP), a topical antifungal agent (Taylor 1988). Since the late 1970s, Sodium Benzoate has been used in the treatment of hyperammonemia in patients with inborn errors of the urea cycle. The treatment is based on the synthesis and excretion of hippurate as an alternative pathway to eliminate nitrogen versus urea synthesis (Brusilow et al. 1979, 1980). An extensive review of this therapeutic use of benzoates by Tremblay and Qureshi (1993) noted that laboratory models have yet to corroborate clinical Ž ndings. Further, animal studies demonstrated that Sodium Benzoate, at some doses, potentiated Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVP 26 27 BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE Product category Benzoic Acid Other baby products Bath oils, tablets, and salts Bubble baths Other bath preparations Eye shadow Eye makeup remover Mascara Other eye makeup preparations Other fragrance preparations Hair conditioners Hair straighteners Shampoos (noncoloring) Tonics, dressings, and other hair grooming aids Other hair preparations Blushers (all types) Face powders Foundations Lipstick Makeup bases Other makeup preparations Cuticle softeners Other manicuring preparations Mouthwashes and breath fresheners Other oral hygiene products Bath soaps and detergents Aftershave lotion Shaving cream Cleansing Face and neck skin care (excluding shaving) Body and hand skin care (excluding shaving) Moisturizing Night skin care Paste masks (mud packs) Skin fresheners Other skin care preparations Suntan gels, creams and liquids Indoor tanning preparations 1998 total for Benzoic Acid Sodium Benzoate Bath oils, tablets and salts Other bath preparations Eyeliner Eye shadow Eye makeup remover Other eye makeup preparations Hair conditioners Hair sprays (aerosol Ž xatives) No. of formulations in category No. containing ingredient 29 124 200 159 506 84 167 120 148 636 63 860 549 276 238 250 287 790 132 135 19 61 49 6 385 216 139 653 263 796 769 188 255 184 692 136 62 1 2 26 32 5 3 1 1 2 2 1 3 5 2 1 3 7 37 1 1 1 1 12 2 8 4 2 12 2 8 8 1 3 9 9 2 3 223 124 159 514 506 84 120 636 261 1 1 3 4 5 2 5 24 (Continued on next page) Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVQ TABLE 3 Frequency of use of Benzoic Acid and Sodium Benzoate (FDA 1998) 28 COSMETIC INGREDIENT REVIEW Product category Hair straighteners Rinses (noncoloring) Shampoos (noncoloring) Tonics, dressings, and other hair grooming aids Wave sets Hair bleaches Face powders Other makeup preparations Dentifrices Mouthwashes and breath fresheners Other oral hygiene products Bath soaps and detergents Deodorants (underarm) Other personal cleanliness products Aftershave lotion Shaving cream Other shaving preparation products Cleansing Face and neck skin care (excluding shaving) Body and hand skin care (excluding shaving) Moisturizing Night skin care Paste masks (mud packs) Skin fresheners Other skin care preparations 1998 total for Sodium Benzoate ammonia toxicity in mice (O’Connor et al. 1982, 1989) and rats (Maswoswe et al. 1986). Conditions for benzoate therapy typically include reduced nitrogen intake and a priming intravenous (IV) dose of 250 mg/kg administered over 0.5 to 2 hours, followed by an additional 250 to 500 mg/kg/day administered with meals (Tremblay and Qureshi 1993). GENERAL BIOLOGY Absorption, Distribution, Metabolism, and Excretion The available human absorption, distribution, metabolism, and excretion data were sufŽ ciently extensive that animal data were not included. Therefore, the following section cites clinical studies only. Benzyl Alcohol When metabolized, Benzyl Alcohol is converted to Benzoic Acid by simple oxidation (Flavor and Extract Manufacturers’ Association 1984). The relevant data, therefore, relate to Benzoic Acid and Sodium Benzoate. No. of formulations in category No. containing ingredient 63 40 860 549 55 113 250 135 38 49 6 385 250 291 216 139 60 653 263 796 769 188 255 184 692 1 3 20 5 1 2 2 1 6 1 2 1 1 4 15 7 1 5 4 8 6 3 2 1 9 156 Benzoic Acid and Sodium Benzoate Even after administration of high doses of Sodium Benzoate, the hourly excretion of hippuric acid increases to a maximum and then remains constant until all but a small portion is eliminated (Quick 1931). The rate of hippuric acid formation in humans after oral administration of 5 g Benzoic Acid increased with the concomitant administration of glycine. Bridges et al. (1970) reported on the metabolism of Benzoic Acid in humans and various animal species. The FASEB (1973) and GRAS reports (Informatics 1972) reported that Benzoic Acid and Sodium Benzoate are rapidly absorbed from the gastrointestinal tract of mammals and conjugated with glycine in the liver. The resulting hippuric acid is excreted in the urine rapidly (75% to 100% of the dose is excreted within 6 hours; the remaining dose is excreted within 2 to 3 days). The availability of glycine was the rate-limiting factor in the formation of hippuric acid. When insufŽ cient glycine was available benzoyl glucuronide was formed. Feldman and Maibach (1970) reported that 42.6% § 16.5% of a dermally applied [14 C]-Benzoic Acid dose (4 ¹g/cm2 ; in acetone) was excreted in the urine within 24 hours. When applied Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVR TABLE 3 Frequency of use of Benzoic Acid and Sodium Benzoate (FDA 1998) (Continued) BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE Cellular Effects Benzyl Alcohol Benzyl Alcohol is a membrane “ uidizer” that affects lipid bilayer structure (Ebihara et al. 1979). It has been demonstrated to act on membranes of erythrocytes (Burgen et al. 1970; Bass´e et al. 1992) and hepatocytes (Gordon et al. 1980). Studies reported Benzyl Alcohol to increase activity of membrane-bound Ca2C -dependent enzymes such as adenylate cyclase (Voorheis and Martin 1982; Martin, McConkey, and Stokes 1985; Needham and Houslay 1988) and thiol proteinase (Ahkong et al. 1980). Conversely, Benzyl Alcohol inhibited activities of various glycosyltransferases of the rat liver Golgi membrane (Mitranic, Boggs, and Moscarello 1982). The activities of erythrocyte-bound p-nitrophenylphosphatas e and acetylcholinesterase were increased at some concentrations of Benzyl Alcohol and inhibited by others (Tanaka 1984). The effect on cell membranes was considered the mechanism by which Benzyl Alcohol inhibited lymphocyte-mediated cytolysis in vitro (Kemp and Berke 1973a, 1973b). Benzyl Alcohol induced time-, dose-, and temperaturedependent hemolysis of erythrocytes (Ohmiya and Nakai 1978). Benzoic Acid and Sodium Benzoate Sodium Benzoate inhibited activity of D-amino acid oxidase (Brada and Bulba 1980; London and Gabel 1988). In an in vitro study, Sodium Benzoate at doses ¸500 ¹g/ml suppressed the activities of marker enzymes in the mitochondria and cytosol of rat liver hepatocytes. Suppression of DNA synthesis was noted at 100 ¹g/ml (Oyanagi et al. 1987). Radical Scavenging Activity Benzoic Acid and Sodium Benzoate Benzoic Acid and Sodium Benzoate are recognized as hydroxyl radical scavengers and researchers have reported that benzoates inhibited mechanisms that generated free radicals. In in vitro studies, benzoates reduced the cytotoxicity of drugs/chemicals such as hydroxyure a in L5178Y cells (Przybyszewski and Malec 1982), 6-hydroxydopamin e in mouse pancreatic islets (Grankvist, Sehlin, and Taeljedal 1986), doxorubicin in a Doxsensitive human ovarian cancer cell line (Cervantes et al. 1988), and inhibited argemone oil – induced enzymatic and nonenzymatic hepatic lipid peroxidation in rat cells (Upreti, Das, and Khanna 1991). In other in vitro studies, benzoates inhibited some chemical-induced DNA lesions (Kaneko et al. 1984; Sugioka et al. 1984; Daniel, Mao, and SafŽ otti 1983; Mahmood et al. 1993). In in vivo studies using rats, Sodium Benzoate had a protective effect against gentamicin-induced renal failure (Walker and Shah 1988), and demonstrated a dose-dependent reduction in ethanol-induced gastric lesions (Evangelista and Meli 1985). However, Rotstein and Slaga (1988) reported that the scavenging activity of Sodium Benzoate did not signiŽ cantly inhibit tumor progression when tested in a murine skin multistage carcinogenesis model. Benzoic Acid and Sodium Benzoate also inhibited immune responses that relied on reactive oxygen intermediates such as natural killer cells (Suthanthiran et al. 1984), some neutrophil activity (Cheung, Archibald, and Robinson 1984; Thomas, Smith, and Pang 1991; Kumar, Anand, and Ganguly 1993), and phagocytes (Weitzman and Stossel 1982; Weitberg et al. 1985). However, Kraut, Segal, and Sagone (1982) reported that granulocyte aggregation in response to cell membrane injury was not affected by oxygen radical scavengers. Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVS in petrolatum, 60.5% of the dose was absorbed (Bronaugh and Franz 1986). By quantifying 24-hour urine excretion, Rougier et al. (1986) demonstrated that dermal application of 1000 nmol [14 C]Benzoic Acid (10¡3 ¹Ci/nmol) produced the following penetration scale: forehead > abdomen > thigh > chest > arm > back. The 4-day penetration through the forehead (27.65 § 3.61 nmol/cm2 ) was three times greater than absorption through the back (8.55 § 1.32 nmol/cm2 ). Benzoic Acid had been applied to two sites of each body area; one site was tape stripped to determine the amount of test material in the stratum corneum. The quantiŽ ed values from the urine were comparable to predicted values estimated from the tape stripping. In a study investigating the effects of aging on dermal absorption, Roskos, Maibach, and Guy (1989) applied [14 C]-Benzoic Acid (in acetone) to the forearm of two groups of panelists, “young” (22 to 40 years) and “old” (>65 years). A 24-hour protective patch was placed on the skin and the site was washed after patch removal. A second protective patch was then applied and remained in place until day 7. Analysis of 7-day urine excretion indicated that 36.2% § 4.6% of the applied dose was absorbed by the young panelists, whereas 19.5% § 1.6% was absorbed by the old panelists. The difference was statistically signiŽ cant ( p < .01). Kubota and Ishizaki (1991) demonstrated that biotransformation of Benzoic Acid to hippuric acid follows saturable or Michaelis-Menten kinetics in humans following ingestion of Sodium Benzoate. No statistical difference ( p > .05) was found by Lotte et al. (1993) in the percutaneous absorption of Benzoic Acid by Asian, Black, and Caucasian panelists. [14 C]-Benzoic Acid (1 ¹mol/ cm2 ) was applied to two sites of the upper arm and the sites were washed after 30 minutes of contact. (The two applications occurred on contralateral arms and were made 48 hours apart.) Urine was collected for 24 hours and one site was tape stripped to measure Benzoic Acid in the stratum corneum. Amounts absorbed were 1.43% § 0.27% by Asian skin, 1.07% § 0.17% by black skin, and 1.2% § 0.19% by Caucasian skin. Gregus et al. (1993, 1996) reported that both lipoic acid (1993) and valproic acid (1996) reduced the clearance of Benzoic Acid in rats that had been “loaded” with glycine. Both acids reduced the availability of hepatic coenzyme A that is needed for the adenosine triphosphate (ATP)-dependent conjugation with glycine. 29 COSMETIC INGREDIENT REVIEW Glycine Competition Benzoic Acid and Sodium Benzoate The metabolism of the benzoates depletes glycine concentrations and can therefore alter the glycine-dependent metabolism of other compounds. Amsel and Levy (1969) and Levy, Amsel, and Elliott (1969) demonstrated that Benzoic Acid or Sodium Benzoate successfully competed with aspirin for glycine, resulting in increased concentration and persistence of salicylic acid in the body. Almost total inhibition of salicyluric acid formation in humans was achieved using either 2.7 g Benzoic Acid or 3.2 g Sodium Benzoate. The GRAS report (Informatics Inc. 1972) cited studies in which ingestion of Sodium Benzoate reduced the glycinedependent formation of creatine, glutamine, urea, and uric acid and increased the effects of procaine, lidocaine, cocaine, tetracaine, and dibucaine. Under conditions of severely restricted  uid and salt intake, benzoates increased and prolonged the concentration of serum penicillin. Enzyme Inhibition Benzyl Alcohol Messiha (1991) reported that short-term intake of 2% Benzyl Alcohol in the drinking water resulted in an inhibition of hepatic alcohol dehydrogenase and mitochondrial aldehyde dehydroge nase isoenzyme activities in female rats. The effects were not noted in male rats. Compared to control rats, Benzyl Alcohol noncompetitively inhibited activity of hepatic alcohol dehydrogenase (L-ADH) of rats maintained for a short term on 5% ethanol (Messiha, Pasi, and Morniroli 1992). ANIMAL TOXICOLOGY Acute Oral Toxicity Benzyl Alcohol The literature review by the Flavor and Extract Manufacturers’ Association (1984) cited the following oral LD50 values for Benzyl Alcohol: mouse 1580 mg/kg; rat 1230 to 3200 mg/kg (four studies), and rabbit 1040 mg/kg. Benzoic Acid and Sodium Benzoate The RTECS (Registry of Toxic Effects of Chemical Substances) cited that the human low lethal oral dose of Benzoic Acid was 500 mg/kg (RTECS 1995). The oral LD50 of Benzoic Acid in mice was 1996 mg/kg (Flavor and Extract Manufacturers’ Association, 1984). In rats, the oral LD50 for Benzoic Acid was 2000 to 2500 mg/kg, for Sodium Benzoate it was 2100 to 4070 mg/kg. The LD50 of Sodium Benzoate in rabbits and dogs was 2000 mg/kg. The oral LD100s for Benzoic Acid for rabbits, cats, and dogs were 1520 to 2000, 2000, and 2000 mg/kg, respectively (FASEB 1973). Short-Term Oral Toxicity Benzyl Alcohol In a gavage study by the National Toxicology Program (NTP 1989), technical grade Benzyl Alcohol (99% pure) in corn oil at doses of 125, 250, 500, 1000, or 2000 mg/kg was administered to groups of 10 F344/N rats and B6C3F1 mice (5 of each sex). Animals were dosed 5 days a week for 16 days (total of 12 doses). Feed and water were provided ad libitum. On days 8 and 9, both rats and mice of the 125-mg/kg group received doses that were 10-fold too high. All rats that received 2000 mg/kg and two of Ž ve males and three of Ž ve females that received 1000 mg/kg Benzyl Alcohol died before the end of the study. Rats of the two highest dose groups had blood around the nose and mouth, subcutaneous hemorrhages, and blood in the urinary and gastrointestinal tracts. Final body weight of male rats of the 1000 mg/kg group was 18% less than that of vehicle controls. Lethargy was observed in rats of the two highest dose groups; rough coats were noted in males of the 500- and 1000-mg/kg groups and in females of the 250- and 500-mg/kg groups. No compound-related histopathologic changes were noted. All mice that received 2000 mg/kg and one of Ž ve males and two of Ž ve females that received 1000 mg/kg Benzyl Alcohol died before the end of the study. Lethargy and rough coats were noted in males that received ¸500 mg/kg and in females that received ¸1000 mg/kg. Blood in the urinary bladder was noted at necropsy in mice of the two highest dose groups. No compoundrelated histopathologic changes were noted (NTP 1989). Reviewing this study, the United States Environmental Protection Agency (EPA) determined that the lowest-observableadverse-effect level (LOAEL) was ·500 mg/kg for male rats, and ·250 mg/kg for female rats. EPA determined that the noobservable-adverse-effect level (NOAEL) was ·250 mg/kg for male mice and ·500 mg/kg for female mice (EPA 1989). Benzoic Acid and Sodium Benzoate Fujitani (1993) fed groups of 10 F344/N rats and B6C3F1 mice (5 of each sex) 1.81%, 2.09%, or 2.40% (rats) or 2.08%, 2.50%, or 3.00% (mice) Sodium Benzoate for 10 days. The doses were selected based on earlier reports that repeated dosing with 2.5% Sodium Benzoate was lethal to rats. One male rat of the high-dose group had signs of “hypersensitivity” and died on day 8. Rats of the mid- and high-dose groups had signiŽ cantly reduced mean body weight as compared to nontreated controls. Relative liver and kidney weights, as well as serum concentrations of albumin and total protein, were signiŽ cantly increased in male rats of the mid- and highdose group and in female rats of the high-dose group. Serum ° -glutamyltranspeptidase activity was signiŽ cantly increased in males and signiŽ cantly decreased in females of the high-dose group. Serum cholesterol was signiŽ cantly decreased in males of the high-dose group and in all dosed females as compared to controls. Changes in other parameters such as serum phospholipid Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVT 30 BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE Subchronic Oral Toxicity Benzyl Alcohol Groups of 20 F344/N rats and B6C3F1 mice (10 of each sex) received 50, 100, 200, 400, or 800 mg/kg Benzyl Alcohol, 5 days a weeks for 13 weeks (NTP 1989). Experimental conditions were the same as in the 16-day study. The death of Ž ve rats was attributed to rupture caused by the gavage procedure. Gavagerelated deaths were considered to result from the trauma of the gavage procedure combined with the neurotoxic/anesthetic effect of the compound. Aside from these, four male rats and one female of the 800-mg/kg group, as well as one female of the 400-mg/kg group and one male of the 200-mg/kg group died on study. The 800-mg/kg group had signs of neurotoxicity, including staggering, labored breathing, and lethargy after dosing. Blood around the nose and mouth was noted in 5 of 10 males of this group after week 8. Compared to vehicle controls, Ž nal mean body weights were 7% and 5% smaller, respectively, in male and female rats of the highest dose group. At histopathologic evaluation, lesions observed in rats of the highest dose group included necrosis of the dentate gyrus of the hippocampus in 7 of 7 males and 9 of 9 females; skeletal muscle necrosis in 5 of 10 males, thymic congestion, hemorrhage, and atrophy in 8 of 10 males, and nephrosis in 6 of 9 males. Renal lesions were similar to those noted in age-related spontaneous renal disease. Nine of 10 deaths (mice) were attributed to the gavage procedure. Final mean body weights of females of the 400- and 800-mg/kg groups were 5% and 8% lower, respectively, than the vehicle control. Staggering was noted during the Ž rst and second weeks of dosing in mice of the high-dose group. No compound-related histopathologic alterations were observed. A Sendai virus infection was suspected (NTP 1989). Reviewing the 91-day study, the EPA extrapolated the high dose for rats and mice into human doses of 84 and 39 mg/kg/day, respectively (for a 70-kg person). The EPA determined the NOAEL was 143 mg/kg for female rats, “which were the more sensitive sex.” Using this level, and applying an uncertainty factor of 100 (10 for interspecies extrapolation multiplied by 10 to protect unusually sensitive individuals), resulted in a human reference dose (RfD) for subchronic oral exposure of 1.43 mg/kg/day, which was rounded to 1 mg/kg/day. The subchronic or partial lifetime RfD was described as “an estimate of an exposure level which would not be expected to cause adverse effects when exposure occurs during a limited time interval, i.e., for an interval which does not constitute a signiŽ cant portion of the lifespan” (EPA 1989). Benzoic Acid and Sodium Benzoate Subchronic oral studies on the benzoates which were cited in the GRAS report (Informatics Inc. 1972) and in the literature review by the Flavor and Extract Manufacturers’ Association (1984) are summarized in Table 4. Reviewing the studies, the GRAS report (Informatics Inc. 1972) concluded that “ : : : at a level of approximately 1%, the benzoates are at maximum nontoxic level; higher than this, they result in decreased food intake, depressed growth, and toxic effects on test animals.” Despite feed consumption comparable to controls, signiŽ cant reduction in weight gain was noted in mice treated for 3 months with 80 mg/kg/day Benzoic Acid (Shtenberg and Ignat´ev 1970), and in rats treated for 90 days with 8% Sodium Benzoate (Deuel et al. 1954). Chronic Oral Toxicity Benzyl Alcohol Groups of 100 F344/N rats (50 each sex) were dosed with 200 or 400 mg/kg Benzyl Alcohol in corn oil, 5 days per week for 103 weeks. Groups of 100 B6C3F1 mice were dosed with 100 or 200 mg/kg Benzyl Alcohol following the same schedule. During week 80, mice were mistakenly dosed for four days Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVU and uric acid concentrations were sometimes signiŽ cant but were non – dose-dependent. Enlarged hepatocytes with glassy cytoplasm were noted at microscopic examination of tissues from males of the high-dose group. All mice of the high-dose group had signs of “hypersensitivity”; 3 of 10 had convulsions and 2 of the 3 (both females) died before the end of the study. Mean body weights of mice of the treated groups were not signiŽ cantly different from untreated controls. A dose-dependent increase in absolute and relative liver weight was noted; the increase was signiŽ cant in mice of the high-dose group. Female mice of the high-dose group also had greater relative kidney weights. Serum cholesterol and phospholipid concentrations in male mice of the highdose group, serum cholinesterase activities in male mice of the mid- and high-dose groups, and serum ° -glutamyltranspeptidase activities of female mice of the mid-dose group were signiŽ cantly greater than those of the control group. No signiŽ cant changes were noted in serum concentrations of triglyceride, uric acid, and urea nitrogen, and activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or in the AST/ALT ratio. Enlargement, vacuolation and necrosis of hepatocytes were noted in male mice of the 3.0% group (Fujitani 1993). The GRAS report (Informatics, Inc. 1972) and the literature review by the Flavor and Extract Manufacturers’ Association (1984) cited several short-term oral studies of Benzoic Acid and Sodium Benzoate toxicity (Table 4). Supporting the above Ž ndings of Fujitani, Kreis et al. (1967) reported signiŽ cantly decreased weight gain in rats dosed with 1.1% Benzoic Acid for 35 days, and toxicity following Ž ve days of dosing with 3%. Studies in which approximately 2% Sodium Benzoate was administered for 4 to 8 weeks recorded: no adverse effects (Kramer and Tarjan 1962), lesions (Smyth and Carpenter 1948), or signiŽ cant weight reduction (noted in male rats only) (Fanelli and Halliday 1963). Severe reduction of growth rate was recorded at slightly larger doses of Sodium Benzoate (White 1941). Sodium Benzoate was toxic at 5% (Kieckebusch and Lang, 1960; Fanelli and Halliday 1963). 31 32 COSMETIC INGREDIENT REVIEW TABLE 4 Multiple-dose oral toxicity studies on Benzoic Acid and Sodium Benzoate Results/comments Benzoic Acid 40 Sprague-Dawley rats (20 each sex) received feed containing either 0.5% or 2% for 1 year. Some other groups also received sorbic acid Royal Wistar rats dosed with 3% for 1, 2, 3, or 5 days (»1500 mg/kg/day); basal diet followed for 19 to 30 days Royal Wistar rats (number not stated) dosed with 1.1% for 7, 14, or 35 days (»550 mg/kg/day) 100 mice (50 each sex) dosed for 3 months with 80 mg/kg/day (oral intubation) 50 mice (25 each sex) dosed with 40 mg/ kg/day; fed as a paste for 17 months, followed by 5 days of oral intubation Mice (number not stated) dosed with 40 or 80 mg/kg/day for 3, 8, or 18 months 20 rats (10 each sex) dosed with 40 mg/kg/ day; fed as a paste for 18 months, followed by 13 days of oral intubation Rats (number not stated) dosed with 40 or 80 mg/kg/day for 3, 8, or 18 months 50 Wistar rats (20 female, 30 male), 20 male Wistar rats, and 20 male Osborne-Mendel rats, dosed with 1.5% in feed for 18 months Four generations of Bayer-Elberfeid rats dosed with 0.5 or 1.0% in feed Sodium Benzoate 28 rats dosed with 5% in feed 12 Sherman rats (6 each sex) dosed with 2% or 5% in feed for 28 days Groups of 10 Sherman rats (5 each sex) dosed with 16 to 1090 mg/kg/day (four doses) for 30 days No effect noted at 0.5%; slight reduction of growth rate noted at 2%. No additive toxicity noted of Benzoic Acid plus sorbic acid Fourteen of 35 rats dosed for 5 days died; necrosis of parenchymal cells noted in brain in all 5-day treated rats and occasionally in 3-day treated rats SigniŽ cantly poor weight gain; no signs of neurotoxicity or pathological changes in the brain Weight gain in treated animals was 66% (females) and 71% (females) of gain in controls, values signiŽ cant; however, feed intake comparable Major Ž nding was a reduced response to physiological stress in treated animals compared to controls Negative effect on body weight and viability; treatment-related carcinogenic effects noted (not speciŽ ed); increased liver weights, enlarged spleens, ovaries, and lungs Developed increased tolerance to lethal doses of Sodium Benzoate; daily feed and water intake signiŽ cantly less for treated males; limited data reported No apparent effect on body weight or viability; no changes noted in parenchymatous organs; developed increased tolerance to lethal doses of Benzoic Acid Decreased feed intake and reduced growth Reference Ohno et al. 1978¤ Kreis et al. 1967 Kreis et al. 1967 Shtenberg and Ignat´ev 1970 Shtenberg and Ignat´ev 1970 Ignat´ev 1965 Shtenberg and Ignat´ev 1970 Ignat´ev 1965 Marquardt 1960 No adverse effect noted; increased life span noted in treated rats Kieckebusch and Lang 1960 Nineteen of 28 died within two weeks of dosing; remaining 9 died by end of week 3 Slight weight depression (signiŽ cant in males) noted at 2%; 5% toxic to all rats No toxic effects; increased body weight, reduced appetite (compared to control), noted. Lesions of adrenal glands, upper intestine, kidneys, liver, and spleen Kieckebusch and Lang 1960 Fanelli and Halliday 1963 Smyth and Carpenter 1948 (Continued on next page) Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSQVV Protocol 33 BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE TABLE 4 Multiple-dose oral toxicity studies on Benzoic Acid and Sodium Benzoate (continued) Protocol Results/comments Rats (numbers not stated) dosed with 1947 to 2195 mg/kg/day for 3 to 6 weeks Wistar rats dosed with 1.5% in feed for 6 or 8 weeks (after week 4, carotene was added to diet) Groups of 10 Sherman rats (5 each sex) dosed with 1%, 2%, 4%, and 8% in feed for 90 days White rats (number not stated) dosed with 1.5%, 2.0%, 2.5%, 3.0% in feed for unknown duration Severe reduction of growth rate White 1941 No signiŽ cant effect noted. Vitamin A content in liver and kidneys comparable to control Kramer and Tarjan 1962 No adverse effects at ·4%. At 8% reduced growth rate (feed consumption comparable to control), signiŽ cantly increased liver and kidney weight with lesions noted No effects noted in rats of ·2.5% groups; distinct growth reduction noted in rats of 3.0% group though feed intake was comparable to control. One third of rats of this group died Deuel et al. 1954 GrifŽ th 1929 Study completed since the GRAS report (see text), but included for completeness. with 375 (low-dose group) and 750 mg/kg (high-dose group) of ®-methylbenzyl alcohol. No adverse effects were apparent (NTP 1989). Mean body weights were comparable among dosed and vehicle control rats throughout the study. A number of accidental deaths was due to gavage procedures in female rats of both dose groups (17 deaths, low-dose; 13 deaths, high-dose) and in males of the 400 mg/kg group (14 deaths). Survival of female rats of the low- and high-dose groups was signiŽ cantly lower than that of vehicle controls after weeks 71 and 50, respectively. At the end of the study, 17 female rats survived from each of the dose groups, compared to 35 female vehicle-controls; 27 low-dose males and 24 high-dose males survived, compared to 28 male vehicle controls. Clinical signs characteristic of sialodacryoadenitis (cervical swelling, pink eyes, red exudate around eyes) were observed in dosed and vehicle-control rats. The diagnosis was conŽ rmed by serum analysis. Epithelial hyperplasia of the nonglandular stomach was noted in four high-dose males. A squamous cell papilloma was noted in 1 of 19 low-dose and 1 of 50 high-dose males. (It was not stated why only 19 low-dose male rats were examined.) No other compound-related clinical signs were observed. Mean body weight was comparable among dosed and vehicle control mice throughout the study. Survival of female vehicle controls was signiŽ cantly lower than that of the high-dose group after week 74 (female: vehicle control, 26/50; low dose, 32/50; high dose, 36/50). Corpora amylacea (foci of mineralization in the thalamus) was observed at an increased incidence in highdose mice (male: vehicle control, 15/49; low dose, 21/48; high dose, 22/50; female: 14/50; 15/48; 25/50), but was noted to be a common and spontaneously occurring lesion (NTP 1989). Reviewing the 2-year study, the EPA extrapolated the rat high dose to a human dose of 52 mg/kg/day (for a 70-kg person). The EPA determined that the LOAEL was 286 mg/kg for male rats. (Data from male rats were selected because mortality in female rats was not deŽ nitively associated with Benzyl Alcohol treatment.) Using this level, and applying an uncertainty factor of 1000 (10 for interspecies extrapolation, 10 to protect unusually sensitive individuals, and 10 to extrapolate a LOAEL to a NOAEL) resulted in a human RfD for chronic oral exposure of 0.286 mg/kg/day, which was rounded up to 0.3 mg/kg/day (EPA 1989). Benzoic Acid and Sodium Benzoate Table 4 summarizes chronic oral studies of the benzoates that were included in the GRAS report (Informatics Inc. 1972) and in the literature review by the Flavor and Extract Manufacturers’ Association (1984). Decreased feed intake and reduced growth were noted in rats fed 1.5% Benzoic Acid for up to 18 months (Marquardt 1960). No adverse effects were noted in most rat studies that used ·1% Benzoic Acid (Ohno et al. 1978; Ignat´ev 1965; Kieckebusch and Lang 1960). One 18-month study reported signiŽ cantly decreased feed and water intake in male rats fed 40 mg/kg/day (Shtenberg and Ignat´ev 1970). A dosedependent response to doses of Benzoic Acid well below 1% was noted in mice (Ignat´ev 1965; Shtenberg and Ignat´ev 1970). Acute Inhalation Toxicity Benzyl Alcohol Three groups of six Sherman rats were exposed for 4 hours to a 2000-ppm concentration of Benzyl Alcohol vapor in normal atmosphere. Nine rats died within 14 days of exposure. The investigators considered the compound to be a moderate hazard (Carpenter, Smyth, and Pozzani 1949). Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMM ¤ Reference COSMETIC INGREDIENT REVIEW Smyth, Carpenter, and Weil (1951) reported that rats could inhale air saturated with Benzyl Alcohol vapor for a maximum of 2 hours. Similar to the results reported by Carpenter, Smyth, and Pozzani (1949), inhalation at a concentration of 1000 ppm for 8 hours caused death of three of six animals within 14 days of exposure. Acute Parenteral Toxicity Benzyl Alcohol In a study to determine the toxicity of various vehicles, Montaguti, Melloni, and Cavalletti (1994) administered undiluted Benzyl Alcohol intravenously (via the tail vein) to groups of 10 mice (5 of each sex). Three different mice strains were used with the following dose ranges. CD2 F1 mice received 0.05 to 0.2 ml/kg, B6 D2 F1 mice received 0.05 to 0.4 ml/kg, and C57BL/6N mice received 0.025 to 0.1 ml/kg. All mice weighed between 14 and 18 g. The highest dose given did not exceed the LD50 . Body weight was determined prior to the start of dosing, and 1 week thereafter. Animals were observed for 14 days and postmortem examinations were performed on day 15. Blood samples were withdrawn from the abdominal aorta and analyzed for hemolysis and precipitation potential. Convulsions, dyspnea, and reduced mobility were noted at the Ž rst 24-hour observation in mice treated with all but the lowest dose of Benzyl Alcohol. Decreased body weight gain or slight decrease in body weight was noted in B6 D2 F1 and C57BL/6N mice treated with all but the lowest dose. Postmortem alteration included hyperemia and edema in most animals that had died during the observation period (number not reported). Occasional hemorrhagic foci were observed in the spleen of C57BL/6N mice from all dose groups that had survived Benzyl Alcohol treatment. The blood from Benzyl Alcohol – treated mice had a potential for hemolysis and precipitation. Undiluted Benzyl Alcohol was ranked the most toxic of the Ž ve vehicles tested, which included dimethyl sulfoxide, polyethylene glycol 400, dimethylformamide, and absolute ethanol (Montaguti, Melloni, and Cavalletti 1994). The literature review by the Flavor and Extract Manufacturers’ Association (1984) cites several earlier animal studies in which Benzyl Alcohol was administered as either single or multiple doses via the intraperitoneal, intravenous, and subcutaneous routes. Neurotoxicity Benzoic Acid and Sodium Benzoate In response to concerns about the role of food additives in cases of childhood hyperactivity, Crane and Lachance (1985) performed a neurobiological study of Sodium Benzoate using rats. Groups of eight Wistar dams received feed containing 0.1%, 0.5%, or 1.0% Sodium Benzoate beginning on gestation day (GD) 5 and continuing throughout pregnancy and lactation. The control group was untreated. At birth, the number of pups in each litter was equalized to eight. Locomotor activity of the pups was measured on various days. One pup from each litter was killed on days 9, 15, and 21 and the brain removed and examined. On day 22, pups were weaned onto the same diet as their respective dam. On day 24, one male pup from each litter was caged individually and monitored for spontaneous locomotor activity. Rats were killed on day 45 and brain concentrations of norepinephrine, dopamine, and serotonin were measured. No signiŽ cant difference was noted in feed intake and body weight gain of dams and pups of the treated groups compared to controls. No consistent differences in motor activity and monoamine concentrations were noted. Dermal Irritation Benzyl Alcohol In a primary irritation study 10% Benzyl Alcohol in squalane was applied (0.3 ml) in a 24-hour occlusive patch to the back of eight male albino rabbits. The sites had been clipped free of hair and were abraded in four rabbits. Sites were evaluated according to the Draize scoring system at the time of patch removal and 72 hours later. No irritation was observed; there was a score of zero on a scale of 0 to 8 (Shiseido Research Center 1972). In a cumulative irritation study, three male albino guinea pigs received a daily open application of 10% Benzyl Alcohol in squalane (0.3 ml) on the back for 3 successive days. Sites were evaluated for erythema and edema 24 hours after each application and scored on a scale of 0 to 4. Benzyl Alcohol in squalane received a cumulative score of 0.4, falling in the ·2.0 range of “none to weak irritant” (Shiseido Research Center 1972). A polyvinyl chloride (PVC) cup containing 10% w/v Benzyl Alcohol was fastened (using surgical tape) to the dorsal side of three male nude mice for 24 hours of contact. The mice (MF 1 h) were 4 weeks old and weighed 10 to 22 g. Following exposure, mice were immediately killed and specimens of the exposed areas and of an adjacent untreated area were taken for microscopic examination. The skin sections were Ž xed in formalin, dehydrated, and embedded in parafŽ n. Sections were stained with hematoxylin and eosin and scored using the Ingram & Grasso system. A typical section from Benzyl Alcohol– treated areas had severe compact hyperkeratosis, acanthosis, spongiosis, intracellular edema, and some areas of ulceration of the epidermis. The collagen bundles in the dermis appeared slightly fragmented and slight cell inŽ ltration of the area was noted. The Ž nal score for Benzyl Alcohol was 22, the modal score for at least three animals. Scores greater than 21 were considered “unacceptably severe damage.” The investigators acknowledged that male nude mice were not an ideal model for human skin; however, the study was done to establish the relative dermal tolerance of various penetration enhancers (Lashmar, Hadgraft, and Thomas 1989). Benzoic Acid and Sodium Benzoate RTECS (1995) cited that the human low toxic dermal dose of Benzoic Acid was 6 mg/kg. Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMN 34 BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Oral Studies Benzyl Alcohol In a study by Inveresk Research International Ltd. (1983), a group of 50 speciŽ c pathogen – free (SPF) CD-1 mice received 750 mg/kg/day Benzyl Alcohol (in distilled water) by gavage on GDs 7 to 14. (Earlier toxicity studies had determined the maximum tolerated dose was between 645 and 1300 mg/kg/day, and the 750-mg/kg/day dose was selected for the reproduction study.) The concurrent vehicle control had 50 mice. Mice were individually caged and feed and water were available ad libitum. Clinical observations were made daily. Maternal body weights were recorded prior to dosing, on day 18, and on postnatal day 3; the weight on day 7 determined the dose volume administered over the entire treatment period. Mice were allowed to deliver their litters and nurse the pups for 3 days. There were 18 compound-related deaths during the dosing period, and one on GD 15. Mice that died were discarded without necropsy. No procedure-related deaths (i.e., gavage error) were recorded. Body tremors, hunching, subdued behavior, prostration, ataxia, swelling, and/or cyanosis of the abdomen and piloerection were noted in mice that died during the study as well as those that produced litters. No signiŽ cant differences in reproductive and gestation indices, or in mean gestation length were noted between treated and control mice. A signiŽ cantly lower day 18 mean body weight and a marginally reduced maternal weight on postpartum day 3 were noted in dosed dams. Decreased mean litter mean pup weight was noted on postpartum days 1 ( p < .01) and 3 ( p < .001). On postpartum days 1 to 3, a decreased mean litter weight change ( p < .05) and decreased mean litter mean pup weight ( p < .001) were noted. No signiŽ cant differences were noted between treated and control pups in group litter viability. The investigators considered Benzyl Alcohol a suspect reproductive hazard and recommended further investigation (Inveresk Research International Ltd. 1983). Citing that study, the EPA (1989) noted that the extrapolated human dose (for a 70-kg person) was 58 mg/kg/day. In screening a new developmental toxicity assay, 50 pregnant CD-1 mice were gavaged on GDs 6 to 13 with Benzyl Alcohol at a rate of 750 mg/kg/day. The dose selected was the LD10 value determined in preliminary dose-Ž nding studies. Mice were allowed to deliver. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were measured. Nineteen (38%) of the dams of the Benzyl Alcohol group died prior to delivery; the corresponding vehicle control group (which received water) had no maternal death. (Mice that died were not necropsied.) Maternal weight was signiŽ cantly less changed in the Benzyl Alcohol group (6.2 § 3.6 g) as compared to controls (7.9 § 2.3 g). Viability in the Benzyl Alcohol group was 21 of 22 litters (controls had 29/29 viability) with an average of 10.0 liveborns per litter. Birth weight (1.6 g/pup) and 3-day weight gain (0.5 g/pup) for pups of the Benzyl Alcohol treatment group were signiŽ cantly less ( p < .05) than the corresponding values in controls (1.7 and 0.7 g/pup, respectively). The reduced birth weight was classiŽ ed as “some evidence of developmental toxicity.” The researchers noted the 10% false-negative rate for toluene, a “presumptive teratogen” (Hardin et al. 1987). A group of 50 pregnant SPF CD-1 albino mice was dosed with 550 mg Benzyl Alcohol/kg/day on GDs 6 to 15 by gavage. The Benzyl Alcohol was dissolved in corn oil; a vehicle-control group was maintained. Maternal status (survival, body weight changes), gestation index (length of gestation), reproductive index, postnatal survival, average litter weight, and average pup weight were comparable between treated and control animals (Environmental Health Research & Testing, Inc. 1986). Benzoic Acid and Sodium Benzoate Benzoic Acid at doses of 6, 30, 60, and 600 mg/kg was administered by stomach tube to groups of 21 to 24 pregnant golden hamsters on GDs 6 to 10. Two negative-control groups were maintained; one was treated with water, the other with 0.5% carboxymethylcellulose. A positive-control group received either thalidomide or aspirin. Dams were killed on day 16. No adverse effect in maternal survival was noted. A signiŽ cant number of resorptions was noted in hamsters which received ¸30 mg/kg. The incidence of fetal malformations reached statistical signiŽ cance at >600 mg/kg (Polish Academy of Sciences 1977). Benzoic Acid at doses of 5, 25, 50, and 500 mg/kg was administered by stomach tube to groups of 20 pregnant Wistar rats on GDs 6 to 15. Two negative-control groups were maintained; one was treated with water, the other with 0.5% carboxymethylcellulose (used to keep the Benzoic Acid in suspension). A positivecontrol group received either thalidomide or aspirin. Dams were killed on day 21. Maternal survival was similar for treated and control groups. A signiŽ cant number of resorptions was noted in rats which received ¸25 mg/kg. The incidence of fetal malformations in Benzyl Alcohol treated rats did not reach statistical signiŽ cance (Polish Academy of Sciences 1977). No evidence of teratogenicity was noted in rats administered 510 mg/kg of Sodium Benzoate by gavage on GDs 9 to 11 (Kimmel, Wilson, and Schumacher 1971). Sodium Benzoate at doses of 1.75, 8, 38, and 175 mg/kg was administered by oral intubation to groups of at least 20 pregnant Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMO Phototoxicity In Vitro Suspensions of human erythrocytes were incubated with Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate. Each material was tested at 10¡5 , 10¡4 , and 10¡3 mol/l. Erythrocytefree samples were also incubated with the test materials and used as controls. Following incubation, suspensions and samples were exposed to varying amounts of ultraviolet A (UVA) light from one of three sources. Hemolysis was measured as a function of absorbance of 550 nm light. None of the three substances produced signiŽ cant photohemolysis (Eberlein-Ko¨ nig et al. 1993). 35 Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 Chromosome aberration in Chinese hamster ovary cells (ABS in CHO) L5178Y tkC/tk¡ forward mutation in mouse lymphoma cell line Mammalian Cells L5178Y tkC/tk¡ forward mutation in mouse lymphoma cell line Bacterial Cells Ames: S. typhimurium TA 100 Ames: S. typhimurium TA 98, TA 100 Ames: S. typhimurium TA 98, TA 100, TA 1535, TA 1537 Assay TABLE 5 Benzyl Alcohol genotoxicity studies Negative 100; 333; 1000; 3333; 5000; 6666 ¹g/plate § S9 Results/comments Negative WEAK POSITIVE WEAK POSITIVE WEAK POSITIVE Negative POSITIVE Negative Negative Negative ·2500; lethal at 3500 ¹g/ml POSITIVE at 5000 ¹g/ml POSITIVE at 4500; lethal at 5000 ¹g/ml Negative ·2500; lethal at 3500 ¹g/ml Negative ·2500; lethal at 3500 ¹g/ml Negative ·2500; lethal at 3500 ¹g/ml Negative ·2500; lethal at 5000 ¹g/ml POSITIVE at 4500; lethal at 5000 ¹g/ml Negative ·2500; lethal at 3500 ¹g/ml Negative Negative Not stated [cells incubated with agent for 4 h, then plated to determine thymidine resistance] (¡) S9: 156.25; 312.5; 625; 1250; 2500; 5000 ¹g/ml 2500; 3000; 3500; 4000; 4500; 5000 ¹g/ml 250; 500; 1500; 2500; 3500 ¹g/ml 3200; 3400; 3600; 3800 ¹g/ml (C) S9: 250; 500; 1500; 2500; 3500 ¹g/ml 250; 500; 1500; 2500; 3500 ¹g/ml (¡) S9: 156.25; 312.5; 625; 1250; 2500; 5000 ¹g/ml 2500; 3000; 3500; 4000; 4500; 5000 ¹g/ml 250; 500; 1500; 2500; 3500 ¹g/ml (C) S9: 250; 500; 1500; 2500; 3500 ¹g/ml (¡) S9: [cells incubated with agent for 8 – 10 h] 160; 500; 1600; 5000 ¹g/ml 2000; 3000; 4000; 5000 ¹g/ml 250; 500; 1600; 3000 ¹g/ml 500; 1600; 3000; 4000 ¹g/ml (C) S9: [cells incubated with agent for 2 h] 50; 160; 500; 1600; 5000 ¹g/ml 500; 1600; 3000; 4000 ¹g/ml 1600; 3000; 4000; 5000 ¹g/ml 1600; 3000; 4000; 5000 ¹g/ml Negative 100, 250, 500, 1000 ¹g/plate Concentration/method t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMP 36 NTP 1989 NTP 1989 McGregor et al. 1988 NTP 1989 Ball Foxall-Van Aken, and Jensen 1984 Rogan et al. 1986 Reference Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 In vivo: Mammalian Replicative DNA synthesis (RDS) In vivo: Fruit Fly Sex-linked recessive lethal in Drosophila melanogaster SCE in CHO Sister Chromatid Exchange (SCE) in CHO ABS in CHO Male rats were killed at various times post dosing (300 or 600 mg/kg by either single oral gavage or SC injection) and hepatocytes obtained from perfused liver samples were incubated with [3 H]thymidine. RDS measured as percentage of [3 H]thymidine-incorporating cells relative to 2000 hepatocytes Following dosing either orally with 5000 ppm or injected with 8000 ppm, males were mated with untreated females, progeny observed as indication of mutagenic activity (¡) S9: 160; 500; 1600; 5000 ¹g/ml 2000; 3000; 4000; 5000 ¹g/ml 250; 500; 1600 ¹g/ml 500; 1600; 3000 ¹g/ml (C) S9: 50; 160; 500; 1600; 5000 ¹g/ml 500; 1600; 3000; 4000 ¹g/ml 1600; 3000; 4000 ¹g/ml 1600; 3000; 4000 ¹g/ml (¡) S9: [cells incubated with agent for 2 h, Brd-U added, then incubated for another 24 h] 16; 50; 160; 500; 1600 ¹g/ml 500; 750; 1000; 1250; 1500 ¹g/ml (C) S9: [cells incubated with agent for 2 h, Brd-U added after cells washed] 16; 50; 160; 500; 1600; 5000 ¹g/ml 500; 1600; 3000; 4000; 5000 ¹g/ml (¡) S9: 16; 50; 160; 500 ¹g/ml 500; 750; 1000; 1250 ¹g/ml (C) S9: 16; 50; 160; 500; 1600 ¹g/ml 500; 1600; 3000; 4000 ¹g/ml t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMQ 37 Negative; at various times cell viability for Benzyl Alcohol – treated cells was signiŽ cantly reduced Negative Questionable results WEAK POSITIVE at 4000 ¹g/ml Negative WEAK POSITIVE at 1250 ¹g/ml Negative ·1600; lethal at 5000 ¹g/ml WEAK POSITIVE; lethal at 5000 ¹g/ml Negative ·500; lethal at 1600 ¹g/ml WEAK POSITIVE; lethal at 1500 ¹g/ml Negative POSITIVE at 4000 ¹g/ml POSITIVE at 4000 ¹g/ml POSITIVE at 4000 ¹g/ml Negative Negative Negative Negative Uno et al. 1994 Foureman et al. 1994 Anderson et al. 1990 NTP 1989 Anderson et al. 1990 COSMETIC INGREDIENT REVIEW albino CD-1 outbred mice and Wistar albino rats on GDs 6 to 15. Groups of 21 to 22 pregnant hamsters were dosed with 3, 14, 65 or 300 mg Sodium Benzoate/kg on GDs 6 to 10. Groups of 10 Dutch-belted rabbits were artiŽ cially inseminated and then dosed by oral intubation with 2.5, 12, 54 or 250 mg Sodium Benzoate/kg on GDs 6 to 18. Dams were individually caged and feed and water were available ad libitum. Positive-control groups for mice, rats, and hamsters received aspirin. A positive-control group of rabbits received 6-aminonicotinamide. Sham groups for each animal type served as negative controls. Caesareans were performed on mice, rats, hamsters, and rabbits on days 17, 20, 14, and 29, respectively. Neither adverse effects on maternal or fetal survival nor a signiŽ cant increase in fetal abnormalities in either soft or skeletal tissues was noted in any of the animals (Food and Drug Research Labs Inc. 1972). Parenteral Studies Benzyl Alcohol In a study which assayed the teratogenic activity of ethinyloestradiol sulfonate in Wistar rats, a vehicle control group that was treated with Benzyl Alcohol/peanut oil was maintained. On GDs 10, 13, 6 to 10, or 10 to 14, rats (number not stated) received intraperitoneal (IP) injections of either the test material or an unspeciŽ ed amount of vehicle. Fetuses were removed on day 21 and examined. No teratogenic effect was noted (Chemnitius, Oettel, and Lemke 1979). Benzoic Acid and Sodium Benzoate Sprague-Dawley rats were injected intraperitoneally with 100, 315, or 1000 mg/kg Sodium Benzoate on GDs 9 to 11 or 12 to 14. Reduced fetal body weight, increased in utero deaths (by 12%), and gross anomalies were noted at the highest dose (Minor and Becker 1971). GENOTOXICITY Benzyl Alcohol Benzyl Alcohol was negative in the Ames test with and without metabolic activation (Ball, Foxall-Van Aken, Jensen 1984; Rogan et al. 1986; NTP 1989), sex-linked recessive lethal ( ies) (Foureman et al. 1994), and replicative DNA synthesis (male rats) (Uno et al. 1994) assays. McGregor et al. (1988) considered results of a mouse lymphoma forward mutation assay in the absence of S9 activation to be “questionable,” whereas NTP (1989) reported a positive response at concentrations associated with toxicity. Both studies were negative with S9 activation. Benzyl Alcohol, with S9 activation, was positive in the chromosome aberration test in Chinese hamster ovary (CHO) cells (NTP 1989; Anderson et al. 1990). Equivocal results were noted in the sister chromatid exchange (SCE) assay (NTP 1989; Anderson et al. 1990). Genotoxicity studies concerning Benzyl Alcohol are summarized in Table 5. Benzoic Acid and Sodium Benzoate Benzoic Acid was negative in the Ames (Fujita and Sasaki 1986; Zeiger et al. 1988) and SCE assays (Oikawa et al. 1980). Sodium Benzoate was negative in the host-mediated (Litton Bionetics 1974), Ames (Prival, Simmon, and Mortelmans 1991), dominant lethal (rats) (Litton Bionetics 1974), and cytogenetics (both in vitro and in rats) (Litton Bionetics 1974) assays. When tested in the CHO cell line, Sodium Benzoate was positive in the chromosomal aberrations assay (Ishidate and Odashima 1977) and, at a high dose (2 mM), in the SCE assay (Abe and Sasaki 1977). Njagi and Gopalan (1980) reported that incubation of adenosine, guanosine, uridine, or calf thymus DNA with Sodium Benzoate for up to 12 hours resulted in small shifts in the UV spectra. No shifts in the absorption peaks of the nucleoside cytidine were noted following incubation with Sodium Benzoate. The investigators noted that “DNA fragments do not have such shifts, thus the DNA must have remained intact during the course of incubation.” Sodium Benzoate was considered not to act at the genetic level. Genotoxicity studies concerning Benzoic Acid and Sodium Benzoate are summarized in Table 6. CARCINOGENICITY Oral Studies Benzyl Alcohol The 2-year gavage study performed by the NTP (detailed in the Oral Toxicity—Chronic section of this report) also tested for Benzyl Alcohol-induced carcinogenicity in rats and mice. Doserelated negative trends were noted in the incidences of anterior pituitary gland neoplasms in female rats (vehicle control, 29/50; low dose, 17/47; high dose, 9/49) and of Harderian gland adenomas in male mice (8/50; 3/50; 2/50). Epithelial hyperplasia of the nonglandular stomach was noted in 4 of 50 high-dose male rats; it was not found in controls or low-dose male rats. An increased incidence of adenomas of the adrenal cortex noted in high-dose male mice (0/48; 0/44; 3/48) was within historical range and not considered compound-related (NTP 1989). The NTP investigators considered the study negative for Benzyl Alcohol– induced carcinogenicity. However, reviewing the study, the EPA (1989) considered the 3 of 48 incidence of adrenal cortex adenoma to be “equivocal evidence of carcinogenic activity rather than negative.” Benzoic Acid and Sodium Benzoate For 18 to 24 months, groups of Fischer 344 rats (50 males and 52 females per group) received feed containing 2% or 1% Sodium Benzoate. The doses corresponded to the maximum tolerated dose (MTD) and 1=2 MTD as determined in 6-week toxicity studies. A control group of 25 male and 43 female rats received untreated feed. Average daily Sodium Benzoate intake was 280 and 202 mg, respectively, for male and female rats of the 2% group, and 141 and 102 mg, respectively, for male and female Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMR 38 Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 Cytogenetic (rats) Cytogenetics (human embryonic lung cells) In vivo: Mammalian Dominant lethal (rats) ABS in CHO Mammalian Cells SCE in CHO SCE in CHO Ames: S. typhimurium TA 97A, TA 102 Ames: S. typhimurium TA 97, TA 98, TA 100, TA 1535, TA 1537 Ames: S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538; E. coli WP2 Bacterial Cells Host-Mediated Assay Following dosing by oral intubation (50, 500, 5000 mg/kg Sodium Benzoate either single dose or Ž ve doses each 24 h apart), male rats were mated with two females per week for 8 weeks. Corpora lutea, early and late fetal deaths, and total implantations monitored Rats dosed by gastric intubation (50, 500, 5000 mg/kg Sodium Benzoate either single dose or Ž ve doses each 24 h apart, killed at various times after dosing (were given colcemid to arrest cells in metaphase) Maximum effective dose: 2.00 mg/ml (138.8 £ 10¡4 M) Sodium Benzoate 2, 20, 200 mg/kg Sodium Benzoate Negative (checked for aberrations in bone marrow metaphase chromosomes) Negative Negative POSITIVE at ¸2 mM (considered a high dose) POSITIVE: aberrations noted in 38% Negative (checked for aberrations in anaphase chromosomes) Negative 0.033 – 10 mg Sodium Benzoate per plate § S9 1, 3, 10 mM Benzoic Acid 1, 2, 5, 10 mM Sodium Benzoate Negative Negative Negative (slight increases in mutation frequencies noted; non-dose dependent) Results/comments Benzoic Acid at 100 – 6666 ¹g/plate or 100 – 10,000 ¹g/plate § S9 (either rat or hamster liver) Mice orally dosed (either single dose or Ž ve doses each 24 h apart) with 50, 500, 5000 mg/kg Sodium Benzoate, then inoculated with Salmonella TA-1530, G-46, and Saccharomyces D3; 3 h later animals were killed and the bacteria were removed (by peritoneal wash) and plated 33 – 10000 ¹g Benzoic Acid/plate § S9 Concentration/method TABLE 6 Benzoic Acid and Sodium Benzoate genotoxicity studies t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMS 39 Litton Bionetics 1974 Litton Bionetics 1974 Ishidate and Odashima 1977 Litton Bionetics 1974 Oikawa et al. 1980 Abe and Sasaki 1977 Prival, Simmon, and Mortelmans 1991 Fujita and Sasaki 1986 Zeiger et al. 1988 Litton Bionetics 1974 Reference COSMETIC INGREDIENT REVIEW rats of the 1% group. No clinical signs of toxicity, differences in average body weight or mortality rates were noted in treated rats when compared with controls. Neoplasms that were present in treated rats were similar in type and number to those in controls. No evidence of Sodium Benzoate– related carcinogenicity was observed (Sodemoto and Enomoto 1980). In a life time drinking water study, 100 Albino Swiss mice (50 of each sex) were supplied with water containing 2% Sodium Benzoate. A control group of 200 mice was supplied with untreated water. Average daily intake of Sodium Benzoate was 124.0 and 119.2 mg for males and females, respectively. Sodium Benzoate treatment did not affect survival. No carcinogenic effect attributable to treatment was noted at necropsy (Toth 1984). In Vitro Studies Benzoic Acid and Sodium Benzoate In an in vitro study hippurate and its parent compound Sodium Benzoate had antitumor effects on cells derived from Skalsky lymphoma, N´emeth-Kellner lymphoma (LYNK), L-asparaginase – sensitive 6C3HED Gardner lymphoma (GS), and LP-2 plasmacytoma. In a follow-up in vivo study, mice received subcutaneous implantations of GS or LYNK cells followed by twice daily IP injections of hippurate. A “high level of signiŽ cance” in inhibition of tumor growth was reported. The in vivo study was not done using Sodium Benzoate (Spustov´a and Oravec 1989). Dermal Studies Jacobs et al. (1984) performed a skin-painting study using groups of 120 Eppley Swiss mice (60 each sex). A nonoxidative hair dye containing 2.0% Benzyl Alcohol and 0.016% Benzoic Acid was painted onto the skin at a dose of 0.05 ml/application, three times weekly for 20 months. Sites were shaved of hair 24 hours before each application and a new bottle of dye was used each week. Two groups of control animals were shaved but not treated. Nine months into the study, 10 mice/sex/group were killed. Body weights and survival differed little between treatment and control groups. Varying degrees of chronic dermal in ammation were noted in all groups, including the controls. A signiŽ cant ( p < .01) increase in malignant lymphomas was noted in treated females (23/60). However, the researchers noted that one concurrent control group had a very low incidence (7/60 or 12%) for that tumor type. The rate was 22% for the other control group and had averaged 33% for three control groups in previous studies. Thus, the Ž ndings were not considered treatment related. The incidence of pulmonary adenomas and hepatic hemangiomas, which are common to this mouse strain, were similar between treated and control groups. No unusual neoplasms were observed. CLINICAL ASSESSMENT OF SAFETY Clinical Experience Benzyl Alcohol In 1981 and 1982 several neonatal deaths were ascribed to Benzyl Alcohol present as a preservative in isotonic saline (9 mg/ml) that had been used to  ush catheters (Brown et al. 1982; Gershanik et al. 1982). The syndrome consisted of metabolic acidosis, central neural depression, respiratory distress progressing to gasping respiration, hypotension, renal failure, and sometimes seizures and intracranial hemorrhages. In alerting pediatricians of the Ž ndings, the FDA (1982) reported an estimated daily intake of 99 to 404 mg/kg, which was 20 to 90 times the 4.5-mg/kg dose considered safe for healthy adults (Kimura et al. 1971). Although the infants involved had “serious underlying disease,” biochemical evidence of Benzyl Alcohol toxicity was found. Blood and urine specimens contained high concentrations of Benzyl Alcohol, Benzoic Acid, and hippuric acid. The FDA stated that no cases of toxicity were observed in older infants, children, or adults. In May 1985, FDA published a notice of intent that it was considering prohibiting use of all antimicrobial preservatives in single-dose containers of parenteral drug products for human use, and requiring multiple-dose parenteral drugs that contain any antimicrobial preservative to bear a warning that caution should be used in the administration to newborn infants. This intent was withdrawn in 1989 with the explanation that manufacturers of bacteriostatic water for injection and bacteriostatic sodium chloride injection had voluntarily agreed in 1982 that these two classes of products would contain a warning label against their use in newborns. Further, a 1983 revision of the US Pharmacopeia monograph required that these two classes of products bear the warning “not for use in newborns.” The withdrawal by the FDA noted that the increased awareness brought about by these steps, in conjunction with the lack of additional reports of toxicity, prompted the decision that further regulation was not necessary. Studies that compared infants born before and after the discontinuation of Benzyl Alcohol – containing solutions have generally supported the above measures (Menon et al. 1984; Benda, Hiller, and Reynolds 1986; Hiller et al. 1986; LeBel et al. 1988; Jardine and Rogers 1989; Cronin, Brown, and Ahdab-Barmada 1991). Reports are available contraindicating the use of neuromuscular blocking agents containing Benzyl Alcohol (Craig and Habib 1977; Hahn, Feasby, and Gilbert 1983). Use of these agents was not advised in neonates (van der Hal et al. 1987) or in the epidural space (King and Hart 1994). Reynolds and Smith (1995) reported that nebulizers of bacteriostatic saline containing Benzyl Alcohol as a preservative can cause bronchitis in healthy adults. Benzoic Acid and Sodium Benzoate FASEB (1973) reported no adverse effects following ingestion of Benzoic Acid at doses of 100 mg/day (82 doses in 86 days), 500 and 1000 mg/day (for 44 days), and 1000 mg/day (88 doses in 92 days). The number of participants was not reported. In another study, participants initially ingested Benzoic Acid at 1000 mg/day for 5 days and progressed to 1500 then 2000 Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMT 40 BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE Dermal Irritation Benzyl Alcohol Benzyl Alcohol (3%) was applied in a polypropylene chamber to the same site on the back of nine healthy female panelists for 4 consecutive days. The duration of exposure was not speciŽ ed. Sites were visually evaluated on the Ž fth day. Benzyl Alcohol was an irritant according to the Frosch-Kligman scoring system (Harvell et al. 1994). Benzoic Acid and Sodium Benzoate A liquid/powder foundation containing 0.2% Benzoic Acid was applied in a 24-hour occlusive patch to the backs of 12 panelists. A total of three exposures occurred within 1 week. Sites were evaluated at the time of patch removal and 24 hours later (i.e., prior to application of the subsequent patch). No reactions were observed (Biosearch Inc. 1992a). Forty-eight female panelists participated in an in-use study that investigated the acnegenic and irritation potential of a liquid/powder foundation containing 0.2% Benzoic Acid. Complying with the test protocol, approximately half of the test population had “mild to moderate” acne. Panelists were instructed to apply the product to the entire face and neck area at least twice a day for 45 days. Acne lesions and irritation were evaluated by a dermatologist on days 0, 3, 7, 10, 28, and 45. Objective and subjective evaluations of irritation were made by a nurse or technician on days 15, 21, and 35. Panelists also maintained daily response logs. The dermatologist noted “no significant changes the lesion counts of the non acne subjects and the acne subjects had a decrease. All objective irritation grades were 0’s.” Transient grade 1 irritation was noted by the technician; panelists’ logs recorded occasional instances of dryness, itching, and  akiness (Education and Research Foundation, Inc. 1992). Dermal Sensitization DeGroot (1994) compiled the following recommended patch test concentrations from the published literature: Benzyl Alcohol at 1%, 5%, or 10% in petrolatum, Benzoic Acid at 2%, 5%, or 10% in petrolatum (with an advised test concentration of <5%), and Sodium Benzoate at 2% or 5% in petrolatum (with a note that the 5% concentration may be an irritant). Benzyl Alcohol A repeat-insult patch test (RIPT) was conducted using a nonexclusive group of 110 panelists. Two mascara formulations each containing 0.65% Benzyl Alcohol were tested. During a 3-week induction period nine occlusive 24-hour patches (containing »0.15 g of test material) were applied to the same site on either the upper arm or back. Sites were evaluated 24 hours after patch removal (i.e., prior to application of subsequent patch). Following a 12- to 20-day nontreatment period, a challenge patch was applied to both the original site and a previously unexposed site. Challenge sites were evaluated at 24 and 48 hours after patch removal. No reactions were noted during induction or at challenge to either formulation (Hill Top Research 1997a, 1997b). Patch testing with Benzyl Alcohol (5% in petrolatum) was part of the American standard series (Adams 1982) and the North American Contact Dermatitis Group (NACDG) perfume screening series (Emmons and Marks 1985). The Research Institute for Fragrance Materials, Inc. (RIFM) report on Benzyl Alcohol cited an unpublished Kligman Maximization study that tested 10% Benzyl Alcohol in petrolatum using 25 male volunteers (skin types: 10 were Caucasian and 15 were Black). Benzyl Alcohol (and three other test materials) was applied under occlusive patches to the forearm of panelists. A total of Ž ve 48-hour exposures occurred during induction and each was preceded by a 24-hour occlusive pretreatment of the sites with 5% aqueous sodium lauryl sulfate (SLS). Following a 10-day nontreatment period, panelists were challenged on the scapular back with a 48 hour patch. Challenge sites were pretreated for 1 hour with 10% SLS. Challenge sites were examined at 48 and 72 hours. No reactions were observed (Kligman 1970; Opdyke 1973). Adams and Maibach (1985) compiled patch test results from 12 dermatologists over a 6-year period. Patches had been applied to the upper back for 48 hours of contact, and sites were evaluated at 48 and 72 hours. Three cutaneous reactions to 5% Benzyl Alcohol in petrolatum were noted among 713 cosmetic dermatitis patients. Van Joost, Stolz, and Van der Hoek (1985) reported four positive patch tests to 6.5% Benzyl Alcohol among 242 patients with histories of contact allergy of varying origin. An index of simultaneous reactivity in which the number of reactions to other perfume ingredients was divided by the number of positive Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMU and Ž nally 2500 mg/day staying at each protocol for 5 days before increasing the dose. Three of the 12 participants took the entire dose of 35 g in 20 days. This total dose produced marked symptoms of discomfort and malaise, which included nausea, headache, weakness, esophageal burning and irritation, hunger, and indigestion (Wiley and Bigelow 1908). In an early study (Lucas 1909), 12 men drank apple juice containing 0.1% Sodium Benzoate and had the following signs and symptoms: burning taste, fullness in the head, headache, nervousness, nausea, vomiting, itching of the skin, unusual perspiration, constipation, decreased urine  ow, increased speciŽ c gravity of the urine, and albuminuria. A liter of Ž ltered cider containing 0.2% to 0.3% Sodium Benzoate (2 to 3 g) caused albuminuria within 3 hours of ingestion. However, Lucas himself ingested as much as 6 g/day for 3 successive days without adverse effect. A single oral dose of 33 g of Sodium Benzoate to a 60-kg individual resulted in “clear signs of poisoning.” Signs and symptoms including deep pallor, weak and infrequent pulse, general discomfort, cephalea, and nausea. Similar effects were noted after ingestion of 50 g of Sodium Benzoate over a 5-hour period (Bignami and Boraccia 1924). 41 COSMETIC INGREDIENT REVIEW reactions to Benzyl Alcohol had a value of 0.50 (one individual responded to eugenol and another to isoeugenol). Broeckx et al. (1987) reported results of a cosmetic intolerance assay that patch tested 5202 patients with possible allergic contact dermatitis (537 of the patients had a history of “intolerance,” allergy, or irritation to cosmetics). Patch test conditions were not speciŽ ed. A reaction was noted in 48 (0.92% incidence) to Benzyl Alcohol. Reactions were noted in 2 of the 155 patients with cosmetic allergy. Cross-sensitization to Benzyl Alcohol has been reported in subjects sensitized to Peru balsam (Opdyke 1973). Benzoic Acid and Sodium Benzoate A liquid/powder foundation containing 0.2% Benzoic Acid was tested in a modiŽ ed Draize repeat-insult patch test using 75 panelists. Nine 24-hour occlusive patches were applied to the back during a 3-week induction period. Following a 2-week nontreatment period, panelists were challenged at a previously unexposed site. Sites were evaluated at 24 and 48 hours after patch removal. No reactions were noted during induction or at challenge (Biosearch Inc. 1992b). The RIFM report on Benzoic Acid cited an unpublished maximization test that tested 2% Benzoic Acid in petrolatum using 25 volunteers (skin types: 5 Black females, 2 Black males, 5 Caucasian females, 14 Caucasian males). During induction, a total of Ž ve 48-hour occlusive patches were applied to the same site (either forearm or back). Each was preceded by a 24-hour occlusive pretreatment of the site with 2.5% SLS. Following a 10-day nontreatment period, panelists were challenged at a different site with a 48-hour occlusive patch; the site had been pretreated for 1 hour with 5% to 10% SLS. Challenge sites were examined at the time of patch removal and 24 hours thereafter. No reactions were observed (Kligman 1977; Opdyke 1979). Benzoic Acid (5% in petrolatum) did not elicit an allergic reaction when applied to the skin of 10 panelists who, in a previous Kligman-maximization assay, had tested positive for benzoyl peroxide sensitivity (Leyden and Kligman 1977). Broeckx et al. (1987) reported results of a cosmetic intolerance assay that patch tested 5202 patients with possible allergic contact dermatitis (537 of the patients had a history of “intolerance,” allergy, or irritation to cosmetics). Patch test conditions were not speciŽ ed. A reaction to Benzoic Acid was noted in 34 (0.7% incidence). A reaction was noted in 1 of the 155 patients with cosmetic allergy. Urticarial Reactions Benzyl Alcohol and especially Benzoic Acid and Sodium Benzoate are among various compounds (such as some food additives) recognized in the published literature to induce nonimmunologic contact reactions in certain populations. Lahti (1980) reported that these agents “produce the reaction without any previous sensitization in most or almost all exposed persons.” The hypersensitivity has been indicated by  exural dermatitis, rhinitis, and/or asthma. However, cutaneous changes such as urticaria, angioneurotic edema, and contact urticaria were the more common manifestations (Emmons and Marks 1985; Hannuksela and Haahtela 1987; Fisher 1990; DeGroot 1994). The terms nonimmunologic contact urticaria or nonimmunologic immediate contact reactions were used to describe the occurrence. Using Benzoic Acid, Kligman (1990) demonstrated that immediate reactions to urticariogens were concentration dependent and ranged from wheals induced with the highest test concentration, erythema with a Ž vefold dilution, and pruritus alone with a 25-fold dilution. (The panelists had been selected because they had developed a raised wheal to 1.0% Benzoic Acid.) The methodology, test population, and results of various clinical studies demonstrating urticarial reactions are cited in Table 7. In addition to the study cited in Table 7, Lahti (1980) presented results of various tests using dermatologic patients. SigniŽ cantly more ( p < .001) redness and edema were produced by Benzoic Acid (5% in petrolatum) under conditions of the open-test method as compared to the chamber test (both tests were conducted on upper back of 51 atopic and 55 nonatopic patients). Further, reactions were signiŽ cantly more frequent ( p < .01) in nonatopic dermatologic patients than in atopic patients when tested using the chamber test; the difference was almost signiŽ cant in the open test ( p < .05). However, when summarizing the Ž ndings Lahti ultimately concluded that “no signiŽ cant differences were found in the frequency or strength of the nonimmunologic contact urticaria reactions between atopics and nonatopics.” Most reactions appeared within 45 minutes and disappeared within 2 hours, with some persisting for longer than 24 hours (0.1 ml of test material was applied to the volar forearm of 29 atopic and 74 nonatopic physicians and nurses, evaluations were made every 15 minutes for 6 hours). The substance produced more reactions in a water vehicle than when applied in petrolatum; the lowest concentration needed to elicit a wheal and  are reaction was 0.050% Benzoic Acid in water or 0.10% Benzoic Acid in petrolatum (tested on 16 atopic and 16 nonatopic patients). The back, chest, dorsal sides of the forearm and upper arm, and thighs were the most sensitive areas. Neither scratching (11 atopics and 11 nonatopics) nor stripping (7 patients) of the skin prior to Benzoic Acid application increased the severity of the reaction. A diminished skin response was noted after repeated application of Benzoic Acid. In this aspect of the study, 0.1 ml of 5% Benzoic Acid in petrolatum was applied for 40 minutes to the dorsal side of the forearm of 17 nurses and physicians and 1 patient with a venous leg ulcer. The application was repeated on the same site 14 times at 2-hour intervals on the two subsequent days. Sites were evaluated after each exposure. A histamine scratch test was performed on two subjects after the skin had stopped reacting to Benzoic Acid (on the second day). Similar reactivity to histamine was noted between the test site forearm and the control arm. The Ž nding suggested that the decreased reaction to Benzoic Acid resulted from an “emptying of the storage of mediator(s) in the skin rather than . . . fatigue of the dermal vessels and thus a failure to react.” Lastly, Lahti Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRMV 42 Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 125 children; patch tested over 7-year period (observed at 20 min for palpable pruritic erythema) 40 patients with urticaria, bronchial asthma, or chronic rhinitis; oral provocation test 25 patients with clinical symptoms suggestive of food allergy; oral provocation test to Sodium Benzoate and 4-methylhydroxybenzoate 132 patients with chronic urticaria and angioneurotic edema (suggested link to food additives); in a double-blind, placebo control study; oral provocation 10 subjects with chronic urticaria and angioneurotic edema who had ¸1 positive reaction in histamine equivalent skin test; oral provocation test 100 mg Sodium Benzoate—46 patients with history of chronic or acute urticaria/angioedema, chronic urticaria, chronic angioedema, or anaphylactoid reactions; DBPC oral challenge 110 dermatological patients (36 atopics, 23 chronic urticaria, 26 nonatopic dermatitis, 25 non-allergic patients); chamber method with 20-min occlusion to upper back 80 housewives (none with known perfume allergy); 20-min occlusive patch to forearm Benzyl Alcohol 5% Benzyl Alcohol in petrolatum, 15 patients with eczematous dermatitis, 16 with history of cosmetic sensitivity, 19 controls; open testing (45-min exposure) and 48-h patch test Benzoic Acid and Sodium Benzoate 200 volunteers with no speciŽ c skin condition at test site; 125 and 500 mM applied for 20 min to volar forearm using Finn Chamber Test Population; method Ibero et al. 1982 Monta˜no Garc´õ a and Orea 1989 Malanin and Kalimo 1989 Sanchez-Borges and Suarez-Chacon 1992 5 positive reactions (4%) to Sodium Benzoate 1 positive reaction (10%) to Benzoic Acid 15 positive reactions (32.6%); 12 reactions were in the 37 patients with chronic urticaria/angioedema Wu¨ thrich and Fabro 1981 Rademaker and Forsyth 1989 Safford et al. 1990 Intolerance demonstrated in 2.5% of rhinitis patients and in 11.5% of asthma patients Positive reaction to benzoates noted in 34.21% 2% Benzoic Acid in petrolatum, 76 erythematous reactions of varying severity (95%), 15 incidences of edema (19%), 17 incidences of itching, stinging, burning, irritation sensations (21%) 14 positive reactions (11%) to Benzoic Acid Basketter and Wilhelm 1996 To 125 mM: (on scale of 0– 8) no. with erythema/no. with edema: score of 0 was 53/175, score of 1 was 44/19, score of 2 was 41/5, score of 3 was 25/1, score of 4 was 26/0, score of 5 was 10/0, score of 6 was 1/0 (none scored higher) To 500 mM: erythema/edema score of 0 was 43/164, score of 1 was 35/30, score of 2 was 41/5, score of 3 was 31/1, score of 4 was 39/0, score of 5 was 9/0, score of 6 was 2/0 (none scored higher) 5% Benzoic Acid in petrolatum, 43 positive reactions (39%) Lahti 1980 Emmons and Marks 1985 Reference Open testing: contact urticaria noted in 7/15 (47%), 10/16 (63%), and 15/19 (79%) No positive patch tests No. of reactions (incidence)/comments TABLE 7 Clinical patch and oral provocation tests demonstrating urticarial reactions t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRNM 43 COSMETIC INGREDIENT REVIEW noted the lack of correlation between dermal and oral exposure studies and concluded that the skin test “could not be used to predict sensitivity to preservatives taken perorally.” Shriner and Maibach (1996) investigated the variation of the nonimmunologi c contact urticaria response in different areas of the body within and between two groups of panelists, “young” (10 women aged 23 to 47), and “old” (5 women aged 72 to 90). Panelists were not selected if they had a current or chronic history of dermatitis and/or current antihistamine use. A closed application method was used to apply 2.5% Benzoic Acid to the forehead, nose, nasolabial area, cheek, perioral area, chin, neck, and volar forearm for 20 minutes of exposure. In both age groups, the neck area was the most reactive followed by the perioral and nasolabial areas; the forearm was the least reactive. The younger group consistently demonstrated greater reactivity to Benzoic Acid at each site. The investigators noted that an earlier study had found the cheek to be the most responsive site. Studying the mechanism behind these reactions, many investigators suggested a nonspeciŽ c histamine release (Forsbeck and Skog 1977; Guin et al. 1984; Larsen 1985), whereas Lahti (1987) argued for other (undetermined) mechanisms. A 29- to 8000-fold increase in plasma concentrations of prostaglandin PGD2 and a 72- to 370-fold increase in 9®, 11¯-PGF 2 concentrations (the stable metabolite of PGD2 ) was noted in four healthy panelists following topical application of 10% Benzoic Acid in petrolatum. Benzoic Acid had been applied to the forearm and covered with plastic wrap for 60 minutes of contact; blood had been drawn from the antecubital vein from the treated sites. The changes were not observed in blood drawn from the contralateral arm. The increased PGD2 biosynthesis was dose-dependent over a concentration range of 0.01% to 15%. No cutaneous erythema was noted at <1%, patchy erythema was noted at 1%, maximal and con uent erythema was noted with ¸5% Benzoic Acid. Pretreatment with oral acetylsalicylic acid resulted in no erythema. The increased PGD2 synthesis was not accompanied by histamine release. The investigators concluded that PGD2 mediated the vasodilation associated with topical application of Benzoic Acid (Downard, Roberts, and Morrow 1995). Lahti, Pylva¨ nen, and Hannuksela (1995) reported that washing of the upper arm skin with a liquid detergent enhanced the immediate reactivity of the skin to Benzoic Acid. Benzoic Acid (10 ¹l) was applied without occlusive patches to test sites on the upper left and right arms of 12 healthy panelists on days 0, 3, and 6. The upper right arm was treated with the vehicle, a mixture of 2-propyl alcohol and 1,2-propylene glycol. Panelists were instructed to wash their upper left arm with a diluted dishwashing liquid, twice a day for 6 days. Sites were graded visually, and blood  ow (measured by a LDF  owmeter), skin color, transepidermal water loss (TEWL), and electrical capacity were measured. Washing alone increased TEWL and decreased electrical capitance. Benzoic Acid produced immediate skin reactions in all panelists. The reactions were stronger on washed skin, suggesting that “even subclinical changes in the skin caused by repeated washing increase the skin response to benzoic acid.” Phototoxicity/Photosensitization Benzoic Acid and Sodium Benzoate Clinical studies have demonstrated that ultraviolet (UV) light can produce a dose-dependent inhibition of Benzoic Acid – induced nonimmunologic immediate contact reactions (Larmi, Lahti, and Hannuksela 1988; Larmi 1989a, 1989b). Biosearch Inc. (1991) tested a matte eye shadow and base formulation each containing 0.1% Benzoic Acid under the conditions of the Draize-Shelanski repeat-insult patch test using 77 panelists. The test materials were applied in 48-hour occlusive patches to one of three sites on the back. Every third patch was applied to the same site. (This protocol allowed for the observation of delayed reactions.) Sites on the back were irradiated for 1 minute with UV light (365 nm, at a distance of 12 inches) following removal of induction patches 1, 4, 7, and 10. At the same time, the materials were applied in 48-hour open patches to the volar aspect of the right forearm. The protocol was followed for a total of 10 applications within a 31=2 -week period. Following a 2-week nontreatment period, closed and open challenge patches were applied to previously unexposed sites. Sites on the back were irradiated after removal of the challenge patch. No reactions were noted during induction or at challenge and no reactions were noted in response to irradiation (Biosearch Inc. 1991). A liquid/powder foundation containing 0.2% Benzoic Acid was applied at two sites to the back of 10 panelists with Fitzpatrick Skin types I, II, and III. Sites were not covered. One site on each panelist was irradiated with UV light; the exposure was initiated 30 to 60 minutes after test material application. Sites were irradiated with 0.5 of the previously determined minimal erythema dose (MED) of UVA and UVB light (290 to 400 nm from a Model 12S ultraviolet solar simulator), followed by a total of 14 Joules/cm2 of UVA (290 to 320 nm). A control site that had not been dermally treated was also irradiated. Panelists were instructed to avoid natural or artiŽ cial sunlight exposure throughout the study. All sites were evaluated at 24, 48, and 72 hours after irradiation. No reactions were observed (Biosearch Inc. 1992c). A liquid/powder foundation containing 0.2% Benzoic Acid was tested in a photosensitization study using 30 panelists with varying Fitzpatrick Skin Types (degree of pigmentation was stated not to interfere with UV light response or skin reaction evaluation). During induction, six 24-hour occlusive patches were applied to the back within a 3-week period. At the time of patch removal sites were irradiated with 2.0 MEDs of UVB light and 4 Joules/cm2 of UVA light. Following an 18-day nontreatment period panelists were challenged at two previously unexposed sites. Challenge sites were scored after 24 hours of exposure and one site was then irradiated with 0.5 MED of UVB and 4 Joules/cm2 of UVA. Another site, not dermally treated, was also irradiated at challenge and served as the UV light Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRNN 44 BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE Ocular Benzyl Alcohol In each of two double-blind studies, 25 patients suffering from early progressive idiopathic cataracts, subcapsular or cortical in site, received one drop of saline containing 0.07% Benzyl Alcohol every 8 hours (Testa et al. 1987). The eyelid was held open for at least 2 minutes. Treatment continued for 22 months. In one study, a control group received placebo, whereas in the other study, the control group received an anticataract medication. Clinical Ž ndings were recorded every 30 days for the Ž rst 14 months, then patients were followed for up to 18 and 22 months. A signiŽ cant ( p < .01) increase in visual acuity (VA) was observed in patients treated with Benzyl Alcohol after 30 and 60 days as compared to those receiving either placebo or the medication. Compared to those placebo or medication treated, a signiŽ cant ( p < .01) decrease in lens opacity was noted in 19 and 17 patients treated with Benzyl Alcohol, respectively. In the course of the studies, a signiŽ cant increase in the number of surgeries for cataracts was noted in patients not receiving Benzyl Alcohol. One patient treated with Benzyl Alcohol required surgery after 22 months compared to 38 total who had received either placebo or medication. Benzyl Alcohol was well tolerated except in two patients (4%) where tolerance was fair in one and poor in the other. The investigators encouraged a large scale prospective trial noting that Benzyl Alcohol is already contained (though not at anticataract concentrations) in ophthalmic solutions (Testa et al. 1987). Benzoic Acid and Sodium Benzoate An eye shadow plus base containing 0.1% Benzoic Acid was tested in a 28-day in-use study using 52 women. Half of the panelists were contact lens wearers. Panelists were instructed to use the product (one of four eye shadow colors plus base) at least twice a day. Examinations were made at the beginning and end of the study by an ophthalmologist, weekly by a nurse or technician, and the panelists maintained daily logs. Slight conjunctival hyperemia without chemosis was noted in eight women; the condition was nonpersistent in all cases. Another two women presented with slight hyperemia and were also experiencing allergy symptoms; erythema was noted around the eye of one of these two panelists. One panelist had an incidence of red and mildly swollen caruncles at the Ž fth observation. Four other panelists reported occasional itching; dryness was reported by another two panelists. One panelist reported redness, pufŽ ness, and irritation of the left upper eyelid that prevented her from wearing her contact lenses for 2 days. The investigators concluded that “any reactions observed or sensations perceived were minor, transient and/or sporadic and there were no appar- ent differences among the four shades of eye shadow. Based on these Ž ndings, all of the four products tested were regarded as safe for their intended use” (TKL Research 1991). SUMMARY Benzyl Alcohol Benzyl Alcohol is an aromatic alcohol that is used in cosmetics as a fragrance component, preservative, solvent, and/or viscosity decreasing agent. As of January 1998 it was used in 322 formulations. Data from 1984 indicated use at ·25%. Benzyl Alcohol is used as a food additive, in OTC drug preparations, and in clinical settings. It is a membrane  uidizer and a local anesthetic. Benzyl Alcohol is metabolized to Benzoic Acid, which is then conjugated with glycine and excreted as hippuric acid. EPA reviews of mouse and rat oral-dosing studies conducted by the NTP determined subchronic and chronic oral reference doses for humans of 1 and 0.3 mg/kg/day, respectively. Earlier, the WHO established an ADI of up to 5 mg/kg. Investigators considered Benzyl Alcohol to be a moderate respiratory hazard and toxic when administered by the parenteral route. It produced severe irritation when applied to the skin of nude mice. In oral-dose teratogenicity studies using mice, Benzyl Alcohol was negative in one study (550 mg/kg/day), gave questionable results in another (750 mg/kg/day), and was considered a suspect reproductive hazard in the third (750 mg/kg/day [which EPA extrapolated to a human dose of 58 mg/kg/day]). Mutagenicity studies reported both positive and negative results. It was negative for carcinogenicity when dermally tested on mice at 2.00% in a nonoxidative hair dye. NTP considered it negative for carcinogenicity following 2 years of oral dosing in rats and mice, but EPA considered the results equivocal. In clinical settings, Benzyl Alcohol can produce nonimmunologic contact urticaria or nonimmunologi c immediate contact reactions. It was not a sensitizer when tested in a maximization test at 10% in petrolatum, and demonstrated a low incidence of sensitization in provocation studies. Therapeutic ocular studies indicated it may be beneŽ cial in the management of cataracts. Benzoic Acid and Sodium Benzoate Benzoic Acid is an aromatic acid that is used in cosmetics as a pH adjustor and/or preservative. Sodium Benzoate is its sodium salt and is used in cosmetics as a preservative. As of January 1998 they were used in 223 and 156 cosmetic formulations, respectively. Data from 1984 indicated use primarily at ·1% (with some use at 5% and 25%, respectively). Both substances are GRAS ingredients. WHO established an ADI of up to 5 mg/kg. Benzoic Acid can be used in ointments and antifungal agents. Sodium Benzoate has been used clinically in the treatment of hyperammonemia. The benzoates are recognized hydroxy radical scavengers. Benzoic Acid is rapidly absorbed following dermal application. Its metabolism can deplete glycine supplies. Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRNO control. Challenge sites were evaluated at 24, 48, and 72 hours postirradiation. Panelists were instructed to avoid natural or artiŽ cial sunlight exposure throughout the study. No reactions were observed (Biosearch Inc. 1992d). 45 COSMETIC INGREDIENT REVIEW In animal multiple-dose oral toxicity studies decreased feed consumption, depressed growth, and toxic effects were noted at doses of Benzoic Acid or Sodium Benzoate >1%. A neurobiological study was negative. In oral-dose teratogenicity studies, Benzoic Acid (600 mg/kg) produced signiŽ cant results in hamsters, but was negative in two rat studies (up to at least 500 mg/kg/day). Sodium Benzoate was negative for teratogenicity in mice and rats (175 mg/kg/day), hamsters (300 mg/kg/day), and rabbits (250 mg/kg/day). Benzoic Acid was negative in mutagenicity studies. Sodium Benzoate was positive in assays done on the CHO cell line, but negative in other studies. Benzoic Acid was negative for carcinogenicity when dermally tested on mice at 0.016% in a nonoxidative hair dye. Sodium Benzoate was negative for carcinogenicity when administered orally at up to 2% to rats (in feed for up to 2 years) or mice (in a life-time drinking water study). In clinical studies, toxic symptoms were noted following doses far exceeding the ADI established by the WHO. The benzoates are recognized to produce nonimmunologic contact urticaria or nonimmunologic immediate contact reactions, but it is not clear whether the reactions, are histamine or prostaglandin mediated. Dermal sensitization, phototoxicity, and photosensitization studies were negative. DISCUSSION The Cosmetic Ingredient Review (CIR) Expert Panel was satisŽ ed that results of toxicity, mutagenicity, carcinogenicity, reproductive/developmental, and sensitization studies cited in this report support the safety of these ingredients in cosmetic formulations. The focus of the Panel’s safety assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate concerned the ability of these ingredients to induce contact urticaria or other contact reactions. The Panel was interested in knowing the threshold and frequency of occurrence of these so-called nonimmunologic reactions. The Panel used the studies cited in Table 7 to establish a pattern. Dermal studies demonstrated that 5% Benzyl Alcohol elicited a reaction in a sizeable portion of the population. One study noted reactions in almost all panelists following brief exposure to 2% Benzoic Acid. The Panel was of the opinion that these urticarial reactions were strictly cutaneous, possibly involving a cholinergic mechanism and not immunoglubolin E (IgE) mediated. Further, predictive clinical sensitization studies using the maximization protocol indicated that 10% Benzyl Alcohol and 2% Benzoic Acid were not sensitizers. In provocative studies, Benzyl Alcohol had a low incidence of sensitization. Utilizing all of the dermal exposure data, the CIR Expert Panel was of the opinion that these ingredients could be used safely at concentrations up to 5%. However, cosmetic manufacturers should consider the nonimmunologic contact urticaria phenomena when using these ingredients in formulation, especially in products designed for use on infants and children. The Expert Panel received comments suggesting that the available data support the safety of Benzyl Alcohol in hair dyes at concentrations up to 10%. The Panel recognized that hair dye use involves limited body area exposure, has a controlled exposure time per use, and has limited frequency of use (weeks or months between uses). Because of this pattern of use, the Expert Panel concluded that contact urticaria would not be a concern. Therefore, the Panel was of the opinion that Benzyl Alcohol could be used up to 10% in hair dye formulations. Frequency of use data indicated that these ingredients are used in formulations where inhalation is a route of exposure. The Expert Panel decided that the toxicity data contained in this report were insufŽ cient to assess the inhalation risk of these ingredients. Section 1, paragraph (p) of the CIR Procedures states that “A lack of information about an ingredient shall not be sufŽ cient to justify a determination of safety.” In accordance with Section 30( j)(2)(A) of the Procedures, the Expert Panel informed the public of its decision that the data were not sufŽ cient for determination whether the ingredients, under relevant conditions of use, were either safe or unsafe. The Panel released a Notice of InsufŽ cient Data on April 4, 1997, requesting inhalation toxicity data. No comments were received. CONCLUSION Based on the available data, the CIR Expert Panel concludes that Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate are safe for use in cosmetic formulations at concentrations up to 5%. The available data are insufŽ cient to support the safety of these ingredients in cosmetic products in which a primary route of exposure is inhalation. Benzyl Alcohol is safe for use in hair dyes at concentrations up to 10%. REFERENCES Abe, S., and M. Sasaki. 1977. Chromosome aberrations and sister chromatid exchange s in Chinese hamster cells exposed to various chambers. J. Natl. Cancer Inst. 58:1635 – 1641. Adams, R. M. 1982. Patch testing in occupationa l dermatitis. In Occupational and Industrial Dermatology, ed. H. I. Maibach and G. A. Gellin, 345 – 352. Chicago: Year Book Medical Publishers. Adams, R. M., and H. I. Maibach. 1985. A Ž ve-year study of cosmetic reactions. J. Am. Acad. Dermatol. 13:1062 – 1069. Ahkong, Q. F., G. M. Botham, A. W. Woodward, and J. A. Lucy. 1980. 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Submitted by the FDA in response to a 1995 FOI request (42 pages. )2 Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRNS BENZYL ALCOHOL, BENZOIC ACID, AND SODIUM BENZOATE COSMETIC INGREDIENT REVIEW Prival, M. J., V. F. Simmon, and K. E. Mortelmans. 1991. Bacterial mutagenicity testing of 49 food ingredients give very few positive results. Mutat. Res. 260:321 – 329. Przybyszewski, W. M., and J. Malec. 1982. Protection against hydroxyurea induced cytotoxic effects in L5178Y cells by free radical scavengers . Cancer. Lett. 17:223 – 228. Quick, A. J. 1931. The conjugation of benzoic acid in man. J. Biol. Chem. 92:65 – 85. Rademaker, M., and A. Forsyth. 1989. Contact dermatitis in children. Contact Dermatitis 20:104 – 107. Rasmussen, L. H., M. Zachmann, and P. Nilsson. 1989. Authentic recombinant human growth hormone. Results of a multicenter clinical trial in patients with growth hormone deŽ ciency. Helv. Paediatri. Acta 43:443 – 448. Registry of Toxic Effects of Chemical Substances (RTECS). 1995. Benzoic Acid. Toxnet database. Bethesda, MD: National Library of Medicine. Reynolds, R. D., and R. M. Smith. 1995. Nebulized bacteriostatic saline as cause of bronchitis. J. Fam. Pract. 40:35 – 40. Rogan, E. G., E. L. Cavalieri, B. A. Walker, R. Balasubramanian , P. G. Wislocki, R. W. Roth, and R. K. Saugier. 1986. Mutagenicity of benzylic acetates, sulfates and bromides of polycyclic aromatic hydrocarbons . Chem. Biol. Interact. 58:253 – 275. Roskos, K. V., H. I. Maibach, and R. H. Guy. 1989. The effect of aging on percutaneous absorption in man. J. Pharmacokinet . Biopharm. 17:617 – 630. Rothschild, D. L., Jr. 1990. The Food Chemical News Guide guide to the current status of food additives and color additives. Washington, DC: Food and Chemical News. Rotstein, J. B., and T. J. Slaga. 1988. Effect of exogenou s glutathione on tumor progression in the murine skin multistage carcinogenesi s model. Carcinogenesis 9:1547 – 1551. Rougier, A., D. Dupuis, C. Lotte, R. Roguet, R. C. Wester, and H. I. Maibach. 1986. Regional variation in percutaneou s absorption in man: measuremen t by the stripping method. Arch. Dermatol. Res. 278:465 – 469. Safford, R. J., D. A. Basketter, C. F. Allenby, and B. F. Goodwin. 1990. Immediate contact reactions to chemicals in the fragrance mix and a study of the quenching action of eugenol. Br. J. Dermatol. 123:595 – 606. Sanchez-Borges , M., and R. Suarez-Chacon. 1992. Additives in allergic or pseudo-allergi c reactions. Prog. Allergy. Clin. Immunol. 333 – 338. Santucci, L. G., ed. 1999. List of Japanese cosmetic ingredients. 4rd ed. Washington, DC: CTFA. Shiseido Research Center. 1972. Primary skin irritation (rabbit) and cumulative skin irritation (guinea pig) testing 10% Benzyl Alcohol in squalane. Unpublished data submitted by CTFA. (5 pages.)2 Shtenberg, A. J., and A. D. Ignat´ev. 1970. Toxicological evaluation of some combinations of food preservatives. Food Cosmetics Toxicol. 8:369 – 380. Shriner, D. L., and H. I. Maibach. 1996. Regional variation of nonimmunologi c contact urticaria. Functional map of the human face. Skin Pharmacol. 9:312 – 321. Smyth, H. F., Jr., and C. P. Carpenter. 1948. Further experience with the rangeŽ nding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30:63 – 68. Smyth, H. F., Jr., C. P. Carpenter, and C. S. Weil. 1951. Range-Ž nding toxicity data: List IV. Arch. Ind. Hyg. Occup. Med. 4:119 – 122. Sodemoto, Y., and M. Enomoto. 1980. Report on the carcinogenesi s bioassay of sodium benzoate in rats: absence of carcinogenicity of sodium benzoate in rats. J. Environ. Pathol. Toxicol. 4:87 – 95. Spustov´a. V., and C. Oravec 1989. Antitumor effect of hippurate. An experimental study using various mouse tumor strains. Neoplasma 36:317 – 320. Sugioka, K., H. Nakano, J. Tsuchiya, M. Nakano, and Y. Sugioka. 1984. Clear evidence for the participation of OH in lambda DNA breakage induced by the enzymatic reduction of adriamycin in the presence of iron-ADP. Importance of local OH concentration for DNA strand cleavage. Biochem. Int. 9:237 – 242. Suthanthiran, M., S. D. Solomon, P. S. Williams, and A. L. Rubin. 1984. Hydroxyl radical scavenger s inhibit human natural killer cell activity. Nature 307:276 – 278. Tanaka, R. 1984. Effect of benzyl alcohol on adenosine triphosphatase, p-nitrophenylphosphatas e and acetylcholinesteras e in rat erythrocyte membrane. J. Toxicol. Sci. 9:109 – 116. Taylor, E. J., ed. 1988. Dorland’s illustrated medical dictionary, 27th ed., 200. Philadelphia, PA: WB Saunders. Testa, M., G. Iuliano, P. Morton, and A. Longoni . 1987. Topical benzyl alcohol reduces cataract surgery need: Two long-term double blind studies. J. Ocul. Pharmacol. 3:211 – 225. Thomas, M. J., S. Smith, and J. A. Pang. 1991. The use of water-soluble radical scavenger s to detect hydroxyl radical formation by polymorphonuclea r leukocytes. Free. Radic. Res. Commun. 12 – 13(pt 1):53 – 57. TKL Research. 1991. 28-Day safety in-use study of eye shadow containing 0.1% Benzoic Acid. TKL No. 919226. Unpublished data submitted by CTFA. (240 pages.)2 Toth, B. 1984. Lack of tumorigenicity of sodium benzoate in mice. Fundam. Appl. Toxicol. 4(3 pt 1):494 – 496. Tremblay, G. C., and I. A. Qureshi. 1993. The biochemistry and toxicology of benzoic acid metabolism and its relationship to the elimination of waste nitrogen. Pharmacol . Ther. 60:63 – 90. Uno, Y., H. Takasawa, M. Miyagawa, Y. Inoue, T. Murata, and K. Yoshikawa. 1994. An in vivo-in vitro replicative DNA synthesis (RDS) test using rat hepatocyte s as an early prediction assay for nongenotoxi c hepatocarcinogen s screening of 22 known positive and 25 noncarcinogens . Mutat. Res. 320:189 – 205. Upreti, K. K., M. Das, and S. K. Khanna. 1991. Role of antioxidants and scavenger s on argemone oil-induced toxicity in rats. Arch. Environ. Contam. Toxicol. 20:531 – 537. van der Hal, A. L., H. M. MacDonald, L. Shaw, S. Sreepathi, and S. A. Beasley. 1987. Benzyl alcohol in neuromuscula r blocking agents [letter]. Pediatrics 79:841 – 842. Van Joost, T., E. Stolz, and J. C. S. Van der Hoek. 1985. Simultaneous allergy to perfume ingredients. Contact Dermatitis 12:115 – 116. Voorheis, H. P., and B. R. Martin. 1982. Local anesthetics including benzyl alcohol activate the adenylat e cyclase in Trypanosoma brucei by a calciumdependen t mechanism. Eur. J. Biochem. 123:371 – 376. Walker, P. D., and S. V. Shah. 1988. Evidence suggesting a role for hydroxyl radical in gentamicin-induce d acute renal failure in rats. J. Clin. Invest. 81:334 – 341. Weitberg, A. B., S. A. Weitzman, E. P. Clark, and T. P. Stossel. 1985. Effects of antioxidants on oxidant-induce d sister chromatid exchange formation. J. Clin. Invest. 75:1835 – 1841. Weitzman, S. A., and T. P. Stossel. 1982. Effects of oxygen radical scavenger s and antioxidants on phagocyte-induce d mutagenesis. J. Immunol. 128:2770 – 2772. Wenninger, J. A., R. C. Canterbery, and G. N. McEwen, Jr., eds. 2000. International cosmetic ingredient dictionary and handboo k. 8th ed., Vol. I, 126, 131, Vol. 2, 1255. Washington, DC: CTFA. White, A. 1941. Growth inhibition produced in rats by the oral administration of sodium benzoate. Effects of various dietary supplements. Yale. J. Biol. Med. 13:759 – 768. Wightman, M. A., and R. W. Vaughan. 1976. Comparison of compound s used for intradermal anesthesia. Anesthesiology 45:687 – 689. Wiley, H. M., and W. D. Bigelow. 1908. In uence of benzoic acid and benzoates on digestion and health. Bulletin 84, pt. IV, Bureau of Chemistry, U.S. Department of Agriculture. Williams, J. M., and N. R. Howe. 1994. Benzyl Alcohol attenuates the pain of lidocaine injections and prolongs anesthesia. J. Dermatol. Surg. Oncol. 20:730 – 733. 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Downloaded from ijt.sagepub.com at Auburn University on December 2, 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRNT 50 Drugs.com Print Version Print   Close Midazolam Hydrochloride Class: Benzodiazepines VA Class: CN302 Chemical Name: 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine monohydrochloride Molecular Formula: C18H13ClFN3•HCl CAS Number: 59467-96-8 Warning(s) Use only when adequate treatment facilities for appropriate management of therapy and complications are available.1 250 For deeply sedated pediatric patients, an individual other than the clinician performing the procedure should be dedicated to monitoring the patient throughout the procedure.1 250 Respiratory Effects Associated with respiratory depression and respiratory arrest, especially when used for sedation in non-critical-care settings.1 250 (See Respiratory and Cardiovascular Effects under Cautions.) Death or hypoxic encephalopathy has resulted when respiratory depression was not recognized promptly and treated effectively.1 250 Initial IV dose for healthy adults should not exceed 2.5 mg.1 250 (See Dosage under Dosage and Administration.) Lower dosages are necessary in patients >60 years of age, debilitated patients, and patients receiving concomitant opiates or other CNS depressants.1 250 (See Dosage and also Special Populations, under Dosage and Administration.) Titrate initial and subsequent dosages slowly; administer the appropriate dose over ≥2 minutes and wait an additional 2 or more minutes to fully evaluate the sedative effect.1 Administer by direct IV injection as the 1-mg/mL solution or dilute the 1- or 5-mg/mL solution to facilitate slower administration.1 Pediatric Dosage and Administration Considerations Calculate pediatric dosage on a mg/kg basis.1 Initial dose is dependent on age, procedure, and route; titrate subsequent dosages slowly.1 (See Dosage: Pediatric Patients, under Dosage and Administration.) Do not administer by rapid IV injection in neonates.1 Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant administration of fentanyl.1 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRNU Dosage and Administration Considerations for Procedural Sedation Drugs.com Print Version Introduction Benzodiazepine;2 3 4 5 6 7 17 157 sedative, anxiolytic, amnesic,1 3 157 219 and hypnotic.2 4 7 70 84 86 104 177 178 Uses for Midazolam Hydrochloride Preoperative Sedation, Anxiolysis, and Anterograde Amnesia Preoperatively, to produce sedation, relieve anxiety, and provide anterograde amnesia.1 3 157 219 Some clinicians consider midazolam the benzodiazepine of choice for preoperative use for short surgical procedures because of its relatively rapid onset and short duration of effect and improved local tolerance at the site of injection compared with other currently available parenteral benzodiazepines.2 4 7 14 32 173 174 181 Procedural Sedation For procedural sedation, anxiolysis, and amnesia (alone or in combination with an opiate agonist)1 3 157 when administered prior to dental2 4 7 14 35 66 130 131 176 or minor surgical procedures or diagnostic, therapeutic, or endoscopic procedures such as upper GI endoscopy,1 2 3 7 71 72 73 74 75 76 77 78 79 bronchoscopy,1 2 3 80 157 cystoscopy,1 2 7 115 157 cardiac catheterization,1 2 7 35 85 157 coronary angiography,1 50 85 157 oncology procedures,1 radiologic procedures1 (e.g., computerized tomography),1 89 or suture of lacerations.1 Some clinicians consider midazolam the benzodiazepine of choice for moderate sedation (formerly known as conscious sedation) prior to short procedures14 181 because of its relatively rapid onset2 4 7 14 74 75 79 86 178 and short duration of action,4 7 26 46 74 75 86 87 176 178 pronounced amnesic effect,7 25 73 74 75 78 79 115 178 and improved local tolerance at the site of injection2 7 14 25 74 75 76 78 79 86 87 176 177 178 compared with other currently available IV benzodiazepines. Induction of general anesthesia prior to administration of other anesthetic agents.1 2 3 4 7 14 25 35 70 84 87 95 99 100 101 102 103 104 105 106 107 108 125 157 Induction with midazolam provides anxiolysis, anterograde amnesia, and doserelated hypnotic effects (progressing from sedation to loss of consciousness), but not analgesia.2 4 7 70 84 86 104 177 178 An acceptable alternative to thiopental for induction of anesthesia; midazolam’s slow onset and long duration of action and variability in response relative to those of thiopental preclude it from becoming the drug of choice for induction of anesthesia in most patients, particularly outpatients and patients undergoing short surgical procedures.2 4 7 181 182 Maintenance of anesthesia during short surgical procedures,1 2 3 4 14 27 100 113 114 usually in conjunction with inhalation anesthetic agents, balanced anesthesia (e.g., nitrous oxide and oxygen), and/or opiate agonists (e.g., fentanyl).1 70 112 113 184 Should not be used alone for maintenance of anesthesia.2 27 70 184 Use for maintenance of anesthesia during relatively long surgical procedures has not been fully evaluated to date.1 3 27 70 157 181 Sedation in Critical-care Settings Sedation of intubated and mechanically ventilated patients in a critical-care setting.1 220 221 222 223 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRNV Induction and Maintenance of Anesthesia Drugs.com Print Version A preferred drug for sedation of acutely agitated patients in critical-care settings because of its rapid onset and short duration of action.235 As effective as propofol and appears to have a better adverse effect profile (e.g., less hypotension) than propofol;220 221 223 however, midazolam appears to have a more variable effect on recovery of consciousness and time to recovery of function after cessation of therapy than propofol.220 223 Recommended for short-term (≤24 hours) sedation only, since the effects of the drug on awakening and the time to extubation are unpredictable when midazolam infusions are administered over longer periods (e.g., exceeding 48–72 hours).235 Insomnia Has been used for short-term management of insomnia†.4 7 116 117 118 119 120 121 122 123 Agitation Has been used for management of acute agitation†.53 90 146 147 148 181 Midazolam Hydrochloride Dosage and Administration General Adjust dosage according to individual requirements and response, age, body weight, physical and clinical status, underlying pathologic condition(s), type and amount of premedication or concomitant medication, and the nature and duration of the surgical or other procedure; however, individual response also may vary independent of these factors.1 3 157 163 193 Facilities for administration of oxygen and controlled respiration should be readily available during and immediately following IV administration.1 3 193 Oral solution is intended for use in monitored settings (e.g., hospital, ambulatory care settings including physician and dental offices) only; is not intended for chronic or home use.219 Administer orally,219 by IM injection, or by slow IV injection 1 2 3 4 7 14 157 193 or continuous IV infusion.1 36 90 150 181 219 Avoid intra-arterial injection or extravasation of the drug.1 Do not administer intrathecally or epidurally.1 Oral Administration Consult manufacturer’s labeling for instruction on use of the special press-in bottle adapter and oral dispensers for administration of the oral solution.219 Administer from the individual oral dispenser directly into the child’s mouth; do not mix the oral solution with any other liquid (e.g., grapefruit juice) prior to administration.219 Effect of food on absorption of the oral solution has not been determined, but food intake generally is precluded prior to procedural sedation in pediatric patients.219 IM Administration Administer deeply into a large muscle mass.1 3 157 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROM Administration Drugs.com Print Version IV Administration For solution and drug compatibility information, see Compatibility under Stability. Direct IV injection should be made in incremental doses.1 3 157 163 Use of the 1-mg/mL injection is recommended to facilitate slow direct IV injection of the drug;1 193 the 1and 5-mg/mL injections may be diluted with a compatible diluent (see Solution Compatibility under Stability) to facilitate slower injection.1 Dilution For administration as a continuous IV infusion, dilute the 5-mg/mL injection to a concentration of 0.5 mg/mL with a compatible diluent (see Solution Compatibility under Stability).1 Rate of Administration: General Rapid IV administration may result in respiratory depression, airway obstruction, and/or respiratory arrest.1 Rate of Administration: Pediatric Patients IV injection for preoperative or procedural sedation: Administer IV midazolam over 2–3 minutes; wait an additional 2–3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose.1 Do not administer by rapid IV injection in neonates.1 (See Boxed Warning.) Continuous IV infusion: Individualize the infusion rate.1 (See General and also Pediatric Patients: Sedation in Critical-care Settings, under Dosage and Administration.) Rate of Administration: Adults IV injection for procedural sedation: Administer the appropriate dose as a 1-mg/mL solution over ≥2 minutes; allow ≥2 minutes to evaluate the sedative effect.1 163 193 Continuous IV infusion: Individualize the infusion rate.1 (See General and also Adults: Sedation in Critical-care Settings, under Dosage and Administration.) Dosage Available as midazolam hydrochloride; dosage expressed in terms of midazolam.1 3 Pediatric Patients The depth of sedation/anxiolysis needed depends on the type of procedure being performed.1 It is vital to titrate the midazolam dose and the dose of other concomitant drugs slowly to achieve the desired clinical effect.1 Unlike adult patients, pediatric patients generally receive increments of midazolam on a mg/kg basis; calculate dosage in obese children on the basis of ideal body weight.1 219 Pediatric patients generally require higher dosages on a mg/kg basis than adults;1 patients <6 years of age generally require higher drug dosages on a mg/kg basis than older children and may require closer monitoring.1 219 It is essential to wait 2–3 minutes to fully evaluate the sedative effect before starting the procedure or http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRON IV injection for induction of anesthesia: Administer the appropriate dose as a 1-mg/mL solution over 20–30 seconds; supplemental doses may be given at 2-minute intervals.1 3 157 Drugs.com Print Version administering a repeat dose; peak EEG effects are not achieved as quickly as with diazepam, since midazolam is water soluble.1 Preoperative Sedation, Anxiolysis, and Anterograde Amnesia Oral Children 6 months to 16 years of age: 250–500 mcg/kg as a single dose, depending on the status of the patient and the desired effect (maximum 20 mg).219 250 mcg/kg may be sufficient for children 6–16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.219 Younger children (e.g., 6 months to <6 years of age) and less cooperative patients may require a higher than usual dose of up to 1 mg/kg (maximum 20 mg).219 Consider an initial dose of 250 mcg/kg for patients 6 months to 16 years of age with cardiac or respiratory compromise, other higher-risk surgical patients, and those who have received concomitant opiates or other CNS depressants.219 IV Nonintubated patients <6 months of age: Limited dosing information is available.1 Dosing recommendations are unclear because of uncertainty about when a patient transfers from a neonatal to pediatric physiology; however, titration of the dose in small increments to clinical effect and careful monitoring are essential, since patients <6 months of age are vulnerable to airway obstruction and hypoventilation.1 Children 6 months to 5 years of age: Initially, 50–100 mcg/kg; a total dose of up to 600 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 6 mg.1 Children 6–12 years of age: Initially, 25–50 mcg/kg; a total dose of up to 400 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 10 mg.1 Dosage must be reduced in pediatric patients receiving opiates or other sedatives as premedications; higher-risk or debilitated patients may require lower dosages regardless of whether premedication was administered.1 IM Pediatric patients ≥1 month of age: 100–150 mcg/kg; doses up to 500 mcg/kg have been used for more anxious patients.1 Total dose usually does not exceed 10 mg, although this has not been systematically studied.1 If midazolam is administered with an opiate, reduce the initial dose of each drug.1 Procedural Sedation Oral Children 6 months to 16 years of age: 250–500 mcg/kg as a single dose, depending on the status of the patient and the desired effect (maximum 20 mg).219 250 mcg/kg may be sufficient for children 6–16 years of age or for cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.219 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROO Adolescents 12–16 years of age: Dose as adults; although some patients in this age range may require higher than recommended adult doses, total dose usually does not exceed 10 mg.1 Drugs.com Print Version Younger children (e.g., 6 months to <6 years of age) and less cooperative patients may require a higher than usual dose of up to 1 mg/kg (maximum 20 mg).219 Consider an initial dose of 250 mcg/kg for patients 6 months to 16 years of age with cardiac or respiratory compromise, other higher-risk surgical patients, and those who have received concomitant opiates or other CNS depressants.219 IV Nonintubated patients <6 months of age: Limited dosing information is available.1 Dosing recommendations are unclear because of uncertainty about when a patient transfers from a neonatal to pediatric physiology; however, titration of the dose in small increments to clinical effect and careful monitoring are essential, since patients <6 months of age are vulnerable to airway obstruction and hypoventilation.1 Children 6 months to 5 years of age: Initially, 50–100 mcg/kg; a total dose of up to 600 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 6 mg.1 Children 6–12 years of age: Initially, 25–50 mcg/kg; a total dose of up to 400 mcg/kg may be required to reach the desired endpoint, but total dose usually does not exceed 10 mg.1 Adolescents 12–16 years of age: Dose as adults;1 some patients may require higher than recommended adult doses, but total dose usually does not exceed 10 mg.1 Dosage must be reduced in pediatric patients receiving opiates or other sedatives as premedications; higher-risk or debilitated patients may require lower dosages regardless of whether premedication was administered.1 IM Children ≥1 month of age: 100–150 mcg/kg; doses up to 500 mcg/kg have been used for more anxious patients.1 Total dose usually does not exceed 10 mg, although this has not been systematically studied.1 If midazolam is administered with an opiate, reduce the initial dose of each drug.1 Neonates IV IV loading doses should not be used in neonates; rather, the infusion may be administered more rapidly for the first several hours to establish therapeutic plasma drug concentrations.1 Preterm neonates (<32 weeks’ gestation): Initially, 30 mcg/kg per hour (0.5 mcg/kg per minute).1 Term neonates (≥32 weeks’ gestation): Initially, 60 mcg/kg per hour (1 mcg/kg per minute).1 Reassess the infusion rate carefully and frequently, particularly after approximately the first 24 hours, to administer the lowest possible effective dosage and to reduce the potential for drug accumulation.1 This is particularly important because of the potential for adverse effects related to benzyl alcohol metabolism.1 (See Pediatric Use under Cautions.) Non-neonatal Pediatric Patients (Intubated) IV Initially, 50–200 mcg/kg as a loading dose, followed by a continuous IV infusion initiated at a rate of http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROP Sedation in Critical-care Settings Drugs.com Print Version 60–120 mcg/kg per hour (1–2 mcg/kg per minute) to maintain the clinical effect.1 Increase or decrease the infusion rate as required, generally by 25% of the initial or subsequent infusion rate, or administer supplemental IV doses to increase or maintain the desired effect.1 Perform frequent patient assessments at regular intervals using standard pain/sedation scales.1 Midazolam infusions have been used in children whose trachea was intubated but who were allowed to breathe spontaneously; however, assisted ventilation is recommended in those who are receiving other CNS depressants (e.g., opiates).1 In hemodynamically compromised children, initiate therapy by titrating the usual loading dose in small increments; monitor the patient closely for hemodynamic instability (e.g., hypotension).1 Adults Preoperative Sedation, Anxiolysis, and Anterograde Amnesia IM 70–80 mcg/kg (about 5 mg) administered approximately 30–60 minutes prior to surgery.1 3 14 180 181 If administered concomitantly with an opiate agonist or other CNS depressant, the midazolam dosage must be individualized and reduced.1 Procedural Sedation IV Initial dose of ≤2.5 mg in healthy adults <60 years of age; some patients may respond to as little as 1 mg.1 193 Total dose of ≤5 mg generally is adequate.1 If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses in increments of approximately 25% of the initial dose.1 3 A total dose up to 200 mcg/kg has been used rarely, particularly if an opiate agonist was not used concomitantly;3 157 191 192 avoid such doses, if possible.180 When used concomitantly with an opiate agonist or other CNS depressant, reduce midazolam dosage by about 30%.1 3 14 157 Induction and Maintenance of Anesthesia IV Individual response is variable, especially when opiate agonist premedication is not used; therefore, titrate dosage carefully to the desired clinical effect, taking into consideration the patient’s age and clinical status.1 2 3 70 When used prior to other anesthetic agents for the induction of general anesthesia,1 3 the initial dose of each of these agents may be substantially reduced, in some instances to as low as 25% of the usual initial dose of the individual agents.1 Without Opiate Premedication IV Initial dose of 300–350 mcg/kg administered IV over 20–30 seconds in patients <55 years of age; allow http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROQ Some clinicians recommend initiating dosing with 0.5–2 mg and repeating doses, as necessary, at 2- to 3-minute intervals up to a total dose of 100–150 mcg/kg.14 181 Drugs.com Print Version approximately 2 minutes for clinical effect.1 3 157 180 Alternatively, some clinicians recommend an initial dose of 200 mcg/kg.14 144 181 Supplemental doses of about 25% of the initial dose may be given as necessary to complete induction or for maintenance of sedation or anesthesia.1 3 14 157 Alternatively, induction of anesthesia may be completed with inhalation agents.1 3 157 Total IV induction doses of up to 600 mcg/kg may be required in some resistant patients, but such doses may prolong recovery from anesthesia.1 3 4 100 157 With Opiate or Sedative Premedication IV Initial dose of 150–350 mcg/kg as an induction dose in patients <55 years of age.1 3 157 Usual induction dose is 250 mcg/kg administered IV over 20–30 seconds; allow approximately 2 minutes for clinical effects.1 3 157 For maintenance of anesthesia (as a component of balanced anesthesia) during short surgical procedures: Following premedication with an opiate agonist,1 3 administer in incremental IV doses of approximately 25% of the initial induction dose when lightening of anesthesia is evident.1 3 Repeat as necessary according to patient’s response to maintain the required level of anesthesia.1 3 Sedation in Critical-care Settings IV If a loading dose is necessary to initiate sedation rapidly, 10–50 mcg/kg (approximately 0.5–4 mg) administered slowly or infused over several minutes.1 Repeat this dose at 10- to 15-minute intervals until adequate sedation is achieved.1 Usual initial infusion rate for maintenance of sedation is 20–100 mcg/kg per hour (approximately 1–7 mg per hour).1 Higher loading doses or maintenance infusion rates occasionally may be required.1 Infuse at the lowest rate that produces the desired level of sedation.1 Assess sedation at regular intervals and adjust the infusion rate up or down by 25–50% of the initial infusion rate to ensure adequate titration of the sedation level.1 Larger adjustments or even a small, incremental dose may be necessary if rapid changes in the level of sedation are required.1 Decrease infusion rate by 10–25% every few hours to find the minimum effective infusion rate.1 Consider administering an opiate concomitantly in patients experiencing agitation, hypertension, or tachycardia in response to noxious stimuli but who otherwise are adequately sedated.1 Addition of an opiate generally will reduce the minimum effective midazolam infusion rate.1 Prescribing Limits Pediatric Patients Preoperative Sedation, Anxiolysis, and Anterograde Amnesia or Procedural Sedation Oral Children 6 months to 16 years of age: Maximum 20 mg.219 IV http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROR In patients with residual effects from anesthetic agents or in those currently receiving other sedatives or opiates, use the lowest recommended dosage.1 Drugs.com Print Version Manufacturer states that the total dose usually does not exceed 6 mg in pediatric patients 6 months to 5 years of age or 10 mg in those 6–16 years of age.1 IM Manufacturer states that the total dose usually does not exceed 10 mg in pediatric patients ≥1 month of age, although this has not been systematically studied.1 Procedural Sedation IV Manufacturer states that the total dose usually does not exceed 6 mg in pediatric patients 6 months to 5 years of age or 10 mg in those 6–16 years of age.1 Adults Procedural Sedation IV Initial dose for sedation should not exceed 2.5 mg.1 Special Populations Renal Impairment Use with caution and individualize dosage carefully.1 2 4 7 31 33 34 42 70 163 (See Renal Impairment under Cautions.) CHF Use with caution and individualize dosage carefully.1 3 35 50 163 (See Special Populations under Pharmacokinetics and also Other Populations under Dosage and Administration.) Reduce initial dose, since some degree of impairment in 1 or more organ systems frequently is present.1 3 157 163 193 Dosage requirements in this age group generally appear to decrease with increasing age;1 163 consider the possibility of profound and/or prolonged effects in older and/or debilitated patients.1 Low doses usually are required when midazolam is administered with or without premedication.1 3 157 163 193 Dosage titration should be more gradual in patients ≥60 years of age receiving midazolam for procedural sedation and in those ≥55 years of age receiving the drug for induction of anesthesia.1 157 163 180 Use the smallest effective dose.1 3 Excessive doses or rapid or single large IV injections may result in respiratory depression and/or arrest.1 3 157 163 193 Preoperative Sedation, Anxiolysis, and Anterograde Amnesia in Patients ≥60 Years of Age IM: In patients ≥60 years of age who did not receive concomitant opiate agonist therapy, doses of 2–3 mg (20–50 mcg/kg) have produced adequate preoperative sedation;1 1 mg may be sufficient in some geriatric patients if the anticipated intensity and duration of sedation is less critical.1 Procedural Sedation in Patients ≥60 Years of Age http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROS Geriatric Patients Drugs.com Print Version IV: Initial dose of ≤1.5 mg 1 193 over ≥2 minutes; wait ≥2 minutes to fully evaluate the clinical response.1 If further sedation is required, the dosage may be further titrated in small increments (≤1 mg) of the initial dose to the desired effect (e.g., onset of slurred speech).1 Total dose of ≤3.5 mg usually is adequate.1 If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses that are1 3 reduced by ≥25%.14 When used concomitantly with an opiate or other CNS depressant, reduce midazolam dosage to about 50% of that used in young, unpremedicated adults.1 Induction and Maintenance of Anesthesia in Patients ≥55 Years of Age IV: Manufacturer recommends an initial IV induction dose of 300 mcg/kg if premedication has not been given.1 3 157 If premedication has been given, manufacturer recommends an initial induction dose of 200 mcg/kg if the patient is a good risk (e.g., ASA I and II) surgical patient.1 3 Other Populations Preoperative Sedation, Anxiolysis, and Anterograde Amnesia in Patients with COPD or Other Higher-risk Surgical Patients IM: Individualize and reduce dosage in patients with COPD and in other higher-risk surgical patients.1 Procedural Sedation in Chronically Ill or Debilitated Patients IV: Smaller increments in dosage and slower rate of injection recommended in patients with chronic debilitating illnesses (e.g., CHF) or decreased pulmonary reserve because of the increased risk of underventilation or apnea and because the peak drug effect may occur later.1 3 157 163 180 193 Administer initial dose of ≤1.5 mg 1 193 over ≥2 minutes; wait ≥2 minutes to fully evaluate the clinical response.1 If further sedation is required, the dosage may be further titrated in small increments (≤1 mg) of the initial dose to the desired effect (e.g., onset of slurred speech).1 Total dose of ≤3.5 mg usually is adequate.1 When used concomitantly with an opiate or other CNS depressant, reduce midazolam dosage to about 50% of that used in young, unpremedicated adults.1 Induction and Maintenance of Anesthesia in Patients with Severe Systemic Disease or Other Debilitation IV: Unpremedicated patients: Initial dose of 200–250 mcg/kg usually is adequate; doses as low as 150 mcg/kg may be adequate for induction in some patients.1 3 157 Premedicated patients: Doses as low as 150 mcg/kg may be adequate for induction in some patients.1 3 157 Cautions for Midazolam Hydrochloride Contraindications Known hypersensitivity to midazolam or any ingredient in the formulation; oral solution contraindicated in patients with allergies to cherries.1 219 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROT If a thorough clinical evaluation clearly indicates a need for additional doses to maintain the desired level of sedation, administer additional doses that are1 3 reduced by ≥25%.14 Drugs.com Print Version Acute angle-closure glaucoma (but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy).1 Midazolam hydrochloride injection contains benzyl alcohol and is not intended for intrathecal or epidural administration.1 Warnings/Precautions Warnings Respiratory and Cardiovascular Effects Possible serious and occasionally fatal adverse effects, including respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest, and/or cardiac arrest,1 2 37 137 139 157 163 175 193 particularly in patients receiving midazolam concomitantly with other CNS depressants1 250 and in those undergoing procedures involving the airway without the protective effect of an endotracheal tube, in geriatric or severely ill patients, or in patients with limited pulmonary reserve or unstable cardiovascular status, or if the drug is administered IV too rapidly.1 Possible hypotensive episodes requiring treatment during or following diagnostic or surgical manipulation.1 Concomitant administration of an opiate agonist may increase the risk of severe hypotension.1 4 14 112 Do not administer parenterally to patients with shock, those who are comatose, or those with acute alcohol intoxication and accompanying depression of vital signs.1 Exercise caution if administered IV to patients with uncompensated acute illnesses, including severe fluid or electrolyte imbalances.1 Slow administration and individualized titration of dosage is required.1 Administer orally or IV only in settings in which continuous monitoring of respiratory and cardiac function (i.e., pulse oximetry) is possible.1 250 Potential for hypoxia and/or cardiac arrest if early signs of hypoventilation, airway obstruction, or apnea are not corrected immediately.1 Monitoring of vital signs should continue during recovery period.1 Should be used for procedural sedation only in the presence of personnel experienced in early detection of underventilation, maintenance of an adequate airway, and respiratory support.1 163 193 219 When the complexity of the procedure prohibits adequate monitoring by the attending clinician, additional personnel competent in monitoring and managing potential complications should be in attendance.1 163 175 For deeply sedated pediatric patients, an individual other than the clinician performing the procedure should be dedicated to monitoring the patient throughout the procedure.1 250 Facilities, age- and size-appropriate equipment for bag/mask/valve ventilation and intubation, drugs, skilled personnel necessary for ventilation and intubation, administration of oxygen, assisted or controlled respiration, airway management, and cardiovascular support should be immediately available when midazolam is administered.1 250 Immediate availability of specific reversal agents (e.g., flumazenil) is recommended.1 CNS Depression Performance of activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) may be impaired;1 157 such activities should not be performed until the effects of the drug (e.g., drowsiness) have subsided or until the day after anesthesia and surgery, whichever is longer.1 157 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROU Should be administered as an induction agent only by individuals who are experienced in the use of general anesthesia.1 163 193 219 Drugs.com Print Version Concurrent use of other CNS depressants may increase the extent and duration of impaired performance, cause excessive sedation, and interfere with recall and recognition of events on the day of surgery and the following day.1 250 (See Specific Drugs under Interactions.) Paradoxical Reactions Agitation, involuntary movements, hyperactivity, and/or combativeness may be manifestations of paradoxical reactions or may be signs of inadequate or excessive dosing, improper administration, or cerebral hypoxia.1 163 Evaluate the patient’s response to each dose as well as to any concomitantly administered drug, including local anesthetics, before proceeding.1 163 Intra-arterial Injection Local reactions and isolated reports of seizure activity (causal relationship not established) reported following intra-arterial injection.1 Avoid extravasation and take precautions against unintended intraarterial injection.1 Withdrawal Syndrome Patients receiving continuous infusions of midazolam in critical-care settings over an extended period of time may experience symptoms of withdrawal following discontinuance.1 General Precautions General Anesthesia Does not fully prevent the increase in intracranial pressure or the cardiovascular effects (e.g., increase in BP and/or heart rate) associated with endotracheal intubation under light general anesthesia.1 2 37 70 93 94 126 Does not appear to prevent the usual cardiovascular stimulatory effects associated with administration of some neuromuscular blocking agents (e.g., succinylcholine, pancuronium) or the increase in intracranial pressure associated with succinylcholine.1 Expect more intense and prolonged sedation when midazolam is administered concomitantly with a CYP3A4 inhibitor; use concomitantly with caution.250 Use lower than recommended oral doses.250 (See Interactions.) Specific Populations Pregnancy Category D.1 Preoperative use for obstetric procedures (e.g., cesarean section) or during labor and delivery is not recommended.1 3 Lactation Distributed into milk.1 Use with caution.1 Pediatric Use Safety and efficacy of the oral solution have not been established in infants <6 months of age.219 Children generally require a higher parenteral dosage on a mg/kg basis than do adults;1 children <6 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSROV Interactions with CYP3A4 Inhibitors Drugs.com Print Version years of age generally require higher drug dosages on a mg/kg basis than do older pediatric patients and may require closer monitoring.1 Higher-risk surgical patients may require lower doses, whether or not concomitant sedating drugs have been administered.219 Increased potential for respiratory depression, airway obstruction, or hypoventilation when administered in conjunction with opiates or other sedatives.1 Take particular care to ensure safe ambulation following sedation.1 219 Children with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effects.219 Pediatric patients undergoing procedures involving the upper airway (e.g., upper endoscopy, dental care) are particularly vulnerable to episodes of oxygen desaturation and hypoventilation secondary to partial airway obstruction.219 Neonates are vulnerable to profound and/or prolonged adverse respiratory effects because of reduced and/or immature organ function.1 Do not administer by rapid IV injection (i.e., over <2 minutes) in neonates, since rapid administration has been associated with severe hypotension (particularly when coadministered with fentanyl) and seizures.1 Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates;224 225 226 227 228 229 230 each mL of midazolam hydrochloride injection contains 10 mg of benzyl alcohol.1 Geriatric Use Safe oral dosing regimen of midazolam has not been established.250 Increased incidence of hypoxia reported in geriatric patients receiving midazolam hydrochloride 7.5 mg as premedication prior to general anesthesia.250 Until further information is available, oral midazolam is not recommended in geriatric patients.250 Select parenteral dosage carefully, since distribution may be altered and patients may have decreased hepatic and/or renal function.1 Reduce the dosage, particularly in those ≥70 years of age.1 (See Geriatric Patients under Dosage and Administration.) Fatalities (possibly associated with cardiac or respiratory depression) reported rarely in geriatric and/or high-risk surgical patients receiving IV or IM midazolam (often in combination with other CNS depressants [e.g., opiates]).1 (See Respiratory and Cardiovascular Effects under Cautions.) Monitor closely for signs of cardiac or respiratory depression.1 Hepatic Impairment Plasma clearance may be decreased in some patients with chronic liver disease.48 Renal Impairment Use with caution since the pharmacokinetics of the drug may be altered.1 2 4 7 31 33 34 42 70 163 (See Renal Impairment under Dosage and Administration.) Induction of anesthesia may occur more rapidly, and recovery may be prolonged.2 4 31 33 34 42 70 Common Adverse Effects Parenteral administration: Changes in respiratory rate, BP, pulse rate.1 2 4 7 Oral administration: Emesis, nausea, hypoxia, laryngospasm, agitation.250 http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPM When used for induction of anesthesia, time to recovery may be delayed.1 Drugs.com Print Version Interactions for Midazolam Hydrochloride Metabolized by CYP3A4.1 219 Drugs Affecting Hepatic Microsomal Enzymes Potential pharmacokinetic interaction (increased plasma midazolam concentrations) with inhibitors of CYP3A4.1 219 Use with caution and monitor for excessive sedation.1 216 Dosage adjustment of midazolam and/or other drugs may be needed.219 233 When oral midazolam is administered concomitantly with a CYP3A4 inhibitor, expect more intense and prolonged sedation and use lower than recommended oral doses.250 Potential pharmacokinetic interaction (decreased plasma midazolam concentrations) with inducers of CYP3A4.1 219 Caution advised if midazolam is used concomitantly with CYP3A4 inducers.219 232 233 Dosage adjustment of midazolam and/or other drugs may be needed.219 233 Specific Drugs and Foods Interaction Aminophylline Possible antagonism of sedative effect during anesthesia132 Comments Anesthetic agents, inhalation Minimum alveolar concentration of halothane required for general anesthesia appears to be decreased in a linear, doserelated manner with concomitant administration of IV midazolam1 2 3 70 141 Patients who have received midazolam as an induction agent may require reduced amounts of inhalation agents during maintenance of anesthesia1 2 70 141 Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin) Decreased peak plasma concentration and AUC of midazolam reported with concomitant use of oral midazolam and phenytoin or carbamazepine;250 similar effects expected with phenobarbital219 Use with caution;219 232 233 consider dosage adjustments, if necessary219 Antifungals, azole (fluconazole, itraconazole, ketoconazole) Decreased plasma clearance and increased peak plasma concentration of midazolam reported with oral midazolam;219 potential for intense and prolonged sedation and respiratory depression219 Use oral or parenteral midazolam with caution in patients receiving these antifungals250 Reduce oral midazolam dosage250 Administer oral midazolam concomitantly with itraconazole or ketoconazole only if absolutely necessary and with appropriate equipment and personnel available to manage respiratory insufficiency219 250 Antimycobacterials (rifabutin, Decreased peak plasma 233 Use with caution;1 consider dosage http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPN Drug or Food Drugs.com Print Version rifampin) concentration and AUC of midazolam reported with concomitant use of oral midazolam and rifampin; similar effects expected with rifabutin219 adjustments, if necessary250 Calcium-channel blocking agents (diltiazem, nifedipine, nitrendipine, verapamil) Increased peak plasma concentration of midazolam reported with concomitant use of oral midazolam and diltiazem or verapamil;219 231 233 potential for intense and prolonged sedation and respiratory depression250 Pharmacokinetic interaction unlikely with nifedipine1 or nitrendipine250 Use oral or parenteral midazolam with caution in patients receiving diltiazem or verapamil;1 reduce oral midazolam dosage233 250 CNS depressants (e.g., opiate agonists or other analgesics, barbiturates, sedatives, anesthetics, alcohol) Additive CNS effects, possibly resulting in respiratory depression and profound and/or prolonged underventilation or apnea1 3 4 14 Use with caution; adjust dosage appropriately to avoid overdosage1 3 4 14 (see Dosage under Dosage and Administration) Delavirdine Potential for decreased midazolam metabolism resulting in intense and prolonged sedation and respiratory depression247 Manufacturer of delavirdine states that concomitant use is contraindicated;247 however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations249 Efavirenz Potential for decreased midazolam metabolism resulting in intense and prolonged sedation and respiratory depression248 Manufacturer of efavirenz states that concomitant use is contraindicated;248 however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations249 Grapefruit juice Increased bioavailability of oral midazolam with concomitant administration;196 197 219 does not appear to interfere with metabolism following IV administration197 203 Manufacturer states that oral midazolam should not be taken in conjunction with grapefruit juice219 Histamine H2-receptor antagonists (e.g., cimetidine, ranitidine) Possible increased plasma midazolam concentrations143 160 Carefully observe patient for CNS and respiratory depression; reduce midazolam dosage if necessary160 161 161 219 162 HIV protease inhibitors (e.g., amprenavir [no longer Decreased clearance and increased plasma Manufacturers of HIV protease inhibitors state that concomitant use http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPO 163 175 189 190 Drugs.com Print Version concentrations of midazolam;1 238 250 potential for intense and prolonged sedation and respiratory depression238 239 240 Ketamine Midazolam may antagonize, at least partially, the cardiovascular stimulatory effects and the postoperative emergence delirium usually associated with ketamine4 104 134 Macrolide antibiotics Decreased clearance of midazolam with concomitant use of erythromycin and IV195 or oral midazolam;195 216 218 may result in excessive sedative effects195 216 Pharmacokinetic interaction unlikely with oral midazolam and azithromycin219 Some clinicians state that erythromycin should not be given to patients receiving midazolam or, alternatively, that the midazolam dosage should be reduced in patients receiving the antiinfective195 Opiates (e.g., fentanyl) Increased risk of hypotension and prolongation of the recovery period;1 2 139 severe hypotension reported with concomitant administration of fentanyl in neonates1 Increased potential for respiratory depression, airway obstruction, and hypoventilation219 250 Use with caution; adjust midazolam dosage appropriately to avoid overdosage1 3 4 14 (see Dosage under Dosage and Administration) Quinupristin and Dalfopristin Increased peak plasma concentration and AUC of midazolam reported with concomitant use of a single IV dose of midazolam with quinupristin and dalfopristin234 Use with caution; monitor patients for excessive sedation1 216 Terbinafine No change in midazolam pharmacokinetics219 Thiopental 241 242 243 244 245 246 250 251 is contraindicated;238 239 240 241 242 243 244 245 246 251 however, some experts state that a single midazolam dose can be used with caution for procedural sedation in monitored situations249 Thiopental dosage requirements for induction of anesthesia reduced by about 15% in patients who received preoperative sedation with IM midazolam1 3 Midazolam Hydrochloride Pharmacokinetics Absorption http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPP commercially available in the US], atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir) Drugs.com Print Version Bioavailability Rapidly absorbed following IM administration,1 3 4 5 6 8 9 10 11 12 13 14 15 16 157 with peak plasma concentrations generally attained within 45 minutes.1 8 157 Absolute bioavailability is >90%.1 4 8 9 157 Rapidly absorbed from the GI tract following oral administration,2 4 7 18 19 20 21 22 23 219 with peak plasma concentrations usually attained within 1–2 hours.2 4 7 18 19 20 21 22 23 24 219 The drug undergoes substantial first-pass metabolism in the liver and intestine;2 7 18 22 24 35 219 only about 40–50% (range: 28–72%) of a dose reaches systemic circulation unchanged.2 4 7 18 19 20 21 22 24 Onset Following IM administration, effects usually are apparent within 5–15 minutes1 3 4 9 14 32 81 157 but may not be maximal until 15–60 minutes.1 2 4 8 9 10 11 12 13 15 16 81 157 Following IV administration, the onset of sedative, anxiolytic, and amnesic action usually occurs within 1–5 minutes.1 2 3 4 7 9 13 21 25 26 86 87 157 Induction of anesthesia usually occurs in about 1.5 minutes when midazolam is administered concurrently with opiate agonists and in 2–2.5 minutes when administered without an opiate agonist or other sedatives.1 2 27 28 157 Following administration of the oral solution in children, pharmacologic effects usually are apparent within 10–20 minutes.219 Duration Following IM administration, the duration of action usually is about 2 hours1 3 (range: 1–6 hours).1 3 8 9 10 14 Duration of anterograde amnesia following IM administration is about 1 hour.1 2 10 25 69 Following IV administration, duration of action is usually <2 hours;1 3 4 7 8 9 21 29 157 however, effects may persist up to 6 hours in some patients, and the duration of action appears to be dose related.1 3 8 9 20 29 157 Anterograde amnesia persists for about 20–40 minutes following a single IV dose.2 4 7 25 26 Extent Rapidly and widely distributed following IV administration.1 2 3 4 24 35 36 37 38 Crosses the blood-brain barrier and distributes into CSF.7 14 15 16 Crosses the placenta and 1 2 3 7 23 35 43 157 is distributed into milk.1 Plasma Protein Binding Approximately 94–97% (mainly to serum albumin2 4 7 34 37 42 ) in adults and children >1 year of age.1 2 3 7 18 20 24 31 36 37 41 42 45 157 219 Degree of protein binding appears to be independent of plasma concentration.2 24 41 219 Special Populations Distribution may be altered in geriatric patients.1 Elimination http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPQ Distribution Drugs.com Print Version Metabolism Extensively metabolized in the liver and intestine by CYP3A41 3 7 21 24 54 55 157 219 to active and inactive metabolites.1 5 219 Metabolites undergo rapid conjugation with glucuronic acid in the liver.1 2 3 4 7 17 24 54 55 58 157 Activity is related principally to the parent drug.1 Elimination Route Excreted in urine almost entirely as conjugated metabolites.1 2 3 4 7 17 24 54 55 58 157 Approximately 2–10% of an oral dose is excreted in feces.4 55 Half-life Biphasic; following IV administration, half-life in the initial distribution phase averages 6–20 minutes in adults;2 4 28 19 20 56 terminal half-life averages 1–4 hours (range: 1–12.3 hours).1 2 3 4 7 13 14 19 20 21 22 24 34 35 36 37 38 44 45 46 47 149 157 Terminal elimination half-life of 2.6–6.8 hours reported in pediatric patients 6 months to <16 years of age;219 terminal elimination half-life is substantially prolonged (i.e., 6.5–12 hours) in seriously ill neonates.1 Special Populations Half-life may be prolonged in geriatric patients.2 3 7 18 24 37 49 51 52 Half-life prolonged in patients receiving the drug for induction of anesthesia associated with major surgical procedures.7 52 In some patients with chronic liver disease, plasma clearance may be decreased.48 In patients with CRF, total plasma clearance and volume of distribution of total (bound and unbound) midazolam are increased,1 2 7 42 but these alterations are attributable to changes in protein binding.2 7 42 In patients with CHF, prolonged elimination half-life, increased volume of distribution, and delayed onset of action secondary to prolonged circulation time.1 3 35 50 157 163 Storage Oral Solution 25°C (may be exposed to 15–30°C).250 Parenteral Injection 15–30°C.1 Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPR Stability Drugs.com Print Version Parenteral Solution CompatibilityHID Compatible Dextrose 5% in sodium chloride 0.9% Dextrose 5% in water Sodium chloride 0.9% Incompatible Ringer’s injection, lactated Variable Dextrose 5% in water with potassium chloride 0.15% Drug Compatibility Admixture CompatibilityHID Compatible Cefuroxime sodium Ciprofloxacin Furosemide Gentamicin sulfate Hydromorphone HCl Metronidazole Variable Aminophylline Sodium bicarbonate Y-Site CompatibilityHID Compatible Abciximab Amikacin sulfate Amiodarone HCl Anidulafungin Argatroban http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPS Ranitidine HCl Drugs.com Print Version Atracurium besylate Bivalirudin Calcium gluconate Caspofungin acetate Cefazolin sodium Cefotaxime sodium Ceftaroline fosamil Ciprofloxacin Cisatracurium besylate Clindamycin phosphate Dexmedetomidine HCl Digoxin Diltiazem HCl Dopamine HCl Doripenem Epinephrine HCl Erythromycin lactobionate Esmolol HCl Etomidate Famotidine Fentanyl citrate Fluconazole Gentamicin sulfate Haloperidol lactate Heparin sodium Hetastarch in lactated electrolyte injection (Hextend) Hydromorphone HCl Hydroxyethyl starch 130/0.4 in sodium chloride 0.9% Insulin, regular Labetalol HCl http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPT Fenoldopam mesylate Drugs.com Print Version Linezolid Lorazepam Methadone HCl Methylprednisolone sodium succinate Metronidazole Milrinone lactate Morphine sulfate Nicardipine HCl Nitroglycerin Norepinephrine bitartrate Palonosetron HCl Pancuronium bromide Potassium chloride Ranitidine HCl Remifentanil HCl Sodium nitroprusside Theophylline Tirofiban HCl Tobramycin sulfate Vancomycin HCl Incompatible Albumin human Amphotericin B cholesteryl sulfate complex Ampicillin sodium Bumetanide Butorphanol tartrate Cefepime HCl Ceftazidime Cefuroxime sodium Co-trimoxazole http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPU Vecuronium bromide Drugs.com Print Version Dexamethasone sodium phosphate Foscarnet sodium Fosphenytoin sodium Furosemide Hydrocortisone sodium succinate Imipenem–cilastatin sodium Methotrexate sodium Micafungin sodium Nafcillin sodium Omeprazole Pantoprazole sodium Sodium bicarbonate Variable Clonidine HCl Dobutamine HCl Propofol Actions Advice to Patients Importance of informing patients of the pharmacologic effects of midazolam (e.g., sedation, lack of recall), which in some patients may be profound.1 250 Potential for midazolam to impair mental alertness or physical coordination; avoid driving or operating machinery until the effects of the drug (e.g., drowsiness) have subsided or until the day after anesthesia and surgery, whichever is longer.1 157 Importance of ensuring safe ambulation in pediatric patients receiving oral midazolam.250 Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 250 Use caution with simultaneous ingestion of alcohol during treatment.1 250 Importance of women informing clinicians if they are or plan to become pregnant or plan to breastfeed.1 250 Importance of informing patients of other important precautionary information.1 250 (See Cautions.) http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRPV Effects appear to be mediated through the inhibitory neurotransmitter GABA; the site and mechanism of action within the CNS appear to involve a macromolecular complex (GABAAreceptor-chloride ionophore complex) that includes GABAA receptors, high-affinity benzodiazepine receptors, and chloride channels. Drugs.com Print Version Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1 179 * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Midazolam Hydrochloride Routes Dosage Forms Strengths Brand Names Oral Solution 2 mg (of midazolam) per mL* Midazolam Hydrochloride Syrup (C-IV) Parenteral Injection 1 mg (of midazolam) per mL* Midazolam Hydrochloride Injection (C-IV) 5 mg (of midazolam) per mL* Midazolam Hydrochloride Injection (C-IV) Manufacturer AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. † Use is not currently included in the labeling approved by the US Food and Drug Administration. References 1. Roche Laboratories. Versed (midazolam hydrochloride) prescribing information. Nutley, NJ; 2000 Jun. 3. Hoffmann-La Roche Inc. Product Information Summary on Versed. Nutley, NJ; 1985 Feb. 4. Kanto JH. Midazolam: the first water-soluble benzodiazepine: pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy. 1985; 5:138-55. [IDIS 393485] [PubMed 3161005] 5. Pieri L, Schaffner R, Scherschlicht R et al. Pharmacology of midazolam. Arzneimittelforschung. 1981; 31:2180-201. [PubMed 6120698] 6. Pieri L. Preclinical pharmacology of midazolam. Br J Clin Pharmacol. 1983; 16(Suppl 1):17-27. [IDIS 173158] [PubMed 6349668] 7. Dundee JW, Halliday NJ, Harper KW et al. Midazolam: a review of its pharmacological properties and therapeutic use. Drugs. 1984; 28:519-43. [IDIS 194410] [PubMed 6394264] 8. Crevoisier C, Eckert M, Heizmann P et al. Relation entre l’effet clinique et la pharmacocinétique du midazolam après administration i.v. et i.m. (French; with English abstract.) Arzneim-Forsch. 1981; 31:2211-5. http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRQM 2. Reves JG, Fragen RJ, Vinik HR et al. Midazolam: pharmacology and uses. Anesthesiology. 1985; 62:310-24. [IDIS 199016] [PubMed 3156545] Drugs.com Print Version 9. Ziegler WH, Thurneysen JD, Crevoisier C et al. Relation entre l’effet clinique et la pharmacocinétique du midazolam après administration i.m. et i.v. chez des voluntaires. (French; with English abstract.) Arzneim-Forsch. 1981; 31:2206-10. 10. Fragen RJ, Funk DI, Avram MJ et al. Midazolam versus hydroxyzine as intramuscular premedicant. Can Anaesth Soc J. 1983; 30:136-41. [IDIS 167311] [PubMed 6831292] 11. Reves JG, Vinik HR, Wright D. Midazolam efficacy for intramuscular premedication: a double-blind placebo, hydroxyzine, controlled study. Anesthesiology. 1982; 57:A321. 12. Grote B, Doenicke A, Kugler J et al. Intramuskulare Applikation von Midazolam. (German; with English abstract.) ArzneimForsch. 1981; 31:2224-5. 13. Amrein R, Cano JP, Eckert M et al. Pharmakokinetik von Midazolam nach intravenöser Verabreichung. (German; with English abstract.) Arzneim-Forsch. 1981; 31:2202-5. 14. Anon. Midazolam. Med Lett Drugs Ther. 1986; 28:73-4. [PubMed 2942752] 15. Heinemeyer G, Reinhart K, Nigam S et al. Correlation of sedative and respiratory effects of midazolam with concentrations on serum and liquor cerebrospinalis. Naunyn-Schmeideberg’s Arch Pharmacol. 1982; 321(Suppl):R58. 16. Sjövall S, Kanto J, Himberg JJ et al. CSF penetration and pharmacokinetics of midazolam. Eur J Clin Pharmacol. 1983; 25:24751. [IDIS 177425] [PubMed 6628509] 17. Gerecke M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br J Clin Pharmacol. 1983 16:11-6S. 18. Greenblatt DJ, Abernethy DR, Locniskar A et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984; 61:27-35. [IDIS 187970] [PubMed 6742481] 20. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther. 1981; 30:653-61. [IDIS 142008] [PubMed 6117393] 21. Smith MT, Eadie MJ, Brophy TO. The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol. 1981; 19:271-8. [IDIS 134343] [PubMed 6116606] 22. Heizmann P, Eckert M, Ziegler WH. Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol. 1983; 16:43-9S. 23. Kanto J, Sjövall S, Erkkola R et al. Placental transfer and maternal midazolam kinetics. Clin Pharmacol Ther. 1983; 33:786-91. [IDIS 171775] [PubMed 6851409] 24. Greenblatt DJ, Abernethy DR. Midazolam pharmacology and pharmacokinetics. Anesthesiol Rev. 1985; 12(Suppl):17-20. 25. Conner JT, Katz RL, Pagano RR et al. RO 21-3981 for intravenous surgical premedication and induction of anesthesia. Anesth http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRQN 19. Klotz U, Ziegler G. Physiologic and temporal variation in hepatic elimination of midazolam. Clin Pharmacol Ther. 1982; 32:10712. [IDIS 153275] [PubMed 7083724] Drugs.com Print Version Analg. 1978; 57:1-5. [IDIS 93698] [PubMed 564624] 26. Dundee JW, Wilson DB. Amnesic action of midazolam. Anaesthesia. 1980; 35:459-61. [IDIS 209165] [PubMed 7396149] 27. Fragen RJ, Caldwell NJ. Awakening characteristics following anesthesia induction with midazolam for short surgical procedures. Arzneimittelforschung. 1981; 31:2261-3. [IDIS 209189] [PubMed 7199331] 28. Finucane BT, Judelman J, Braswell R. Comparison of thiopentone and midazolam for induction of anaesthesia: influence on diazepam premedication. Can Anaesth Soc J. 1982; 29:227-30. [IDIS 151410] [PubMed 7074402] 29. Crevoisier C, Ziegler WH, Eckert M et al. Relationship between plasma concentration and effect of midazolam after oral and intravenous administration. Br J Clin Pharmacol. 1983; 16:51-61S. [IDIS 173163] [PubMed 6882622] 30. Dundee JW, Halliday NJ, Loughran PG. Variation in response to midazolam. Br J Clin Pharmacol. 1984; 17:645-6P. 31. Reves JG, Newfield P, Smith LR. Midazolam induction time association with serum albumin. Anesthesiology. 1981; 55:A259. [IDIS 209230] [PubMed 7247063] 32. Mattila MAK, Suurinkeroinen S, Saila K et al. Midazolam and fat-emulsion diazepam as intramuscular premedication: a doubleblind clinical trial. Acta Anaesthesiol Scand. 1983; 27:345-8. [IDIS 209226] [PubMed 6356756] 33. Vinik R, Reves JG, Nixon D et al. Midazolam induction and emergence in renal failure patients. Anesthesiology. 1981; 55:A262. 34. Vinik HR, Reves JG, Greenblatt DJ et al. Pharmacokinetics of midazolam in renal failure patients. Anesthesiology. 1982; 57(Suppl):A366. 35. Weintraub M, Evans P. Midazolam: a water-soluble benzodiazepine for preoperative sedation and endoscopic procedures. Hosp Formul. 1986; 21:647-64. 37. Davis PJ, Cook DR. Clinical pharmacokinetics of the newer intravenous anaesthetic agents. Clin Pharmacokinet. 1986; 11:1835. [IDIS 210960] [PubMed 3512140] 38. Greenblatt DJ, Locniskar A, Ochs HR et al. Automated gas chromatography for studies of midazolam pharmacokinetics. Anesthesiology. 1981; 55:176-9. [IDIS 137261] [PubMed 6114686] 39. Arendt RM, Greenblatt DJ, deJong RH et al. Benzodiazepine entry into CSF and brain: kinetic, dynamic, and in vitro correlations. Clin Pharmacol Ther. 1983; 33:239. 40. Arendt RM, Greenblatt DJ, deJong RH et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther. 1983; 227:98-106. [PubMed 6137558] 41. Moschitto LJ, Greenblatt DJ. Concentration-independent plasma protein binding of benzodiazepines. J Pharm Pharmacol. 1983; 35:179-80. [PubMed 6132978] http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRQO 36. Greenblatt DJ, Divoll M, Abernethy DR et al. Clinical pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet. 1983; 8:233-52. [IDIS 170367] [PubMed 6133664] Drugs.com Print Version 42. Vinik HR, Reves JG, Greenblatt DJ et al. The pharmacokinetics of midazolam in chronic renal failure patients. Anesthesiology. 1983; 59:390-4. [IDIS 178103] [PubMed 6638545] 43. Vree TB, Reekers-Ketting JJ, Fragen RJ et al. Placental transfer of midazolam and its metabolite 1-hydroxymethylmidazolam in the pregnant ewe. Anesth Analg. 1984; 63:31-4. [PubMed 6691561] 44. Carlisle RJT, Dundee JW, Harper KW et al. Prolonged midazolam elimination half-life in a minority of patients. Br J Clin Pharmacol. 1985; 20:534P. 45. Dundee JW, Collier PS, Carlisle RJT et al. Prolonged midazolam elimination half-life. Br J Clin Pharmacol. 1986; 21:425-9. [IDIS 215144] [PubMed 2939863] 46. Dundee JW, Samuel IO, Toner W et al. Midazolam: a water-soluble benzodiazepine. Anaesthesia. 1980; 35:454-8. [IDIS 209164] [PubMed 7396148] 47. Allonen H, Anttila V, Klotz U. Effect kinetics of midazolam: a new hypnotic benzodiazepine derivative. Naunyn-Schmeideberg’s Arch Pharmacol. 1981; 316(Suppl):R74. 48. MacGilchrist AJ, Birnie GG, Cook A et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut. 1986; 27:190-5. [IDIS 214569] [PubMed 2936661] 49. Smith MT, Heazlewood V, Eadie MJ et al. Pharmacokinetics of midazolam in the aged. Eur J Clin Pharmacol. 1984; 26:381-8. [IDIS 185708] [PubMed 6734699] 50. Blumenthal P, Werres R, Rothfeld D et al. Clinical and pharmacokinetic observations after premedication of heart failure patients with midazolam. J Clin Pharmacol. 1984; 24:400. 51. Greenblatt DJ, Abernethy DR, Locniskar A et al. Midazolam kinetics in old age and obesity. Clin Pharmacol Ther. 1984; 35:244. 53. Lowry KG, Lyons SM, Carson IW et al. Midazolam v diazepam for sedation in a cardiac surgical intensive care unit. Br J Anaesth. 1984; 56:1288P. 54. Puglisi CV, Meyer JC, D’Arconte L et al. Determination of water-soluble imidazo-1,4-benzodiazepines in blood by electroncapture, gas-liquid chromatography and in urine by differential pulse polarography. J Chromatogr. 1978; 145:81-96. [PubMed 23388] 55. Heizmann P, Ziegler WH. Excretion and metabolism of14C-midazolam in humans following oral dosing. Arzneimittelforschung. 1980; 31:2220-3. 56. Ziegler WH, Schalch E, Leishman B et al. Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites. Br J Clin Pharmacol. 1983; 16:63-9S. 57. Rubio F, Miwa BJ, Garland WA. Determination of midazolam and two metabolites of midazolam in human plasma by gas chromatography—negative chemical-ionization mass spectrometry. J Chromatogr. 1982; 233:157-65. [IDIS 209208] [PubMed 7161330] http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRQP 52. Harper KW, Collier PS, Dundee JW et al. Age and nature of operation influence the pharmacokinetics of midazolam. Br J Anaesth. 1984; 56:1288-9P. Drugs.com Print Version 58. Vree TB, Baars AM, Booij LHD et al. Simultaneous determination and pharmacokinetics of midazolam and its hydroxymetabolites in plasma and urine of man and dog by means of high-performance liquid chromatography. Arzneimittelforschung. 1981; 31:2215-9. [PubMed 7199323] 59. Sjövall S, Kanto J, Iisalo E et al. Use of atropine in connection with oral midazolam premedication. Int J Clin Pharmacol Ther Toxicol. 1984; 22:184-8. [PubMed 6715087] 60. du Cailar J, Holzer J, Jullien Y et al. Hypnotic efficacy of midazolam in pre-surgical patients: a dose-finding study. Br J Clin Pharmacol. 1983; 16(Suppl):129-32S. 61. Klopfenstein C. Midazolam as oral premedication in local anaesthesia. Arzneimittelforschung. 1981; 31:2238. 62. du Cailar J, Cadi N, Jullien Y et al. Etude en double aveugle du midazolam sur le sommeil pre-operatoire. (French; with English abstract.) Arzneim-Forsch. 1981; 31:2239-43. 63. Sjövall S, Kanto J, Iisalo E et al. Midazolam versus atropine plus pethidine as premedication in children. Anaesthesia. 1984; 39:224-8. [PubMed 6703288] 64. Sjövall S, Kanto J, Kangas L et al. Comparison of midazolam and flunitrazepam for night sedation: a randomized double-blind study. Anaesthesia. 1982; 37:924-8. [PubMed 6127040] 65. Sjövall S, Kanto J, Gronroos M et al. Antidiuretic hormone concentrations following midazolam premedication. Anaesthesia. 1983; 38:1217-20. [PubMed 6140883] 66. Fragen RJ. Parenteral premedication with midazolam. Anesthesiology Rev. 1985; 12:(Suppl):37-9. 67. Kanto J. Benzodiazepines as oral premedicants. Br J Anaesth. 1981; 53:1179-88. [IDIS 167701] [PubMed 6119997] 69. Miller R. Commentary: premedication with intramuscular midazolam. Anesthesiology Rev. 1985; 12(Suppl):47-8. 70. Vinik HR. Midazolam induction and maintenance. Anesthesiology Rev. 1985; 12(Suppl):49-54. 71. Magni VC, Frost RA, Leung JWC et al. A randomized comparison of midazolam and diazepam for sedation in upper gastrointestinal endoscopy. Br J Anaesth. 1983; 55:1095-1101. [IDIS 178038] [PubMed 6139120] 72. Brophy T, Dundee JW, Heazelwood V et al. Midazolam, a water-soluble benzodiazepine, for gastroscopy. Anaesth Intens Care. 1982; 10:344-7. 73. Berggren L, Eriksson I, Mollenholt P et al. Sedation for fibreoptic gastroscopy: a comparative study of midazolam and diazepam. Br J Anaesth. 1983; 55:289-96. [IDIS 169239] [PubMed 6132613] 74. Al-Khudhairi D, McCloy RF, Whitwam JG. Comparison of midazolam and diazepam in sedation during gastroscopy. Gut. 1982; 23:A432-63. http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRQQ 68. Clarke RSJ. New drugs—boon or bane? Premedication and intravenous induction agents. Can Anaesth Soc J. 1983; 30:16673. [IDIS 167314] [PubMed 6339010] Drugs.com Print Version 75. Al-Khudhairi D, Whitwam JG, McCloy RF. Midazolam and diazepam for gastroscopy. Anaesthesia. 1982; 37:1002-6. [PubMed 6127968] 76. Kawar P, Dundee JW, Brophy TO et al. Midazolam: an alternative to diazepam as an intravenous hypnotic for endoscopy. Br J Clin Pharmacol. 1984; 17:221-2P. 77. Green JRB, Ravenscroft MM, Swan CHJ. Diazepam or midazolam for endoscopy. BMJ. 1984; 288:1383. [IDIS 185340] [PubMed 6424864] 78. Bardhan KD, Morris P, Taylor PC et al. Intravenous sedation of upper gastrointestinal endoscopy: diazepam versus midazolam. BMJ. 1984; 288:1046. 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[IDIS 380194] [PubMed 8989173] 222. Burns AM, Shelly MP, Park GR. The use of sedative agents in critically ill patients. Drugs. 1992; 43:507-15. [PubMed 1377117] http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRRP 216. Erythromycin interactions: benzodiazepines. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc., 1993:222-3. Drugs.com Print Version 223. Aitkenhead AR, Pepperman ML, Willatts SM et al. Comparison of propofol and midazolam for sedation in critically ill patients. Lancet. 1989; 2:704-9. [IDIS 259321] [PubMed 2570958] 224. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041] 225. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-1. [PubMed 7188569] 226. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084] 227. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:13848. [IDIS 160823] [PubMed 7133084] 228. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575] 229. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984] 230. Food and Drug Administration. Parenteral drug products containing benzyl alcohol or other antimicrobial preservatives; intent and request for information. [Docket No. 85N-0043] Fed Regist. 1985; 50:20233-5. 231. Forest Pharmaceuticals, Inc. Tiazac (diltiazem hydrochloride) extended release capsules prescribing information. St. Louis, MO; 1999 Oct. 232. Diltiazem (Cardizem) drug interaction: Midazolam (Versed). In: Hansten PD, Horn JR. Drug interactions analysis and management. Vancouver, WA: Applied Therapeutics, Inc; 1997:93. 234. Aventis Pharmaceuticals. Synercid (quinupristin/dalfopristin) for injection prescribing information. Collegeville, PA; 1999 July. 235. Task Force of the American College of Critical Care Medicine (ACCM) in collaboration with the American Society of HealthSystem Pharmacists (ASHP) and in alliance with the American College of Chest Physicians. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Am J Health-Syst Pharm. 2002; 59:150-78. [PubMed 11826570] 236. American Academy of Pediatrics, Committee on Drugs. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics. 1992;89:1110-1115. 237. American Academy of Pediatrics, Committee on Drugs. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: addendum. Pediatrics. 2002;110:836-8. 238. Roche Laboratories. Invirase (saquinavir mesylate) capsules prescribing information. Nutley, NJ; 2005 Sep. http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRRQ 233. Benzodiazepines/diltiazem. In: Tatro DS, Olin BR, Hebel SK, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1998 (April):128a. Drugs.com Print Version 239. GlaxoSmithKline. Agenerase (amprenavir) capsules prescribing information. Research Triangle Park, NC; 2005 May. 240. Bristol-Myers Squibb. Reyataz(atazanavir sulfate) prescribing information. Princeton, NJ; 2006 Feb 241. Merck & Company Inc. Crixivan (indinavir sulfate) capsules prescribing information. West Point, PA;2006 Apr. 242. Abbott Laboratories. Kaletra (lopinavir/ritonavir) oral tablets and solution prescribing information. North Chicago, IL; 2005 Oct. 243. Agouron Pharmaceuticals. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. La Jolla, CA; 2006 Apr 244. Abbott Laboratories. Norvir (ritonavir) soft gelatin capsules and oral solution prescribing information. North Chicago, IL; 2006 Jan. 245. Boehringer Ingelheim. Aptivus (tipranavir) capsules prescribing information. Ridgefield, CT; 2006 Jun 27. 246. GlaxoSmithKline. Lexiva (fosamprenavir calcium) tablets prescribing information. Research Triangle Park, NC; 2006 June. 247. Pfizer. Rescriptor (delavirdine mesylate) tablets prescribing information. La Jolla, CA; 2006 Feb. 248. Bristol-Myers Squibb Company. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2006 Mar 249. Panel on Clinical Practices for Treatment of HIV Infection of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website (). 250. Roxane Laboratories, Inc. Midazolam hydrochloride syrup prescribing information. Columbus, OH; 2004 Mar. HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:793-802. http://www.drugs.com/monograph/midazolam-hydrochloride.html?printable=1[12/2/2014 2:52:46 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRRR 251. Tibotec. Prezista (darunavir) prescribing information. Raritan, NJ; 2006 Jun. 300 Northfield Road Bedford, OH 44146 Telephone: (800) 562-4797 MATERIAL SAFETY DATA SHEET Section I - IDENTITY Common/Trade Name: Midazolam Injection, Preservative Free (1mg/mL and 5mg/mL) Chemical Names: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazole[1,5-a][1,4]benzodiazepine hydrochloride Synonyms: Midazolam Hydrochloride, Versed®, Hypnovel, Rocam Manufacturer's Name: BEN VENUE LABORATORIES, INC. Address: 300 NORTHFIELD ROAD BEDFORD, OH 44146 Emergency Telephone Number: Chemtrec: 1(800) 424-9300 Telephone Number for Info.: (800) 562-4797 or (440) 232-3320 Medical Emergency: Professional Services: 1(800) 521-5169 Date Prepared: June 30, 2000 Date Revised: December 21, 2001 Date Revised: July 17, 2007 Section II - HAZARDOUS INGREDIENTS/COMPOSITION INFORMATION 1mg/mL Midazolam Hydrochloride Sodium Chloride Water for Injection 0.1% 0.8% 99.1% 5mg/mL 0.5% 0.8% 98.7% CAS# Other Limits OSHA PEL ACGIH TLV Recommended 59467-96-8 7647-14-5 7732-18-5 NONE NONE NONE NONE NONE NONE 0.3 mcg/m3 NONE NONE Hydrochloric Acid and Sodium Hydroxide for pH adjustment Midazolam Hydrochloride is a sterile injectable liquid drug provided in a vial. Section III - HEALTH HAZARD DATA Routes of Entry: Exposure may occur via inhalation, ingestion or absorption through the skin or eyes. Product is a Benzodiazepine and is an anesthetic, Schedule IV controlled substance. Health Hazard (Acute & Chronic): Midazolam is an anesthetic used for preoperative sedation. It affects the central nervous system, muscular and digestive systems. Chronic exposure to Midazolam can cause a mild to moderate physical dependence. Carcinogenicity: NTP? NO IARC Monographs? None OSHA Regulated? NO 1 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRRS Component Signs & Symptoms of Exposure: Exposure may cause drowsiness, dizziness, sedation, hypnosis, temporary memory loss, decreased anxiety, muscle relaxation, and diminished reflexes. Exposure may also cause decrease in respiratory rate, lack of muscle coordination, confusion, headache, dry mouth, fatigue, nervousness, nausea, vomiting and hiccups. Medical Conditions Generally Aggravated by Exposure:. Persons sensitive to benzodiazepine drugs may experience allergic reaction. Midazolam exposure may also aggravate glaucoma, lung, heart and kidney disease. Exposure is not recommended for pregnant women since benzodiazepine can cross the placental barrier and can increase the risk of congenital malformations. BVL Hazard Category: 3 Section IV - FIRST AID MEASURES Eye Exposure: Flush eyes with large volumes of water for 15 minutes. Skin Exposure: Wash skin with cool, soapy water for 15 minutes. Ingestion: Seek medical attention from a physician. Induce vomiting if person is conscious. Never induce vomiting in an unconscious person. Inhalation: If difficulty breathing, administer oxygen. Seek attention of a physician immediately. If overdose occurs, monitor vital signs and treat symptomatically. Flumazenil may be given by a physician for complete or partial reversal of the effects of midazolam. Section V - FIRE AND EXPLOSION HAZARD DATA Flash Point (Method Used): Not Applicable Flammable Limits: Not Available LEL: NA UEL: NA Extinguishing Media: Use water or a multi-purpose ABC fire extinguisher. Special Fire Fighting Procedures: As with all fires, evacuate personnel to a safe area. Fire fighters should wear self-contained breathing apparatus to avoid smoke inhalation. Product is aqueous based and presents little concern for fire hazard. Unusual Fire/Explosion Hazards: None Release to Land: Absorb Midazolam with absorbent materials and dispose of according to federal, local, and state guidelines. Release to Air: If aerosolized, reduce exposures by ventilating the area; clean up spill immediately to prevent evaporation. Release to Water: Refer to local water authority. Drain disposal is not recommended; however, refer to local and state disposal guidelines. Section VII - PRECAUTIONS FOR SAFE HANDLING AND USE Steps to be taken in case material is released or spilled: See Section VI above. Wear latex or nitrile gloves and safety glasses when cleaning spills. A dust/mist respirator (N95) may be necessary if aerosols are generated. 2 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRRT Section VI - ACCIDENTAL RELEASE INFORMATION Waste Disposal Method: Incineration in an approved, permitted incinerator is recommended. Refer to local, state, and federal rules. Midazolam is a Schedule IV controlled substance and must be disposed of according to DEA rules. Precautions to be taken in handling and storing: Store at 59-86°F (15-30°C). Other Precautions: Store under security since Midazolam is a Schedule IV controlled substance. Section VIII - CONTROL MEASURES AND PERSONAL PROTECTIVE EQUIPMENT Respiratory Protection: Under normal handling and use, respirators are not required. If aerosols are generated, wear a disposable dust/mist respirator (N95). Personnel wearing respirators should be fit tested and approved for respirator use under the OSHA Respiratory Protection Standard 29 CFR 1910.134. Ventilation: Handle product in a well-ventilated area. Protective Gloves: Nitrile or latex Eye Protection: Safety glasses Other Protective Clothing or Equipment: Lab Coat Work/Hygienic Practices: Wash hands following use. No eating, drinking or smoking when handling this product. Section IX - PHYSICAL/CHEMICAL CHARACTERISTICS Physical State: Liquid Appearance and Odor: Colorless to light yellow, clear aqueous Melting Point: Not applicable Evaporation Rate: Unknown Solubility in Water: Soluble pH: 3.0-4.0 at 1mg/mL solution 3.0-3.6 at 5mg/mL solution Specific Gravity: Unknown Boiling Point: Unknown Vapor Pressure: Unknown Vapor Density: Unknown Stability: Stable Incompatibility (Materials to Avoid): None known Hazardous Decomposition or Byproducts: As with any burning material, carbon monoxide, carbon monoxide, nitrogen oxides and sulfur oxides may be produced. Also, flourine and chlorine gases could be produced. Hazardous Polymerization: Will not occur. Conditions to Avoid: Store away from strong oxidizers. Section XI - TOXICOLOGICAL INFORMATION For Midazolam: LD50 rat, oral = 215 mg/kg TDLO lowest published toxic dose, Child, intravenous = .14 mg/kg TDLO man, intravenous = 71 mg/kg 3 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRRU Section X - STABILITY AND REACTIVITY DATA Additional reproductive health data is available from the National Institute for Occupational Safety and Health (NIOSH) Registry of Toxic Effects of Chemical Substances (RTECS). Section XII - ENVIRONMENTAL IMPACT INFORMATION Information is currently not available on the environmental impact of Midazolam Hydrochloride. Handle in a manner to prevent spills or releases to the environment. Section XIII - DISPOSAL INFORMATION Dispose of as a controlled substance – Schedule IV, according to DEA guidelines. Dispose of by incineration at an approved, permitted incinerator. Review local, state, and federal regulations for your regulatory area. Section XIV - TRANSPORTATION INFORMATION Midazolam is not a DOT Hazardous Material. Midazolam is not a Marine Pollutant. Section XV - REGULATORY INFORMATION SARA 313 listed?: NO CERCLA listed?: NO RCRA listed?: NO Midazolam Hydrochloride is listed on California’s Proposition 65 as Code D 1. Use of this product should be through or under the direction of a physician. This MSDS does not address therapeutic use of this material. 2. Persons administering this drug to patients must be careful to avoid needle sticks to syringes and other sharps used in the administration. All needle sticks must be reported to your company management. 3. BVL Hazard Category Definitions (internal hazard ranking used by Ben Venue Laboratories): 1 = Low Toxicity 2= Moderate Toxicity 3 = Potent or Toxic 4 = Highly Potent or Toxic 5 = Extremely Potent or Toxic 4. OEL=Occupational Exposure Limit. An internal limit set by Ben Venue Laboratories for the recommended limit of employee exposure to airborne dusts or aerosols that should not be exceeded over an eight-hour time-weighted average. 4 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRRV Section XVI - OTHER DATA 5. Midazolam may be considered a Hazardous Drug as described in the NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. Employees who prepare or administer hazardous drugs or who work in areas where these drugs are used should follow specific handling guidelines in order to prevent exposure to these agents in the air or on work surfaces, clothing, or equipment. 6. The Following Guidance Information is excerpted from the NIOSH Alert: Elements of a Hazardous Drug Handling Program include: • Establishment and implementation of written policies and protocols to ensure the safe handling of oncolytic and/or potent drugs, including receipt of product. • Training and education of employees on the recognition, evaluation and control of Hazardous Drugs • Effective Planning and design of the workplace • Use of best practice control measures and specialized equipment such as ventilated cabinets or isolators designed for worker protection • Wearing recommended personal protective equipment • An integrated health surveillance program that: includes the assessment and counseling of prospective employees before they commence any work involving oncolytic and/or potent drugs and related waste 7. Published guidance on the handling and transport of cytotoxic drugs: National Study Commission on Cytotoxic Exposure: Recommendation for handling Cytotoxic Agents: http://www.nih.gov/od/ors/ds/pubs/cyto/index.htm This document is generated to distribute health, safety and environmental data. It is not a specification sheet and none of the displayed data should be construed as a specification. Information on this MSDS sheet was obtained from sources which we believe are reliable, and we believe that the information is complete and accurate. However, the information is provided without any warranty, express or implied, regarding its correctness. Some of the information presented and conclusions drawn are from sources other than direct test data of the substance. The conditions or methods of handling, storage, use and disposal of the product are beyond our control and may also be beyond our knowledge. It is the user’s responsibility to determine the suitability of any material for a specific purpose and to adopt such safety precautions as may be necessary. If the product is used as a component in another product, this MSDS information may not be applicable. For these reasons, we do not assume any responsibility and expressly disclaim liability for any loss, damage or expense arising out of or in any way connected with the handling, storage, use or disposal of this product 5 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSM NIOSH Alert – Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings http://www.cdc.gov/niosh/docs/2004-165/ Drugs.com Print Version Print   Close Pancuronium Bromide Class: Neuromuscular Blocking Agents VA Class: MS300 CAS Number: 15500-66-0 Brands: Pavulon Warning(s) Should be administered only by individuals experienced in the use of neuromuscular blocking agents.a Introduction Nondepolarizing neuromuscular blocking agent.a Uses for Pancuronium Bromide Skeletal Muscle Relaxation Production of skeletal muscle relaxation during surgery after general anesthesia has been induced.a Treatment to increase pulmonary compliance during assisted or controlled respiration.a Pancuronium Bromide Dosage and Administration General Adjust dosage carefully according to individual requirements and response.a Assess neuromuscular blockade and recovery in patients undergoing anesthesia; a peripheral nerve stimulator is recommended to accurately monitor the degree of muscle relaxation and to minimize the possibility of overdosage.a To avoid patient distress, administer only after unconsciousness has been induced.a b c Facilitation of Endotracheal Intubation Endotracheal intubation generally can be performed within 2–3 minutes following administration of 0.06-mg/kg dose.a (See Onset and also Duration under Pharmacokinetics.) http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSN Facilitation of endotracheal intubation.a Drugs.com Print Version Maintenance of Neuromuscular Blockade Supplemental doses to maintain muscle relaxation increase magnitude and duration of neuromuscular blockade.a Reversal of Neuromuscular Blockade To reverse neuromuscular blockade, administer a cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium), usually in conjunction with an antimuscarinic (e.g., atropine, glycopyrrolate) to block adverse muscarinic effects of the cholinesterase inhibitor.a c Administration IV Administration For solution and drug compatibility information, see Compatibility under Stability. Administer IV only; administer initial (intubating) dose by rapid IV injection.a Consult specialized references for specific procedures and techniques of administration.b Dosage Available as pancuronium bromide; dosage expressed in terms of the salt.a Pediatric Patients Skeletal Muscle Relaxation Initial Dosage IV If administering following succinylcholine and/or maintenances doses of inhalation anesthetics (e.g., enflurane, halothane, isoflurane), use dosage at lower end of recommended initial range.a Administer after effects of succinylcholine subside.a Neonates ≤1 month of age: Administer test dose of 0.02 mg/kg to determine responsiveness.a Maintenance Dosage IV Children 3 months to 12 years of age: 0.01 mg/kg administered at 25- to 60-minute intervals to maintain skeletal muscle relaxation during prolonged surgery or assisted respiration;a b 0.015 mg/kg may be used to maintain relaxation for controlled respiration.b Adults Skeletal Muscle Relaxation Initial Dosage IV 0.04–0.1 mg/kg as adjunct to balanced anesthesia.a 0.06–0.1 mg/kg is recommended for endotracheal http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSO Children >1 month of age: 0.04–0.1 mg/kg as adjunct to balanced anesthesia.a 0.06–0.1 mg/kg is recommended for endotracheal intubation.a (See Onset and also Duration under Pharmacokinetics.) Drugs.com Print Version intubation.a (See Onset and also Duration under Pharmacokinetics.) If administering following succinylcholine and/or maintenances doses of inhalation anesthetics (e.g., enflurane, halothane, isoflurane), use dosage at lower end of recommended initial range.a Administer after effects of succinylcholine subside.a Maintenance Dosage IV 0.01 mg/kg administered at 25- to 60-minute intervals to maintain skeletal muscle relaxation during prolonged surgery or assisted respiration.a b 0.015 mg/kg may be used to maintain relaxation for controlled respiration.b Prescribing Limits Pediatric Patients Skeletal Muscle Relaxation Initial Dosage IV Up to 0.16 mg/kg has been used; however, large doses may increase frequency and severity of tachycardia.b Adults Skeletal Muscle Relaxation Initial Dosage IV Special Populations Hepatic Impairment Increased initial dosage may be required to achieve effective neuromuscular blockade; once blockade is established, duration of blockade may be prolonged.a (See Hepatic Impairment under Cautions.) Renal Impairment Careful and individualized dosing recommended.a (See Renal Impairment under Cautions.) Patients with Biliary Disease Increased initial dosage may be required to achieve effective neuromuscular blockade; once blockade is established, duration of blockade may be prolonged.a (See Biliary Disease under Cautions.) Burn Patients Substantially increased doses may be required due to development of resistance.c (See Burn Patients http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSP Up to 0.16 mg/kg has been used; however, large doses may increase frequency and severity of tachycardia.b Drugs.com Print Version under Cautions.) Patients with Neuromuscular Disease Administer small test dose and monitor response.a (See Neuromuscular Disease under Cautions.) Cautions for Pancuronium Bromide Contraindications Known hypersensitivity to pancuronium bromide or any ingredient in the formulation.a Warnings/Precautions Warnings Respiratory Effects Potential for severely compromised respiratory function and respiratory paralysis.c Should be used only by individuals experienced in the use of neuromuscular blocking agents and in the maintenance of an adequate airway and respiratory support.a Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be immediately available.a IV cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium) should be readily available.a (See Reversal of Neuromuscular Blockade under Dosage and Administration.) Use with caution in patients with pulmonary impairment or respiratory depression.c Neuromuscular Disease Possible profound neuromuscular blockade in patients with neuromuscular disease (e.g., myasthenia gravis, Eaton-Lambert syndrome).a Sensitivity Reactions Hypersensitivity Reactions Hypersensitivity reactions (bronchospasm, flushing, redness, hypotension, tachycardia) reported rarely.a General Precautions Burn Patients Resistance to therapy with neuromuscular blocking agents can develop in burn patients,c particularly those with burns over 25–30% or more of body surface area.c Resistance generally becomes apparent ≥1 week after the burn, peaks ≥2 weeks after the burn, persists for several months or longer, and decreases gradually with healing.c Consider possible need for substantially increased doses.c Cardiovascular Effects http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSQ Reduce initial dosage; monitor response carefully with a peripheral nerve stimulator.a Drugs.com Print Version Possible increased heart rate, arterial pressure, and cardiac output.a Use not recommended in patients with preexisting tachycardia or in patients in whom minor elevation in heart rate is undesirable.b Intensive Care Setting Possible prolonged paralysis and/or muscle weakness and atrophy.a Continuous monitoring of neuromuscular transmission recommended during neuromuscular blocking agent therapy in intensive care setting.c Do not administer additional doses before there is a definite response to nerve stimulation tests.c If no response is elicited, discontinue administration until a response returns.c Impaired Circulation Possible delayed onset of action in patients with impaired circulation (e.g., cardiovascular disease, edema);a however, larger than usual doses are not recommended.a Electrolyte Disturbances Possible increased or decreased neuromuscular blockade in patients with electrolyte distrubances (e.g., adrenocortical insufficiency) or acid/base imbalances.a Malignant Hyperthermia Malignant hyperthermia is rarely associated with use of neuromuscular blocking agents and/or potent inhalation anesthetics.c Be vigilant for its possible development and prepared for its management in any patient undergoing general anesthesia.c Obesity Possible airway or ventilatory problems in patients with severe obesity.a Use with caution.a Biliary Disease Specific Populations Pregnancy Category C.a Lactation Not known whether pancuronium is distributed into milk.j Pediatric Use Excessive salivation may occur during very light anesthesia.b Clinically important methemoglobinemia reported rarely in premature neonates receiving pancuronium in combination with fentanyl and atropine for emergency anesthesia and surgery; however, direct causal relationship not established.a Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSR Possible slower onset and prolonged duration of neuromuscular blockade.a (See Elimination: Special Populations, under Pharmacokinetics and also see Patients with Biliary Disease under Dosage and Administration.) Drugs.com Print Version neonates;a d e f g h i each mL of pancucronium bromide injection contains 10 mg of benzyl alcohol.a Neonates (<1 month of age) are particularly sensitive to neuromuscular blocking agents;a administer test dose to determine responsiveness.a (See Pediatric Patients under Dosage and Administration.) Carefully consider risks and benefits of long-term therapy in neonates.a (See Intensive Care Setting under Cautions.) Geriatric Use Use with caution in geriatric or debilitated patients.a c Hepatic Impairment Possible slower onset and prolonged duration of neuromuscular blockade; use with caution.a (See Elimination: Special Populations, under Pharmacokinetics and also see Hepatic Impairment under Dosage and Administration.) Renal Impairment Possible prolonged neuromuscular blockade; use with caution in patients with poor renal perfusion or severe renal disease.a b (See Elimination: Special Populations, under Pharmacokinetics.) Common Adverse Effects Skeletal muscle weakness, slight elevation in pulse rate and excessive salivation.a c Interactions for Pancuronium Bromide Drug Interaction Comments Anesthetics, general (enflurane, halothane, isoflurane) Increased potency of neuromuscular blockadea Select pancuronium dosage at lower end of recommended initial range a Antidepressants, tricyclic Possible ventricular arrhythmias in patients receiving tricyclic antiderpessants concomitantly with pancuronium and halothanea Use with cautiona Anti-infective agents (aminoglycosides, bacitracin, polymyxins, tetracyclines) Possible prolonged duration of neuromuscular blockadea Magnesium salts Possible increased neuromuscular blockadea Reduce pancuronium dosage if necessary a Neuromuscular blocking agents, nondepolarizing (e.g., atracurium, vecuronium) Increased potency of neuromuscular blockadea Concomitant use not recommendeda Quinidine Possible recurrence of paralysisa http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSS Specific Drugs Drugs.com Print Version Succinylcholine Prior administration of succinylcholine may increase potency and prolong duration of neuromuscular blockadea Allow effects of succinylcholine to subside before administering pancuroniuma Pancuronium Bromide Pharmacokinetics Absorption Bioavailability Poorly absorbed from the GI tract.c Onset Onset of paralysis is dose related.b Following IV administration of 0.06 mg/kg, clinically sufficient neuromuscular blockade occurs within 2– 3 minutes.b Duration Duration of paralysis is dose related.b Duration of clinically sufficient neuromuscular blockade induced by 0.06 mg/kg is about 35–45 minutes.b Supplemental doses may increase magnitude and duration of neuromuscular blockade.b Distribution Extent Plasma Protein Binding Approximately 87% (mainly γ-globulin; albumin to a lesser extent).100 101 102 104 May be concentration dependent.101 103 104 Special Populations Hepatic103 or renal105 impairment does not affect protein binding. Impaired hepatic or biliary function may increase volume of distribution.a Elimination Metabolism Undergoes limited biotransformation.b Elimination Route http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRST Crosses the placenta in small amounts.b Drugs.com Print Version Excreted principally in urine as unchanged drug and to a lesser extent in bile.a Half-life Triphasic; terminal half-life is approximately 2 hours.b Special Populations Impaired renal or hepatic function or biliary disease may decrease clearance and prolong half-life.a Stability Storage Parenteral Injection 2–8°C.a Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Solution Compatibilitya Compatible Dextrose 5% in sodium chloride 0.45 or 0.9% Dextrose 5% in water Ringer's injection, lactated Drug Compatibility Admixture CompatibilityHID Compatible Ciprofloxacin Verapamil HCl Y-site CompatibilityHID Compatible Aminophylline Cefazolin sodium Cefuroxime sodium http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSU Sodium chloride 0.9% Drugs.com Print Version Cimetidine HCl Co-trimoxazole Dobutamine HCl Dopamine HCl Epinephrine HCl Esmolol HCl Etomidate Fenoldopam mesylate Fentanyl citrate Fluconazole Gentamicin sulfate Heparin sodium Hetastarch in lactated electrolyte injection (Hextend) Hydrocortisone sodium succinate Isoproterenol HCl Levofloxacin Lorazepam Midazolam HCl Milrinone lactate Nitroglycerin Ranitidine HCl Sodium nitroprusside Vancomycin HCl Incompatible Diazepam Thiopental sodium Variable Propofol Actions http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRSV Morphine sulfate Drugs.com Print Version Produces skeletal muscle relaxation by causing a decreased response to acetylcholine (ACh) at the myoneural (neuromuscular) junction of skeletal muscle.c Exhibits high affinity for ACh receptor sites and competitively blocks access of ACh to motor endplate of myoneural junction; may affect ACh release.a c Blocks the effects of both the small quantities of ACh that maintain muscle tone and the large quantities of ACh that produce voluntary skeletal muscle contraction; does not alter the resting electrical potential of the motor end-plate or cause muscular contractions.c Produces little or no histamine release.b c Advice to Patients Importance of women informing clinicians if they are or plan to become pregnant or plan to breastfeed.a Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, neuromuscular disease).a Importance of informing patients of other important precautionary information.a (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Routes Dosage Forms Strengths Brand Names Manufacturer Oral 1 mg/mL* Pancuronium Bromide Injection (with benzyl alcohol 1%) Abbott, Baxter, Sicor 2 mg/mL* Pancuronium Bromide Injection (with benzyl alcohol 1%) Abbott, Baxter, Sicor Injection, for IV use only AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. References Only references cited for selected revisions after 1984 are available electronically. 100. Pavulon prescribing information. In: Huff BB, ed. Physicians’ desk reference. 42nd ed. Oradell, NJ: Medical Economics Company Inc; 1988:1491-3. 101. Thompson JM. Pancuronium binding by serum proteins. Anaesthesia. 1976; 31:219-27. [PubMed 59554] 102. Foldes FF, Derby A. Protein binding of atracurium and other short-acting neuromuscular blocking agents and their interaction with human cholinesterases. Br J Anaesth. 1983; 55:31-4S. http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTM Pancuronium Bromide Drugs.com Print Version 103. Duvaldestin P, Henzel D. Binding of tubocurarine, fazadinium, pancuronium and Org NC45 to serum proteins in normal man and in patients with cirrhosis. Br J Anaesth. 1982; 54:513-6. [PubMed 6122460] 104. Ramzan MI, Somogyi AA, Walker JS et al. Clinical pharmacokinetics of the non-depolarising muscle relaxants. Clin Pharmacokinet. 1981; 6:25-60. [IDIS 165379] [PubMed 7018787] 105. Wood M, Stone WJ, Wood AJJ. Plasma binding of pancuronium: effects of age, sex, and disease. Anesth Analg. 1983; 62:2932. [IDIS 164399] [PubMed 6849508] a. Baxter. Pancuronium bromide injection prescribing information. Deerfield, IL: 2003 Jun. b. AHFS Drug Information 2004. McEvoy GK, ed. Pancuronium bromide. Bethesda, MD: American Society of Health-System Pharmacists; 2004:1313-4. c. AHFS Drug Information 2004. McEvoy GK, ed. Neuromuscular blocking agents general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004:1303-6. d. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12:10-11. [PubMed 7188569] e. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-91. [IDIS 150868] [PubMed 6810084] f. Gershanik J. Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084] g. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575] i. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041] j. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002:1058-62. HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1281-3. http://www.drugs.com/monograph/pancuronium-bromide.html?printable=1[12/2/2014 2:54:51 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTN h. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984] Drugs.com Print Version Print   Close The following information is not a substitute for the knowledge and judgement of a healthcare professional. It should not be construed to indicate that use of the drug is safe, appropriate, or effective for you. Always consult with your doctor, nurse, or pharmacist before taking medication. Potassium Chloride Injection Dosage Form: injection, solution For Use Only with a Calibrated Infusion Device Highly Concentrated Potassium Chloride Injection in Plastic Container Ready To Use Viaflex® Plus Container Potassium Chloride Injection Description Composition  (g/L) Potassium Chloride, USP (KCl) Osmolarity* (mOsmol/L) (calc) pH Potassium Chloride 10 mEq/100 mL 7.46 200 5.0 (4.0 to 8.0) 100 100 10 mEq/50 mL 20 mEq/100 mL 14.9 400 5.0 (4.0 to 8.0) 200 200 30 mEq/100 mL 22.4 601 5.0 (4.0 to 8.0) 300 300 20 mEq/50 mL 40 mEq/100 mL 29.8 799 5.0 (4.0 to 8.0) 400 400 Potassium Chloride Injection mEq Potassium/Container Ionic Concentration (mEq/L) * Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥600 mOsmol/L) may cause vein damage. http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTO This Potassium Chloride Injection, is a sterile, nonpyrogenic, highly concentrated, ready-to-use, solution of Potassium Chloride, USP in Water for Injection, USP for electrolyte replenishment in a single dose container for intravenous administration. It contains no antimicrobial agents. Drugs.com Print Version This Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic). Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain of its chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Potassium Chloride Injection - Clinical Pharmacology Potassium is the major cation of body cells (160 mEq/liter of intracellular water) and is concerned with the maintenance of body fluid composition and electrolyte balance. Potassium participates in carbohydrate utilization, protein synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in the heart. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base of the body are reflected by changes in the chloride concentration. Normally about 80 to 90% of the potassium intake is excreted in the urine, the remainder in the stools and to a small extent, in the perspiration. The kidney does not conserve potassium well so that during fasting, or in patients on a potassium-free diet, potassium loss from the body continues resulting in potassium depletion. A deficiency of either potassium or chloride will lead to a deficit of the other. Indications and Usage for Potassium Chloride Injection THIS HIGHLY CONCENTRATED, READY-TO-USE Potassium Chloride Injection IS INTENDED FOR THE MAINTENANCE OF SERUM K+ LEVELS AND FOR POTASSIUM SUPPLEMENTATION IN FLUID RESTRICTED PATIENTS WHO CANNOT ACCOMMODATE ADDITIONAL VOLUMES OF FLUID ASSOCIATED WITH POTASSIUM SOLUTIONS OF LOWER CONCENTRATION. When using these products, these patients should be on continuous cardiac monitoring and frequent testing for serum potassium concentration and acid-base balance. Contraindications Potassium Chloride Injection is contraindicated in diseases where high potassium levels may be encountered, and in patients with hyperkalemia, renal failure and in conditions in which potassium retention is present. Warnings THIS HIGHLY CONCENTRATED, READY-TO-USE Potassium Chloride Injection IS INTENDED http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTP Potassium Chloride Injection is indicated in the treatment of potassium deficiency states when oral replacement is not feasible. Drugs.com Print Version FOR THE MAINTENANCE OF SERUM K+ LEVELS AND FOR POTASSIUM SUPPLEMENTATION IN FLUID RESTRICTED PATIENTS WHO CANNOT ACCOMMODATE ADDITIONAL VOLUMES OF FLUID ASSOCIATED WITH POTASSIUM SOLUTIONS OF LOWER CONCENTRATION. TO AVOID POTASSIUM INTOXICATION, DO NOT INFUSE THESE SOLUTIONS RAPIDLY. PATIENTS REQUIRING HIGHLY CONCENTRATED SOLUTIONS SHOULD BE KEPT ON CONTINUOUS CARDIAC MONITORING AND UNDERGO FREQUENT TESTING FOR SERUM POTASSIUM AND ACID-BASE BALANCE, ESPECIALLY IF THEY RECEIVE DIGITALIS. In patients with renal insufficiency, administration of potassium chloride may cause potassium intoxication and life-threatening hyperkalemia. Administer intravenously only with a calibrated infusion device at a slow, controlled rate. (See Dosage and Administration). Because pain associated with peripheral infusion of Potassium Chloride solution has been reported, whenever possible, administration via a central route is recommended for thorough dilution by the blood stream and avoidance of extravasation. Highest concentrations (300 and 400 mEq/L) should be exclusively administered via central route. The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentration. Precautions Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements, or the use of electrolyte-free dextrose solutions to which individualized electrolyte supplements may be added. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with potassium chloride. It is also not known whether potassium chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium chloride should be given to a pregnant woman only if clearly needed. Pediatric Use: http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTQ Serum potassium levels are not necessarily indicative of tissue potassium levels. Solutions containing potassium should be used with caution in the presence of cardiac or renal disease. Drugs.com Print Version These products should not be used in children at this time. Do not administer unless solution is clear and seal is intact. Adverse Reactions Potassium intoxication with mild or severe hyperkalemia has been reported. The signs and symptoms of intoxication include, paresthesia of the extremities, areflexia, muscular or respiratory paralysis, mental confusion, weakness, hypotension, cardiac arrhythmia, heart block, electrographic abnormalities and cardiac arrest. EKG abnormalities serve as a clinical reflection of the seriousness of changes in serum potassium concentrations: peaked T waves and prolonged P-R intervals usually occur with modest elevations above the upper limit of normal potassium concentrations; P waves disappear, the QRS complex widens, and eventual asystole usually occurs with higher elevations. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. Infusion of highly concentrated potassium chloride solutions may cause local pain and vein irritation. (See Warnings). Reactions reported with the use of potassium-containing solutions include nausea, vomiting, and abdominal pain and diarrhea. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. In the event of hyperkalemia, discontinue the infusion immediately and institute corrective therapy to reduce serum potassium levels as necessary. The use of potassium containing foods or medications must also be eliminated. Treatment of mild to severe hyperkalemia with signs and symptoms of potassium intoxication includes the following: 1. Dextrose Injection, USP, 10% or 25%, containing 10 units of crystalline insulin per 20 grams of dextrose administered intravenously, 300 to 500 mL per hour. 2. Absorption and exchange of potassium using sodium or ammonium cycle cation exchange resin, orally and as retention enema. 3. Hemodialysis and peritoneal dialysis. In cases of digitalization, too rapid a lowering of plasma potassium concentration can cause digitalis toxicity. Potassium Chloride Injection Dosage and Administration http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTR Overdosage Drugs.com Print Version The dose and rate of administration are dependent upon the specific condition of each patient. Administer intravenously only with a calibrated infusion device at a slow, controlled rate. Because pain associated with peripheral infusion of Potassium Chloride solution has been reported, whenever possible, administration via a central route is recommended for thorough dilution by the blood stream and avoidance of extravasation. Highest concentrations (300 and 400 mEq/L) should be exclusively administered via central route. Recommended administration rates should not usually exceed 10 mEq/hour or 200 mEq for a 24 hour period if the serum potassium level is greater than 2.5 mEq/liter. In urgent cases where the serum potassium level is less than 2.0 mEq/liter or where severe hypokalemia is a threat, (serum potassium level less than 2.0 mEq/liter and electrocardiographic changes and/or muscle paralysis) rates up to 40 mEq/hour or 400 mEq over a 24 hour period can be administered very carefully when guided by continuous monitoring of the EKG and frequent serum K+ determinations to avoid hyperkalemia and cardiac arrest. Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions where possible. Do not add supplementary medication. How is Potassium Chloride Injection Supplied 2B0826 10 mEq/100 mL NDC 0338-0709-48 2B0821 10 mEq/50 mL NDC 0338-0705-41 2B0827 20 mEq/100 mL NDC 0338-0705-48 2B0823 30 mEq/100 mL NDC 0338-0707-48 2B0822 20 mEq/50 mL NDC 0338-0703-41 2B0824 40 mEq/100 mL NDC 0338-0703-48 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that this product be stored at room temperature (25°C). DIRECTIONS FOR USE OF VIAFLEX® PLUS PLASTIC CONTAINER Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTS Potassium Chloride Injection in Viaflex® Plus plastic containers is available as follows: Drugs.com Print Version To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container.  If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired.  Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Do not add supplementary medication. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA ©Copyright 1988, 1989, 1990, 1991, 1994, Baxter Healthcare Corporation. All rights reserved. 07-19-73-138 Rev. April 2014 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTT PRINCIPAL DISPLAY PANEL http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] Drugs.com Print Version Container Label LOT EXP Highly Concentrated (400 mEq/L) Potassium Chloride Potassium Chloride Injection 20 mEq per 50 mL 50 mL STERILE SINGLE DOSE CONTAINER EACH 50 mL CONTAINS 1.49 g POTASSIUM CHLORIDE pH 5 (4 TO 8) POTASSIUM 400 mEq/L CHLORIDE 400 mEq/L HYPERTONIC 799 mOsmol/L (CALC) USUAL DOSAGE SEE INSERT  USE ONLY WITH A CALIBRATED INFUSION DEVICE  USE  CENTRAL ROUTE WHENEVER POSSIBLE  DO NOT ADD SUPPLEMENTARY MEDICATION STORE IN MOISTURE BARRIER OVERWRAP AT  ROOM TEMPERATURE (77°F or 25°c) UNTIL READY TO USE Rx ONLY BAXTER Logo  USA 2B0822 http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTU NDC 0338-0703-41 Drugs.com Print Version Carton Label Lot: PXXXXXX Exp: XXX XXXX QTY: 24-50 mL NDC: 0338-0703-41 Code: 2B0822 Potassium Chloride Injection 20 mEq per 50 mL (17) XXXXX00 (10) PXXXXXX 11/20/12 12:38:12 Packing #3 http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRTV (01) 50303380703413 Drugs.com Print Version LOT EXP NDC 0338-0705-41 Highly Concentrated (200 mEq/L) Potassium Chloride Potassium Chloride Injection 10 mEq per 50 mL 50 mL STERILE SINGLE DOSE CONTAINER EACH 50 mL CONTAINS 746 mg POTASSIUM CHLORIDE pH 5 (4 TO 8) POTASSIUM 200 mEq/L CHLORIDE 200 mEq/L HYPERTONIC 400 mOsmol/L (CALC) USUAL DOSAGE SEE INSERT USE ONLY WITH A CALIBRATED INFUSION DEVICE    USE   CENTRAL ROUTE WHENEVER POSSIBLE  DO NOT ADD SUPPLEMENTARY MEDICATION STORE IN MOISTURE BARRIER OVERWRAP AT  ROOM http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUM Container Label Drugs.com Print Version TEMPERATURE (77°F or 25°c) UNTIL READY TO USE Rx ONLY BAXTER Logo  USA 2B0821 Carton Label Lot: PXXXXXX Exp: XXX XXXX QTY: 24-50 mL Code: 2B0821 Potassium Chloride Injection 10 mEq per 50 mL (17) XXXXX00 (10) Pxxxxxx (01) 50303380705417 11/16/12 12:37:42 Packing #3 http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUN NDC: 0338-0705-41 Container Label LOT EXP NDC 0338-0707-48 Highly Concentrated (300 mEq/L) Potassium Chloride Potassium Chloride Injection 30 mEq per 50 mL 100 mL STERILE SINGLE DOSE CONTAINER EACH 100 mL CONTAINS 2.24 g POTASSIUM CHLORIDE pH 5 (4 TO 8) POTASSIUM 300 mEq/L CHLORIDE 300 mEq/L HYPERTONIC 601 mOsmol/L (CALC) USUAL DOSAGE SEE INSERT USE ONLY WITH A CALIBRATED INFUSION http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUO Drugs.com Print Version Drugs.com Print Version DEVICE   USE   CENTRAL ROUTE WHENEVER POSSIBLE   DO NOT ADDSUPPLEMENTARY MEDICATION STORE IN MOISTURE BARRIER OVERWRAP AT  ROOM TEMPERATURE (77°F or 25°c) UNTIL READY TO USE Rx ONLY BAXTER Logo  USA 2B0823 Lot: xxxxx Exp: xxx xx QTY: 24-100 mL Code: 2B0823 NDC: 0338-0707-48 Potassium Chloride 30 mEq 100mL Injection (17) xx00 (10) xxxxx (01) 50303380707480 12/8/2006 8:43 51AM Packing #4 http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUP Carton Label Container Label  LOT EXP NDC 0338-0709-48 Highly Concentrated (100 mEq/L) Potassium Chloride Potassium Chloride Injection 10 mEq per 100 mL 100 mL STERILE SINGLE DOSE CONTAINER EACH 100 mL CONTAINS 746 mg POTASSIUM CHLORIDE pH 5 (4 TO 8) POTASSIUM 100 mEq/L CHLORIDE 100 mEq/L HYPERTONIC 200 mOsmol/L (CALC) USUAL DOSAGE SEE  INSERT   USE ONLY WITH A CALIBRATED INFUSION http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUQ Drugs.com Print Version Drugs.com Print Version DEVICE  USE  CENTRAL ROUTE WHENEVER POSSIBLE   DO NOT ADDSUPPLEMENTARY MEDICATION STORE IN MOISTURE BARRIER OVERWRAP AT  ROOM TEMPERATURE (77°F or 25°c) UNTIL READY TO USE Rx ONLY BAXTER Logo  USA 2B0826   Lot: xxxxx Exp: xxx xx QTY: 24-100 mL Code: 2B0826 NDC: 0338-0709-48 Potassium Chloride 10 mEq 100mL Injection (17) xx00 (10) xxxxx (01) 50303380709484 12/5/2008 8:48 01AM Packing 4 POTASSIUM CHLORIDE  Potassium Chloride Injection, solution Product Information http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUR Carton Label Drugs.com Print Version Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0338-0703 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength POTASSIUM CHLORIDE (POTASSIUM CATION and CHLORIDE ION) POTASSIUM CHLORIDE 29.8 g  in 1000 mL Inactive Ingredients Ingredient Name Strength WATER   Packaging # Item Code Package Description 1 NDC:0338-0703-41 24 BAG in 1 CARTON 1 2 50 mL in 1 BAG NDC:0338-0703-48 24 BAG in 1 CARTON 2 100 mL in 1 BAG Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date NDA NDA019904 12/26/1989 Marketing End Date POTASSIUM CHLORIDE  Potassium Chloride Injection, solution Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0338-0705 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength POTASSIUM CHLORIDE (POTASSIUM CATION and CHLORIDE ION) POTASSIUM CHLORIDE 14.9 g  in 1000 mL Inactive Ingredients Ingredient Name Strength WATER   Packaging # Item Code Package Description 1 NDC:0338-0705-41 24 BAG in 1 CARTON 1 2 2 50 mL in 1 BAG NDC:0338-0705-48 24 BAG in 1 CARTON 100 mL in 1 BAG http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUS Product Information Drugs.com Print Version Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date NDA NDA019904 12/26/1989 Marketing End Date POTASSIUM CHLORIDE  Potassium Chloride Injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0338-0707 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength POTASSIUM CHLORIDE (POTASSIUM CATION and CHLORIDE ION) POTASSIUM CHLORIDE 22.4 g  in 1000 mL Inactive Ingredients Ingredient Name Strength WATER   Packaging # Item Code Package Description 1 NDC:0338-0707-48 24 BAG in 1 CARTON 1 100 mL in 1 BAG Marketing Information Application Number or Monograph Citation Marketing Start Date NDA NDA019904 12/26/1989 Marketing End Date POTASSIUM CHLORIDE  Potassium Chloride Injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0338-0709 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength POTASSIUM CHLORIDE (POTASSIUM CATION and CHLORIDE ION) POTASSIUM CHLORIDE 7.46 g  in 1000 mL Inactive Ingredients Ingredient Name Strength WATER   http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUT Marketing Category Drugs.com Print Version Packaging # Item Code Package Description 1 NDC:0338-0709-48 24 BAG in 1 CARTON 1 100 mL in 1 BAG Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date NDA NDA019904 12/26/1989 Marketing End Date Labeler - Baxter Healthcare Corporation (005083209) Establishment Name Address Baxter Healthcare Corporation ID/FEI Operations 189326168 MANUFACTURE(0338-0703, 0338-0705, 0338-0707, 0338-0709), ANALYSIS(03380703, 0338-0705, 0338-0707, 0338-0709), LABEL(0338-0703, 0338-0705, 0338-0707, 0338-0709), PACK(0338-0703, 0338-0705, 0338-0707, 0338-0709), STERILIZE(03380703, 0338-0705, 0338-0707, 0338-0709) Establishment Name Baxter Healthcare Corporation Address ID/FEI Operations 194684502 ANALYSIS(0338-0703, 0338-0705, 0338-0707, 0338-0709) Revised: 06/2014 Baxter Healthcare Corporation t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUU   http://www.drugs.com/pro/potassium-chloride-injection.html?printable=1[12/2/2014 2:51:19 PM] Drugs.com Print Version Print   Close The following information is not a substitute for the knowledge and judgement of a healthcare professional. It should not be construed to indicate that use of the drug is safe, appropriate, or effective for you. Always consult with your doctor, nurse, or pharmacist before taking medication. Rocuronium Bromide Injection Dosage Form: injection, solution Indications and Usage for Rocuronium Bromide Injection Rocuronium Bromide Injection is indicated for inpatients and outpatients as an adjunct to general anesthesia to facilitate both rapid sequence and routine tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Rocuronium Bromide Injection Dosage and Administration The dosage information which follows is derived from studies based upon units of drug per unit of body weight. It is intended to serve as an initial guide to clinicians familiar with other neuromuscular blocking agents to acquire experience with rocuronium bromide. In patients in whom potentiation of, or resistance to, neuromuscular block is anticipated, a dose adjustment should be considered [see Dosage and Administration (2.5), Warnings and Precautions (5.9, 5.12), Drug Interactions (7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.10), and Use in Specific Populations (8.6)]. Dose for Tracheal Intubation The recommended initial dose of rocuronium bromide, regardless of anesthetic technique, is 0.6 mg/kg. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1 (0.4 to 6) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 3 minutes. This dose may be expected to provide 31 (15 to 85) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Under http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRUV Rocuronium Bromide Injection is for intravenous use only. This drug should only be administered by experienced clinicians or trained individuals supervised by an experienced clinician familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents. Doses of Rocuronium Bromide Injection should be individualized and a peripheral nerve stimulator should be used to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered. Drugs.com Print Version halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected [see Drug Interactions (7.3)]. A lower dose of rocuronium bromide (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1.3 (0.8 to 6.2) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 4 minutes. This dose may be expected to provide 22 (12 to 31) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Patients receiving this low dose of 0.45 mg/kg who achieve less than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12 to 15 minutes. A large bolus dose of 0.9 or 1.2 mg/kg can be administered under opioid/nitrous oxide/oxygen anesthesia without adverse effects to the cardiovascular system [see Clinical Pharmacology (12.2)]. Rapid Sequence Intubation In appropriately premedicated and adequately anesthetized patients, rocuronium bromide 0.6 to 1.2 mg/kg will provide excellent or good intubating conditions in most patients in less than 2 minutes [see Clinical Studies (14.1)]. Maintenance Dosing Use by Continuous Infusion Infusion at an initial rate of 10 to 12 mcg/kg/min of rocuronium bromide should be initiated only after early evidence of spontaneous recovery from an intubating dose. Due to rapid redistribution [see Clinical Pharmacology (12.3)] and the associated rapid spontaneous recovery, initiation of the infusion after substantial return of neuromuscular function (more than 10% of control T1) may necessitate additional bolus doses to maintain adequate block for surgery. Upon reaching the desired level of neuromuscular block, the infusion of rocuronium bromide must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator. In clinical trials, infusion rates have ranged from 4 to 16 mcg/kg/min. Inhalation anesthetics, particularly enflurane and isoflurane, may enhance the neuromuscular blocking action of non-depolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion by 30% to 50%, at 45 to 60 minutes after the intubating dose. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVM Maintenance doses of 0.1, 0.15, and 0.2 mg/kg rocuronium bromide, administered at 25% recovery of control T1 (defined as 3 twitches of train-of-four), provide a median (range) of 12 (2 to 31), 17 (6 to 50) and 24 (7 to 69) minutes of clinical duration under opioid/nitrous oxide/oxygen anesthesia [see Clinical Pharmacology (12.2)]. In all cases, dosing should be guided based on the clinical duration following initial dose or prior maintenance dose and not administered until recovery of neuromuscular function is evident. A clinically insignificant cumulation of effect with repetitive maintenance dosing has been observed [see Clinical Pharmacology (12.2)]. Drugs.com Print Version bromide infusion may be expected to proceed at rates comparable to that following comparable total doses administered by repetitive bolus injections [see Clinical Pharmacology (12.2)]. Infusion solutions of rocuronium bromide can be prepared by mixing Rocuronium Bromide Injection with an appropriate infusion solution such as 5% glucose in water or lactated Ringers [see Dosage and Administration (2.6)]. These infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded. Infusion rates of rocuronium bromide can be individualized for each patient using the following tables for three different concentrations of rocuronium bromide solution as guidelines: Table 1: Infusion Rates Using Rocuronium Bromide Injection (0.5 mg/mL)* Patient Weight (kg) (lbs) Drug Delivery Rate (mcg/kg/min) 4 5 6 7 8 9 10 12 14 16 Infusion Delivery Rate (mL/hr) 10 22 4.8 6 7. 2 8. 4 9. 6 10. 8 12 14. 4 16. 8 19.2 15 33 7.2 9 10. 8 12. 6 14. 4 16. 2 18 21. 6 25. 2 28.8 20 44 9.6 12 14. 4 16. 8 19. 2 21. 6 24 28. 8 33. 6 38.4 25 55 12 15 18 21 24 27 30 36 42 48 35 77 16. 8 21 25. 2 29. 4 33. 6 37. 8 42 50. 4 58. 8 67.2 50 110 24 30 36 42 48 54 60 72 84 96 60 132 28. 8 36 43. 2 50. 4 57. 6 64. 8 72 86. 4 100. 8 115. 2 70 154 33. 6 42 50. 4 58. 8 67. 2 75. 6 84 100. 8 117. 6 134. 4 80 176 38. 4 48 57. 6 67. 2 76. 8 86. 4 96 115. 2 134. 4 153. 6 90 198 43. 2 54 64. 8 75. 6 86. 4 97. 2 108 129. 6 151. 2 172. 8 100 220 48 60 72 84 96 108 120 144 168 192 * Table 2: Infusion Rates Using Rocuronium Bromide Injection (1 mg/mL)* Patient Weight Drug Delivery Rate (mcg/kg/min) (kg) (lbs) 4 5 6 7 8 9 10 22 2. 4 3 3. 6 4. 2 4. 8 5. 4 15 33 3. 6 4. 5 5. 4 6. 3 7. 2 20 44 4. 8 6 7. 2 8. 4 25 55 6 7. 5 9 35 77 8.4 10. 5 50 110 12 60 132 70 10 12 14 16 6 7. 2 8. 4 9. 6 8. 1 9 10. 8 12. 6 14. 4 9. 6 10. 8 12 14. 4 16. 8 19. 2 10. 5 12 13. 5 15 18 21 24 12. 6 14. 7 16. 8 18. 9 21 25. 2 29. 4 33. 6 15 18 21 24 27 30 36 42 48 14.4 18 21. 6 25. 2 28. 8 32. 4 36 43. 2 50. 4 57. 6 154 16.8 21 25.2 29. 4 33. 6 37. 8 42 50. 4 58. 8 67. 2 80 176 19.2 24 28.8 33. 6 38. 4 43. 2 48 57. 6 67. 2 76. 8 90 198 21.6 27 32.4 37. 8 43. 2 48. 6 54 64. 8 75. 6 86. 4 100 220 24 30 36 42 48 54 60 72 84 96 Infusion Delivery Rate (mL/hr) http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVN 50 mg rocuronium bromide in 100 mL solution Drugs.com Print Version * 100 mg rocuronium bromide in 100 mL solution Table 3: Infusion Rates Using Rocuronium Bromide Injection (5 mg/mL)* Patient Weight (kg) (lbs) Drug Delivery Rate (mcg/kg/min) 4 5 6 7 8 9 10 12 14 16 Infusion Delivery Rate (mL/hr) 10 22 0. 5 0. 6 0. 7 0. 8 1 1. 1 1. 2 1. 4 1. 7 1. 9 15 33 0. 7 0. 9 1. 1 1. 3 1. 4 1. 6 1. 8 2. 2 2. 5 2. 9 20 44 1 1. 2 1. 4 1. 7 1. 9 2. 2 2. 4 2. 9 3. 4 3. 8 25 55 1. 2 1. 5 1. 8 2. 1 2. 4 2. 7 3 3. 6 4. 2 4. 8 35 77 1. 7 2. 1 2. 5 2. 9 3. 4 3. 8 4. 2 5 5. 9 6. 7 50 110 2. 4 3 3. 6 4. 2 4. 8 5. 4 6 7. 2 8. 4 9. 6 60 132 2. 9 3. 6 4. 3 5 5. 8 6. 5 7. 2 8. 6 10. 1 11. 5 70 154 3. 4 4. 2 5 5. 9 6. 7 7. 6 8. 4 10. 1 11. 8 13. 4 80 176 3. 8 4. 8 5. 8 6. 7 7. 7 8. 6 9. 6 11. 5 13. 4 15. 4 90 198 4. 3 5. 4 6. 5 7. 6 8. 6 9. 7 10. 8 13 15. 1 17. 3 100 220 4. 8 6 7. 2 8. 4 9. 6 10. 8 12 14. 4 16. 8 19. 2 * 500 mg rocuronium bromide in 100 mL solution Dosage in Specific Populations Pediatric Patients For sevoflurane (induction) rocuronium bromide doses of 0.45 mg/kg and 0.6 mg/kg in general produce excellent to good intubating conditions within 75 seconds. When halothane is used, a 0.6 mg/kg dose of rocuronium bromide resulted in excellent to good intubating conditions within 60 seconds. The time to maximum block for an intubating dose was shortest in infants (28 days up to 3 months) and longest in neonates (birth to less than 28 days). The duration of clinical relaxation following an intubating dose is shortest in children (greater than 2 years up to 11 years) and longest in infants. When sevoflurane is used for induction and isoflurane/nitrous oxide for maintenance of general anesthesia, maintenance dosing of rocuronium bromide can be administered as bolus doses of 0.15 mg/kg at reappearance of T3 in all pediatric age groups. Maintenance dosing can also be administered at the reappearance of T2 at a rate of 7 to 10 mcg/kg/min, with the lowest dose requirement for neonates (birth to less than 28 days) and the highest dose requirement for children (greater than 2 years up to 11 years). When halothane is used for general anesthesia, patients ranging from 3 months old through adolescence can be administered rocuronium bromide maintenance doses of 0.075 to 0.125 mg/kg upon return of T1 to 0.25% to provide clinical relaxation for 7 to 10 minutes. Alternatively, a continuous infusion of rocuronium bromide initiated at a rate of 12 mcg/kg/min upon return of T1 to 10% (one http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVO The recommended initial intubation dose of rocuronium bromide is 0.6 mg/kg; however, a lower dose of 0.45 mg/kg may be used depending on anesthetic technique and the age of the patient. Drugs.com Print Version twitch present in train-of-four), may also be used to maintain neuromuscular blockade in pediatric patients. Additional information for administration to pediatric patients of all age groups is presented elsewhere in the label [see Clinical Pharmacology (12.2)]. The infusion of rocuronium bromide must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses [see Clinical Pharmacology (12.2)]. Rocuronium bromide is not recommended for rapid sequence intubation in pediatric patients. Geriatric Patients Geriatric patients (65 years or older) exhibited a slightly prolonged median (range) clinical duration of 46 (22 to 73), 62 (49 to 75), and 94 (64 to 138) minutes under opioid/nitrous oxide/oxygen anesthesia following doses of 0.6, 0.9, and 1.2 mg/kg, respectively. No differences in duration of neuromuscular blockade following maintenance doses of rocuronium bromide were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.2, 12.3)]. Patients with Renal or Hepatic Impairment No differences from patients with normal hepatic and kidney function were observed for onset time at a dose of 0.6 mg/kg rocuronium bromide. When compared to patients with normal renal and hepatic function, the mean clinical duration is similar in patients with end-stage renal disease undergoing renal transplant, and is about 1.5 times longer in patients with hepatic disease. Patients with renal failure may have a greater variation in duration of effect [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. Obese Patients An analysis across all U.S. controlled clinical studies indicates that the pharmacodynamics of rocuronium bromide are not different between obese and non-obese patients when dosed based upon their actual body weight. Patients with Reduced Plasma Cholinesterase Activity Rocuronium metabolism does not depend on plasma cholinesterase so dosing adjustments are not needed in patients with reduced plasma cholinesterase activity. Patients with Prolonged Circulation Time Because higher doses of rocuronium bromide produce a longer duration of action, the initial dosage should usually not be increased in these patients to reduce onset time; instead, in these situations, when feasible, more time should be allowed for the drug to achieve onset of effect [see Warnings and Precautions (5.7)]. Patients with Drugs or Conditions Causing Potentiation of Neuromuscular Block The neuromuscular blocking action of rocuronium bromide is potentiated by isoflurane and enflurane anesthesia. Potentiation is minimal when administration of the recommended dose of rocuronium http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVP In obese patients, the initial dose of rocuronium bromide 0.6 mg/kg should be based upon the patient’s actual body weight [see Clinical Studies (14.1)]. Drugs.com Print Version bromide occurs prior to the administration of these potent inhalation agents. The median clinical duration of a dose of 0.57 to 0.85 mg/kg was 34, 38, and 42 minutes under opioid/nitrous oxide/oxygen, enflurane and isoflurane maintenance anesthesia, respectively. During 1 to 2 hours of infusion, the infusion rate of rocuronium bromide required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia [see Drug Interactions (7.3)]. Preparation for Administration of Rocuronium Bromide Injection Diluent Compatibility: Rocuronium Bromide Injection is compatible in solution with: 0.9% NaCl solution sterile water for injection 5% glucose in water lactated Ringers 5% glucose in saline Rocuronium Bromide Injection is compatible in the above solutions at concentrations up to 5 mg/mL for 24 hours at room temperature in plastic bags, glass bottles, and plastic syringe pumps. amphotericin hydrocortisone sodium succinate amoxicillin insulin azathioprine intralipid cefazolin ketorolac cloxacillin lorazepam dexamethasone methohexital diazepam methylprednisolone erythromycin thiopental famotidine trimethoprim furosemide vancomycin If Rocuronium Bromide Injection is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed between administration of rocuronium bromide and drugs for which incompatibility with rocuronium bromide has been demonstrated or for which compatibility with rocuronium bromide has not been established. Infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded. Rocuronium Bromide Injection should not be mixed with alkaline solutions [see Warnings and Precautions (5.10)]. Visual Inspection: Parenteral drug products should be inspected visually for particulate matter and clarity prior to administration whenever solution and container permit. Do not use solution if particulate matter is present. Dosage Forms and Strengths http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVQ Drug Admixture Incompatibility: Rocuronium Bromide Injection is physically incompatible when mixed with the following drugs: Drugs.com Print Version Rocuronium Bromide Injection is available as • 5 mL multiple dose vials containing 50 mg rocuronium bromide (10 mg/mL) • 10 mL multiple dose vials containing 100 mg rocuronium bromide (10 mg/mL) Contraindications Rocuronium Bromide Injection is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents [see Warnings and Precautions (5.2)]. Warnings and Precautions Appropriate Administration and Monitoring Rocuronium bromide should be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are familiar with the drug’s actions and the possible complications of its use. The drug should not be administered unless facilities for intubation, mechanical ventilation, oxygen therapy, and an antagonist are immediately available. It is recommended that clinicians administering neuromuscular blocking agents such as rocuronium bromide employ a peripheral nerve stimulator to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered. Severe anaphylactic reactions to neuromuscular blocking agents, including rocuronium bromide, have been reported. These reactions have, in some cases (including cases with rocuronium bromide) been life threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported. Need for Adequate Anesthesia Rocuronium bromide has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation. Residual Paralysis http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVR Anaphylaxis Drugs.com Print Version In order to prevent complications resulting from residual paralysis, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Other factors which could cause residual paralysis after extubation in the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice the use of a reversal agent should be considered, especially in those cases where residual paralysis is more likely to occur. Long-Term Use in an Intensive Care Unit Rocuronium bromide has not been studied for long-term use in the intensive care unit (ICU). As with other non-depolarizing neuromuscular blocking drugs, apparent tolerance to rocuronium bromide may develop during chronic administration in the ICU. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor. It is strongly recommended that neuromuscular transmission be monitored continuously during administration and recovery with the help of a nerve stimulator. Additional doses of rocuronium bromide or any other neuromuscular blocking agent should not be given until there is a definite response (one twitch of the train-of-four) to nerve stimulation. Prolonged paralysis and/or skeletal muscle weakness may be noted during initial attempts to wean from the ventilator patients who have chronically received neuromuscular blocking drugs in the ICU. Myopathy after long-term administration of other non-depolarizing neuromuscular blocking agents in the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible and only used in the setting where in the opinion of the prescribing physician, the specific advantages of the drug outweigh the risk. Rocuronium bromide has not been studied in MH-susceptible patients. Because rocuronium bromide is always used with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis, and treatment of malignant hyperthermia prior to the start of any anesthetic. In an animal study in MH-susceptible swine, the administration of Rocuronium Bromide Injection did not appear to trigger malignant hyperthermia. Prolonged Circulation Time Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or advanced age, may be associated with a delay in onset time [see Dosage and Administration (2.5)]. QT Interval Prolongation The overall analysis of ECG data in pediatric patients indicates that the concomitant use of rocuronium bromide with general anesthetic agents can prolong the QTc interval [see Clinical Studies (14.3)]. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVS Malignant Hyperthermia (MH) Drugs.com Print Version Conditions/Drugs Causing Potentiation of, or Resistance to, Neuromuscular Block Potentiation: Non-depolarizing neuromuscular blocking agents have been found to exhibit profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis. Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts, lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Drug Interactions (7.3)]. In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, a decrease from the recommended initial dose of rocuronium bromide should be considered [see Dosage and Administration (2.5)]. Resistance: Resistance to non-depolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine receptors, is associated with burns, disuse atrophy, denervation, and direct muscle trauma. Receptor up-regulation may also contribute to the resistance to non-depolarizing muscle relaxants which sometimes develops in patients with cerebral palsy, patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, or with chronic exposure to nondepolarizing agents. When rocuronium bromide is administered to these patients, shorter durations of neuromuscular block may occur, and infusion rates may be higher due to the development of resistance to non-depolarizing muscle relaxants. Rocuronium bromide-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of rocuronium bromide was significantly enhanced in metabolic acidosis and alkalosis, but was reduced in respiratory alkalosis. In addition, experience with other drugs has suggested that acute (e.g., diarrhea) or chronic (e.g., adrenocortical insufficiency) electrolyte imbalance may alter neuromuscular blockade. Since electrolyte imbalance and acid-base imbalance are usually mixed, either enhancement or inhibition may occur. Incompatibility with Alkaline Solutions Rocuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Increase in Pulmonary Vascular Resistance Rocuronium bromide may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease [see Clinical Studies (14.1)]. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVT Potentiation or Resistance: Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of rocuronium bromide. No data are available in such patients and no dosing recommendations can be made. Drugs.com Print Version Use In Patients with Myasthenia In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants. Extravasation If extravasation occurs, it may be associated with signs or symptoms of local irritation. The injection or infusion should be terminated immediately and restarted in another vein. Adverse Reactions In clinical trials, the most common adverse reactions (2%) are transient hypotension and hypertension. The following adverse reactions are described, or described in greater detail, in other sections: • Anaphylaxis [see Warnings and Precautions (5.2)] • Residual paralysis [see Warnings and Precautions (5.4)] • Myopathy [see Warnings and Precautions (5.5)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical studies in the U.S. (n=1,137) and Europe (n=1,394) totaled 2,531 patients. The patients exposed in the U.S. clinical studies provide the basis for calculation of adverse reaction rates. The following adverse reactions were reported in patients administered rocuronium bromide (all events judged by investigators during the clinical trials to have a possible causal relationship): Adverse reactions in greater than 1% of patients: None Adverse reactions in less than 1% of patients (probably related or relationship unknown): Cardiovascular: arrhythmia, abnormal electrocardiogram, tachycardia Digestive: nausea, vomiting Respiratory: asthma (bronchospasm, wheezing, or rhonchi), hiccup Skin and Appendages: rash, injection site edema, pruritus http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVU • Increased pulmonary vascular resistance [see Warnings and Precautions (5.11)] Drugs.com Print Version In the European studies, the most commonly reported reactions were transient hypotension (2%) and hypertension (2%); these are in greater frequency than the U.S. studies (0.1% and 0.1%). Changes in heart rate and blood pressure were defined differently from in the U.S. studies in which changes in cardiovascular parameters were not considered as adverse events unless judged by the investigator as unexpected, clinically significant, or thought to be histamine related. In a clinical study in patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft, hypertension and tachycardia were reported in some patients, but these occurrences were less frequent in patients receiving beta or calcium channel-blocking drugs. In some patients, rocuronium bromide was associated with transient increases (30% or greater) in pulmonary vascular resistance. In another clinical study of patients undergoing abdominal aortic surgery, transient increases (30% or greater) in pulmonary vascular resistance were observed in about 24% of patients receiving rocuronium bromide 0.6 or 0.9 mg/kg. In pediatric patient studies worldwide (n=704), tachycardia occurred at an incidence of 5.3% (n=37), and it was judged by the investigator as related in 10 cases (1.4%). Post-Marketing Experience In clinical practice, there have been reports, of severe allergic reactions (anaphylactic and anaphylactoid reactions and shock) with Rocuronium Bromide Injection, including some that have been life-threatening and fatal [see Warnings and Precautions (5.2)]. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. Drug Interactions Drugs which may enhance the neuromuscular blocking action of non-depolarizing agents such as rocuronium bromide include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with rocuronium bromide, prolongation of neuromuscular block may occur. Anticonvulsants In 2 of 4 patients receiving chronic anticonvulsant therapy, apparent resistance to the effects of rocuronium bromide was observed in the form of diminished magnitude of neuromuscular block, or shortened clinical duration. As with other non-depolarizing neuromuscular blocking drugs, if rocuronium bromide is administered to patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, shorter durations of neuromuscular block may occur and infusion rates may be higher due to the development of resistance to non-depolarizing muscle relaxants. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor. [See Warnings and Precautions (5.9).] http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSRVV Antibiotics Drugs.com Print Version Inhalation Anesthetics Use of inhalation anesthetics has been shown to enhance the activity of other neuromuscular blocking agents (enflurane > isoflurane > halothane). Isoflurane and enflurane may also prolong the duration of action of initial and maintenance doses of rocuronium bromide and decrease the average infusion requirement of rocuronium bromide by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between rocuronium bromide and halothane has been demonstrated. In one study, use of enflurane in 10 patients resulted in a 20% increase in mean clinical duration of the initial intubating dose, and a 37% increase in the duration of subsequent maintenance doses, when compared in the same study to 10 patients under opioid/nitrous oxide/oxygen anesthesia. The clinical duration of initial doses of rocuronium bromide of 0.57 to 0.85 mg/kg under enflurane or isoflurane anesthesia, as used clinically, was increased by 11% and 23%, respectively. The duration of maintenance doses was affected to a greater extent, increasing by 30% to 50% under either enflurane or isoflurane anesthesia. Potentiation by these agents is also observed with respect to the infusion rates of rocuronium bromide required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates are decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia. The median spontaneous recovery time (from 25% to 75% of control T1) is not affected by halothane, but is prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of rocuronium bromide neuromuscular block is minimally affected by anesthetic technique [see Dosage and Administration (2.5) and Warnings and Precautions (5.9)]. Lithium Carbonate Lithium has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)]. Local anesthetics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)]. Magnesium Magnesium salts administered for the management of toxemia of pregnancy may enhance neuromuscular blockade [see Warnings and Precautions (5.9)]. Non-depolarizing Muscle Relaxants There are no controlled studies documenting the use of rocuronium bromide before or after other nondepolarizing muscle relaxants. Interactions have been observed when other non-depolarizing muscle relaxants have been administered in succession. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMM Local Anesthetics Drugs.com Print Version Procainamide Procainamide has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)]. Propofol The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or recovery characteristics following recommended doses of rocuronium bromide. Quinidine Injection of quinidine during recovery from use of muscle relaxants is associated with recurrent paralysis. This possibility must also be considered for rocuronium bromide [see Warnings and Precautions (5.9)]. Succinylcholine The use of rocuronium bromide before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects. Pregnancy Category C Developmental toxicology studies have been performed with rocuronium bromide in pregnant, conscious, nonventilated rabbits and rats. Inhibition of neuromuscular function was the endpoint for high-dose selection. The maximum tolerated dose served as the high-dose and was administered intravenously 3 times a day to rats (0.3 mg/kg, 15% to 30% of human intubation dose of 0.6 to 1.2 mg/kg based on the body surface unit of mg/m2) from day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from day 6 to 18 of pregnancy. High-dose treatment caused acute symptoms of respiratory dysfunction due to the pharmacological activity of the drug. Teratogenicity was not observed in these animal species. The incidence of late embryonic death was increased at the highdose in rats, most likely due to oxygen deficiency. Therefore, this finding probably has no relevance for humans because immediate mechanical ventilation of the intubated patient will effectively prevent embryo-fetal hypoxia. However, there are no adequate and well-controlled studies in pregnant women. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMN If rocuronium bromide is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of rocuronium bromide 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T1 returned to 75% of control was 36 minutes (range: 14 to 57, n=12) vs. 28 minutes (range: 17 to 51, n=12) without succinylcholine. Drugs.com Print Version Rocuronium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The use of rocuronium bromide in Cesarean section has been studied in a limited number of patients [see Clinical Studies (14.1)]. Rocuronium bromide is not recommended for rapid sequence induction in Cesarean section patients. Pediatric Use The use of rocuronium bromide has been studied in pediatric patients 3 months to 14 years of age under halothane anesthesia. Of the pediatric patients anesthetized with halothane who did not receive atropine for induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. One of the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced this magnitude of change [see Dosage and Administration (2.5) and Clinical Studies (14.3)]. Rocuronium bromide was also studied in pediatric patients up to 17 years of age, including neonates, under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. Onset time and clinical duration varied with dose, the age of the patient, and anesthetic technique. The overall analysis of ECG data in pediatric patients indicates that the concomitant use of rocuronium bromide with general anesthetic agents can prolong the QTc interval. The data also suggest that rocuronium bromide may increase heart rate. However, it was not possible to conclusively identify an effect of rocuronium bromide independent of that of anesthesia and other factors. Additionally, when examining plasma levels of rocuronium bromide in correlation to QTc interval prolongation, no relationship was observed [see Dosage and Administration (2.5), Warnings and Precautions (5.8) and Clinical Studies (14.3)]. Geriatric Use Rocuronium bromide was administered to 140 geriatric patients (65 years or greater) in U.S. clinical trials and 128 geriatric patients in European clinical trials. The observed pharmacokinetic profile for geriatric patients (n=20) was similar to that for other adult surgical patients [see Clinical Pharmacology (12.3)]. Onset time and duration of action were slightly longer for geriatric patients (n=43) in clinical trials. Clinical experiences and recommendations for use in geriatric patients are discussed in other sections [see Dosage and Administration (2.5), Clinical Pharmacology (12.2), and Clinical Studies (14.2)]. Patients with Hepatic Impairment Since rocuronium bromide is primarily excreted by the liver, it should be used with caution in patients http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMO Rocuronium Bromide Injection is not recommended for rapid sequence intubation in pediatric patients. Recommendations for use in pediatric patients are discussed in other sections [see Dosage and Administration (2.5) and Clinical Pharmacology (12.2)]. Drugs.com Print Version with clinically significant hepatic impairment. Rocuronium bromide 0.6 mg/kg has been studied in a limited number of patients (n=9) with clinically significant hepatic impairment under steady-state isoflurane anesthesia. After rocuronium bromide 0.6 mg/kg, the median (range) clinical duration of 60 (35 to 166) minutes was moderately prolonged compared to 42 minutes in patients with normal hepatic function. The median recovery time of 53 minutes was also prolonged in patients with cirrhosis compared to 20 minutes in patients with normal hepatic function. Four of eight patients with cirrhosis, who received rocuronium bromide 0.6 mg/kg under opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. These findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic impairment [see Clinical Pharmacology (12.3)]. If used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged in these cases. The use of doses higher than 0.6 mg/kg has not been studied [see Dosage and Administration (2.5)]. Patients with Renal Impairment Due to the limited role of the kidney in the excretion of rocuronium bromide, usual dosing guidelines should be followed. In patients with renal dysfunction, the duration of neuromuscular blockade was not prolonged; however, there was substantial individual variability (range: 22 to 90 minutes) [see Clinical Pharmacology (12.3)]. Overdosage Reversal of Neuromuscular Blockade: Anticholinesterase agents should not be administered prior to the demonstration of some spontaneous recovery from neuromuscular blockade. The use of a nerve stimulator to document recovery is recommended. Patients should be evaluated for adequate clinical evidence of neuromuscular recovery, e.g., 5- second head lift, adequate phonation, ventilation, and upper airway patency. Ventilation must be supported while patients exhibit any signs of muscle weakness. Recovery may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of certain drugs which enhance neuromuscular blockade or separately cause respiratory depression. Under such circumstances the management is the same as that of prolonged neuromuscular blockade. Rocuronium Bromide Injection Description Rocuronium Bromide Injection is a non-depolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. Rocuronium bromide is chemically designated as 1 - [17ß - (acetyloxy) - 3α - hydroxy - 2ß - (4 - morpholinyl) - 5α - androstan - 16ß - y1] - http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMP Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway, controlled ventilation, and adequate sedation until recovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent in conjunction with an appropriate anticholinergic agent. Drugs.com Print Version 1 - (2 - propenyl) pyrrolidinium bromide. The structural formula is: The chemical formula is C32H53BrN2O4 with a molecular weight of 609.70. The partition coefficient of rocuronium bromide in n-octanol/water is 0.5 at 20°C. Rocuronium Bromide Injection is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only. Each mL contains 10 mg rocuronium bromide and 2 mg sodium acetate. The aqueous solution is adjusted to isotonicity with sodium chloride (3.10 mg/mL) and to a pH of 4 with acetic acid and/or sodium hydroxide. Mechanism of Action Rocuronium bromide is a non-depolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. It acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium. Pharmacodynamics The ED95 (dose required to produce 95% suppression of the first [T1] mechanomyographic [MMG] response of the adductor pollicis muscle [thumb] to indirect supramaximal train-of-four stimulation of the ulnar nerve) during opioid/nitrous oxide/oxygen anesthesia is approximately 0.3 mg/kg. Patient variability around the ED95 dose suggests that 50% of patients will exhibit T1 depression of 91% to 97%. Table 4 presents intubating conditions in patients with intubation initiated at 60 to 70 seconds. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMQ Rocuronium Bromide Injection - Clinical Pharmacology Drugs.com Print Version Table 4: Percent of Excellent or Good Intubating Conditions and Median (Range) Time to Completion of Intubation in Patients with Intubation Initiated at 60 to 70 Seconds Rocuronium Bromide Dose (mg/kg) Administered over 5 sec Percent of Patients With Excellent or Good Intubating Conditions Time to Completion of Intubation [min]          0.45 (n=43) 86% 1.6 (1.0–7.0)      0.6 (n=51) 96% 1.6 (1.0–3.2) Infants 3 mo to 1 yr      0.6 (n=18)   100%   1.0 (1.0-1.5) Pediatric† 1 to 12 yrs           0.6 (n=12) 100% 1.0 (0.5–2.3) Adults* 18 to 64 yrs † Excellent intubating conditions = jaw relaxed, vocal cords apart and immobile, no diaphragmatic movement Good intubating conditions = same as excellent but with some diaphragmatic movement * Excludes patients undergoing Cesarean section † Pediatric patients were under halothane anesthesia Table 5 presents the time to onset and clinical duration for the initial dose of Rocuronium Bromide Injection under opioid/nitrous oxide/oxygen anesthesia in adults and geriatric patients, and under halothane anesthesia in pediatric patients. Time to ≥80% Block (min) Time to Maximum Block (min) Clinical Duration (min)            0.45 (n=50) 1.3 (0.8–6.2) 3.0 (1.3–8.2) 22 (12–31)      0.6 (n=142) 1.0 (0.4–6.0) 1.8 (0.6–13.0) 31 (15–85)      0.9 (n=20) 1.1 (0.3–3.8) 1.4 (0.8–6.2) 58 (27–111)      1.2 (n=18) 0.7 (0.4–1.7) 1.0 (0.6–4.7) 67 (38–160)            0.6 (n=31) 2.3 (1.0–8.3) 3.7 (1.3–11.3) 46 (22–73)      0.9 (n=5) 2.0 (1.0–3.0) 2.5 (1.2–5.0) 62 (49–75)      1.2 (n=7) 1.0 (0.8–3.5) 1.3 (1.2–4.7) 94 (64–138)            0.6 (n=17) — 0.8 (0.3–3.0) 41 (24–68)      0.8 (n=9) — 0.7 (0.5–0.8) 40 (27–70)            0.6 (n=27) 0.8 (0.4–2.0) 1.0 (0.5–3.3) 26 (17–39)      0.8 (n=18) — 0.5 (0.3–1.0) 30 (17–56) Rocuronium Bromide Dose (mg/kg) Administered over 5 sec Adults 18 to 64 yrs Geriatric ≥65 yrs Infants 3 mo to 1 yr Pediatric 1 to 12 yrs n = the number of patients who had time to maximum block recorded Clinical duration = time until return to 25% of control T1. Patients receiving doses of 0.45 mg/kg who achieved less than 90% block (16% of these patients) had about 12 to 15 minutes to 25% recovery. Table 6 presents the time to onset and clinical duration for the initial dose of Rocuronium Bromide http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMR Table 5: Median (Range) Time to Onset and Clinical Duration Following Initial (Intubating) Dose During Opioid/Nitrous Oxide/Oxygen Anesthesia (Adults) and Halothane Anesthesia (Pediatric Patients) Drugs.com Print Version Injection under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia in pediatric patients. Table 6: Median (Range) Time to Onset and Clinical Duration Following Initial (Intubating) Dose During Sevoflurane (induction) and Isoflurane/Nitrous Oxide (maintenance) Anesthesia (Pediatric Patients) Rocuronium Bromide Dose (mg/kg) Administered over 5 sec Time to Maximum Block (min) Time to Reappearance T3 [min] 0.45 (n=5) 1.1 (0.6-2.2) 40.3 (32.5–62.6) 0.6 (n=10) 1.0 (02-2.1) 49.7 (16.6-119.0) 1 (n=6) 0.6 (03-1.8) 114.4 (92.6-136.3) 0.45 (n=9) 0.5 (0.4-1.3) 49.1 (13.5-79.9) 0.6 (n=11) 0.4 (0.2-0.8) 59.8 (32.3-87.8) 1 (n=5) 0.3 (0.2-0.7) 103.3 (90.8-155.4) 0.45 (n=17) 0.8 (0.3-1.9) 39.2 (16.9-59.4) 0.6 (n=29) 0.6 (0.2-1.6) 44.2 (18.9-68.8) 1 (n=15) 0.5 (0.2-1.5) 72.0 (36.2-128.2) 0.45 (n=14) 0.9 (0.4-1.9) 21.5 (17.5-38.0) 0.6 (n=37) 0.8 (0.3-1.7) 36.7 (20.1-65.9) 1 (n=16) 0.7 (0.4-1.2) 53.1 (31.2-89.9) 0.45 (n=18) 1.0 (0.5-1.7) 37.5 (18.3-65.7) 0.6 (n=31) 0.9 (0.2-2.1) 41.4 (16.3-91.2) 1 (n=4) 0.7 (0.5-1.2) 67.1 (25.6-93.8) Neonates birth to <28 days Infants 28 days to ≤3 mo Toddlers >3 mo to ≤2 yrs Children >2 yrs to ≤11 yrs Adolescents >11 to ≤ 17 yrs The time to 80% or greater block and clinical duration as a function of dose are presented in Figures 1 and 2. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMS n = the number of patients with the highest number of observations for time to maximum block or reappearance T3. Drugs.com Print Version Figure 2: Duration of Clinical Effect vs. Initial Dose of Rocuronium Bromide Injection by Age Group (Median, 25th and 75th percentile, and individual values) http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMT Figure 1: Time to 80% or Greater Block vs. Initial Dose of Rocuronium Bromide Injection by Age Group (Median, 25th and 75th percentile, and individual values) Drugs.com Print Version The clinical durations for the first five maintenance doses, in patients receiving five or more maintenance doses are represented in Figure 3 [see Dosage and Administration (2.3)]. Figure 3: Duration of Clinical Effect vs. Number of Rocuronium Bromide Injection Maintenance Doses, by Dose The median spontaneous recovery from 25% to 75% T1 was 13 minutes in adult patients. When neuromuscular block was reversed in 36 adults at a T1 of 22% to 27%, recovery to a T1 of 89 (50 to 132)% and T4/T1 of 69 (38 to 92)% was achieved within 5 minutes. Only 5 of 320 adults reversed received an additional dose of reversal agent. The median (range) dose of neostigmine was 0.04 (0.01 to 0.09) mg/kg and the median (range) dose of edrophonium was 0.5 (0.3 to 1.0) mg/kg. In geriatric patients (n=51) reversed with neostigmine, the median T4/T1 increased from 40% to 88% in 5 minutes. In clinical trials with halothane, pediatric patients (n=27) who received 0.5 mg/kg edrophonium had increases in the median T4/T1 from 37% at reversal to 93% after 2 minutes. Pediatric patients (n=58) who received 1 mg/kg edrophonium had increases in the median T4/T1 from 72% at reversal to 100% after 2 minutes. Infants (n=10) who were reversed with 0.03 mg/kg neostigmine recovered from 25% to 75% T1 within 4 minutes. There were no reports of less than satisfactory clinical recovery of neuromuscular function. The neuromuscular blocking action of rocuronium bromide may be enhanced in the presence of potent inhalation anesthetics [see Drug Interactions (7.3)]. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMU Once spontaneous recovery has reached 25% of control T1, the neuromuscular block produced by rocuronium bromide is readily reversed with anticholinesterase agents, e.g., edrophonium or neostigmine. Drugs.com Print Version Hemodynamics There were no dose-related effects on the incidence of changes from baseline (30% or greater) in mean arterial blood pressure (MAP) or heart rate associated with rocuronium bromide administration over the dose range of 0.12 to 1.2 mg/kg (4 x ED95) within 5 minutes after rocuronium bromide administration and prior to intubation. Increases or decreases in MAP were observed in 2% to 5% of geriatric and other adult patients, and in about 1% of pediatric patients. Heart rate changes (30% or greater) occurred in 0% to 2% of geriatric and other adult patients. Tachycardia (30% or greater) occurred in 12 of 127 pediatric patients. Most of the pediatric patients developing tachycardia were from a single study where the patients were anesthetized with halothane and who did not receive atropine for induction [see Clinical Studies (14.3)]. In U.S. studies, laryngoscopy and tracheal intubation following rocuronium bromide administration were accompanied by transient tachycardia (30% or greater increases) in about one-third of adult patients under opioid/nitrous oxide/oxygen anesthesia. Animal studies have indicated that the ratio of vagal:neuromuscular block following rocuronium bromide administration is less than vecuronium but greater than pancuronium. The tachycardia observed in some patients may result from this vagal blocking activity. Histamine Release In studies of histamine release, clinically significant concentrations of plasma histamine occurred in 1 of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the administration of rocuronium bromide were assessed in clinical trials and reported in 9 of 1,137 (0.8%) patients. Pharmacokinetics Adult and Geriatric Patients Following intravenous administration of rocuronium bromide, plasma levels of rocuronium follow a three-compartment open model. The rapid distribution half-life is 1 to 2 minutes and the slower distribution half-life is 14 to 18 minutes. Rocuronium is approximately 30% bound to human plasma proteins. In geriatric and other adult surgical patients undergoing either opioid/nitrous oxide/oxygen or inhalational anesthesia, the observed pharmacokinetic profile was essentially unchanged. Table 7: Mean (SD) Pharmacokinetic Parameters in Adults (n=22; ages 27 to 58 yrs) and Geriatric (n=20; 65 yrs or greater) During Opioid/Nitrous Oxide/Oxygen Anesthesia PK Parameters Adults (Ages 27 to 58 yrs) Geriatrics (≥65 yrs) Clearance (L/kg/hr) 0.25 (0.08) 0.21 (0.06) Volume of Distribution at Steady State (L/kg) 0.25 (0.04) 0.22 (0.03) 1.4 (0.4) 1.5 (0.4) t1/2β Elimination (hr) In general, studies with normal adult subjects did not reveal any differences in the pharmacokinetics of rocuronium due to gender. Studies of distribution, metabolism, and excretion in cats and dogs indicate that rocuronium is http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSMV In an effort to maximize the information gathered in the in vivo pharmacokinetic studies, the data from the studies was used to develop population estimates of the parameters for the subpopulations represented (e.g., geriatric, pediatric, renal, and hepatic impairment). These population-based estimates and a measure of the estimate variability are contained in the following section. Drugs.com Print Version eliminated primarily by the liver. The rocuronium analog 17-desacetyl-rocuronium, a metabolite, has been rarely observed in the plasma or urine of humans administered single doses of 0.5 to 1 mg/kg with or without a subsequent infusion (for up to 12 hr) of rocuronium. In the cat, 17-desacetylrocuronium has approximately one-twentieth the neuromuscular blocking potency of rocuronium. The effects of renal failure and hepatic disease on the pharmacokinetics and pharmacodynamics of rocuronium in humans are consistent with these findings. In general, patients undergoing cadaver kidney transplant have a small reduction in clearance which is offset pharmacokinetically by a corresponding increase in volume, such that the net effect is an unchanged plasma half-life. Patients with demonstrated liver cirrhosis have a marked increase in their volume of distribution resulting in a plasma half-life approximately twice that of patients with normal hepatic function. Table 8 shows the pharmacokinetic parameters in subjects with either impaired renal or hepatic function. Table 8: Mean (SD) Pharmacokinetic Parameters in Adults with Normal Renal and Hepatic Function (n=10, ages 23 to 65), Renal Transplant Patients (n=10, ages 21 to 45), and Hepatic Dysfunction Patients (n=9, ages 31 to 67) During Isoflurane Anesthesia PK Parameters Normal Renal and Hepatic Function Renal Transplant Patients Hepatic Dysfunction Patients Clearance (L/kg/hr) 0.16 (0.05)* 0.13 (0.04) 0.13 (0.06) Volume of Distribution at Steady State (L/kg) 0.26 (0.03) 0.34 (0.11) 0.53 (0.14) 2.4 (0.8)* 2.4 (1.1) 4.3 (2.6) t1/2β  Elimination (hr) * The net result of these findings is that subjects with renal failure have clinical durations that are similar to but somewhat more variable than the duration that one would expect in subjects with normal renal function. Hepatically impaired patients, due to the large increase in volume, may demonstrate clinical durations approaching 1.5 times that of subjects with normal hepatic function. In both populations the clinician should individualize the dose to the needs of the patient [see Dosage and Administration (2.5)]. Tissue redistribution accounts for most (about 80%) of the initial amount of rocuronium administered. As tissue compartments fill with continued dosing (4 to 8 hours), less drug is redistributed away from the site of action and, for an infusion-only dose, the rate to maintain neuromuscular blockade falls to about 20% of the initial infusion rate. The use of a loading dose and a smaller infusion rate reduces the need for adjustment of dose. Pediatric Patients Under halothane anesthesia, the clinical duration of effects of rocuronium bromide did not vary with age in patients 4 months to 8 years of age. The terminal half-life and other pharmacokinetic parameters of rocuronium in these pediatric patients are presented in Table 9. Table 9: Mean (SD) Pharmacokinetic Parameters of Rocuronium in Pediatric Patients (ages 3 to less than 12 mos, n=6; 1 to less than 3 yrs, n=5; 3 to less than 8 yrs, n=7) During Halothane Anesthesia PK Parameters Patient Age Range http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNM Differences in the calculated t1/2β and Cl between this study and the study in young adults vs. geriatrics (≥65 years) is related to the different sample populations and anesthetic techniques. Drugs.com Print Version 3 to <12 mos 1 to <3 yrs 3 to <8 yrs Clearance (L/kg/hr) 0.35 (0.08) 0.32 (0.07) 0.44 (0.16) Volume of Distribution at Steady State (L/kg) 0.30 (0.04) 0.26 (0.06) 0.21 (0.03) 1.3 (0.5) 1.1 (0.7) 0.8 (0.3) t1/2β Elimination (hr) Pharmacokinetics of rocuronium bromide were evaluated using a population analysis of the pooled pharmacokinetic datasets from 2 trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight. In patients under the age of 18 years clearance (CL) and volume of distribution (Vss) increase with bodyweight (kg) and age (years). As a result the terminal half-life of rocuronium bromide decreases with increasing age from 1.1 hour to 0.7 to 0.8 hour. Table 10 presents the pharmacokinetic parameters in the different age groups in the studies with sevoflurane (induction)and isoflurane/nitrous oxide (maintenance) anesthesia. Table 10: Mean (SD) Pharmacokinetic Parameters of Rocuronium in Pediatric Patients During Sevoflurane (induction) and Isoflurane/Nitrous Oxide (maintenance) Anesthesia PK Parameters Patient Age Range Birth to <28 days 28 Days to ≤3 mos 3 mos to ≤2 yrs 2 to ≤11 yrs 11 to ≤17 yrs Clearance (L/kg/hr) 0.31 (0.07) 0.30 (0.08) 0.33 (0.10) 0.35 (0.09) 0.29 (0.14) Volume of Distribution (L/kg) 0.42 (0.06) 0.31 (0.03) 0.23 (0.03) 0.18 (0.02) 0.18 (0.01) 1.1 (0.2) 0.9 (0.3) 0.8 (0.2) 0.7 (0.2) 0.8 (0.3) t1/2β Elimination (hr) Nonclinical Toxicology Studies in animals have not been performed with rocuronium bromide to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations in mammalian cells, and micronucleus test) conducted with rocuronium bromide did not suggest mutagenic potential. Clinical Studies In U.S. clinical studies, a total of 1,137 patients received Rocuronium Bromide Injection, including 176 pediatric, 140 geriatric, 55 obstetric, and 766 other adults. Most patients (90%) were ASA physical status I or II, about 9% were ASA III, and 10 patients (undergoing coronary artery bypass grafting or valvular surgery) were ASA IV. In European clinical studies, a total of 1,394 patients received Rocuronium Bromide Injection, including 52 pediatric, 128 geriatric (65 years or greater) and 1,214 other adults. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNN Carcinogenesis, Mutagenesis, Impairment of Fertility Drugs.com Print Version Adult Patients Intubation using doses of rocuronium bromide 0.6 to 0.85 mg/kg was evaluated in 203 adults in 11 clinical studies. Excellent to good intubating conditions were generally achieved within 2 minutes and maximum block occurred within 3 minutes in most patients. Doses within this range provide clinical relaxation for a median (range) time of 33 (14 to 85) minutes under opioid/nitrous oxide/oxygen anesthesia. Larger doses (0.9 and 1.2 mg/kg) were evaluated in two studies with 19 and 16 patients under opioid/nitrous oxide/oxygen anesthesia and provided 58 (27 to 111) and 67 (38 to 160) minutes of clinical relaxation, respectively. Cardiovascular Disease In one clinical study, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft received an initial dose of 0.6 mg/kg rocuronium bromide. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 8 mcg/kg/min infusion of rocuronium bromide produced relaxation sufficient to support mechanical ventilation for 6 to 12 hours in the surgical intensive care unit (SICU) while the patients were recovering from surgery. Rapid Sequence Intubation Intubating conditions were assessed in 230 patients in six clinical studies where anesthesia was induced with either thiopental (3 to 6 mg/kg) or propofol (1.5 to 2.5 mg/kg) in combination with either fentanyl (2 to 5 mcg/kg) or alfentanil (1 mg). Most of the patients also received a premedication such as midazolam or temazepam. Most patients had intubation attempted within 60 to 90 seconds of administration of rocuronium bromide 0.6 mg/kg or succinylcholine 1 to 1.5 mg/kg. Excellent or good intubating conditions were achieved in 119/120 (99% [95% confidence interval: 95% to 99.9%]) patients receiving rocuronium bromide and in 108/110 (98% [94% to 99.8%]) patients receiving succinylcholine. The duration of action of rocuronium bromide 0.6 mg/kg is longer than succinylcholine and at this dose is approximately equivalent to the duration of other intermediate-acting neuromuscular blocking drugs. Rocuronium bromide was dosed according to actual body weight (ABW) in most clinical studies. The administration of rocuronium bromide in the 47 of 330 (14%) patients who were at least 30% or more above their ideal body weight (IBW) was not associated with clinically significant differences in the onset, duration, recovery, or reversal of rocuronium bromide-induced neuromuscular block. In one clinical study in obese patients, rocuronium bromide 0.6 mg/kg was dosed according to ABW (n=12) or IBW (n=11). Obese patients dosed according to IBW had a longer time to maximum block, a shorter median (range) clinical duration of 25 (14 to 29) minutes, and did not achieve intubating conditions comparable to those dosed based on ABW. These results support the recommendation that obese patients be dosed based on actual body weight [see Dosage and Administration (2.5)]. Obstetric Patients Rocuronium bromide 0.6 mg/kg was administered with thiopental, 3 to 4 mg/kg (n=13) or 4 to 6 mg/kg (n=42), for rapid sequence induction of anesthesia for Cesarean section. No neonate had APGAR scores greater than 7 at 5 minutes. The umbilical venous plasma concentrations were 18% of maternal concentrations at delivery. Intubating conditions were poor or inadequate in 5 of 13 women receiving 3 to 4 mg/kg thiopental when intubation was attempted 60 seconds after drug injection. Therefore, rocuronium bromide is not recommended for rapid sequence induction in Cesarean section patients. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNO Obese Patients Drugs.com Print Version Geriatric Patients Rocuronium bromide was evaluated in 55 geriatric patients (ages 65 to 80 years) in six clinical studies. Doses of 0.6 mg/kg provided excellent to good intubating conditions in a median (range) time of 2.3 (1 to 8) minutes. Recovery times from 25% to 75% after these doses were not prolonged in geriatric patients compared to other adult patients. [See Dosage and Administration (2.5) and Use in Specific Populations (8.5).] Pediatric Patients Rocuronium bromide 0.45, 0.6, or 1 mg/kg was evaluated under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia for intubation in 326 patients in 2 studies. In 1 of these studies maintenance bolus and infusion requirements were evaluated in 137 patients. In all age groups, doses of 0.6 mg/kg provided time to maximum block in about 1 minute. Across all age groups, median (range) time to reappearance of T3 for doses of 0.6 mg/kg was shortest in the children [36.7 (20.1 to 65.9) minutes] and longest in infants [59.8 (32.3 to 87.8) minutes]. For pediatric patients older than 3 months, the time to recovery was shorter after stopping infusion maintenance when compared with bolus maintenance [see Dosage and Administration (2.5) and Use in Specific Populations (8.4)]. Rocuronium bromide 0.6 or 0.8 mg/kg was evaluated for intubation in 75 pediatric patients (n=28; age 3 to 12 months, n=47; age 1 to 12 years) in 3 studies using halothane (1% to 5%) and nitrous oxide (60% to 70%) in oxygen. Doses of 0.6 mg/kg provided a median (range) time to maximum block of 1 (0.5 to 3.3) minute(s). This dose provided a median (range) time of clinical relaxation of 41 (24 to 68) minutes in 3-month to 1-year-old infants and 26 (17 to 39) minutes in 1- to 12-year-old pediatric patients [see Dosage and Administration (2.5) and Use in Specific Populations (8.4)]. How Supplied/Storage and Handling Mylan Institutional LLC NDC 67457-228-05 50 mg/5 mL, 5 mL Multi-dose vial, cartons of 10 NDC 67457-228-10 100 mg/10 mL, 10 mL Multi-dose vial, cartons of 10 Premier, Inc. NDC 67457-573-05 50 mg/5 mL, 5 mL Multi-dose vial, cartons of 10 NDC 67457-574-10 100 mg/10 mL, 10 mL Multi-dose vial, cartons of 10 Rocuronium Bromide Injection should be stored in a refrigerator, 2° to 8°C (36° to 46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use Rocuronium Bromide Injection within 60 days. Use opened vials of Rocuronium Bromide Injection within 30 days. Safety and Handling: There is no specific work exposure limit for Rocuronium Bromide Injection. In case of eye contact, flush with water for at least 10 minutes. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNP Rocuronium Bromide Injection, 10 mg/mL is available in: Drugs.com Print Version Patient Counseling Information Obtain information about your patient’s medical history, current medications, any history of hypersensitivity to rocuronium bromide or other neuromuscular blocking agents. If applicable, inform your patients that certain medical conditions and medications might influence how Rocuronium Bromide Injection works. In addition, inform your patient that severe anaphylactic reactions to neuromuscular blocking agents, including Rocuronium Bromide Injection, have been reported. Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A. Manufactured by: Gland Pharma Ltd Hyderabad 500 043 India Code No.: AP/DRUGS/103/97 “PREMIERPro™Rx” is a registered trademark of Premier, Inc., used under license. LEA-019588-00 REVISED MAY 2014 MI:ROCUIJ:R4        NDC 67457-228-05 Rocuronium Bromide Injection 50 mg/5 mL (10 mg/mL) For Intravenous Use Only WARNING: Rocuronium Bromide may cause respiratory depression. Facilities for artificial respiration must be immediately available. Rx only     10 x 5 mL Multi-Dose Vials Sterile. Non-pyrogenic. Each mL contains: 10 mg rocuronium bromide, 2 mg sodium acetate. Adjusted to isotonicity with sodium chloride (3.10 mg/mL) and a pH of 4 with acetic acid and/or sodium hydroxide. http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNQ PRINCIPAL DISPLAY PANEL Drugs.com Print Version Usual Dosage: See enclosed full prescribing information. Store refrigerated at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use within 60 days. Use opened vials within 30 days. Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A. Made in India Code No.: AP/DRUGS/103/97 Mylan.com          PRINCIPAL DISPLAY PANEL NDC 67457-573-05 Rocuronium Bromide Injection 50 mg/5 mL (10 mg/mL) For Intravenous Use Only WARNING: Rocuronium Bromide may cause respiratory depression. Facilities for artificial respiration must be immediately available. Rx only     10 x 5 mL Multi-Dose Vials http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNR MI:22805:10C:R3 Drugs.com Print Version Sterile. Non-pyrogenic. Each mL contains: 10 mg rocuronium bromide, 2 mg sodium acetate. Adjusted to isotonicity with sodium chloride (3.10 mg/mL) and a pH of 4 with acetic acid and/or sodium hydroxide. Usual Dosage: See enclosed full prescribing information. Store refrigerated at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use within 60 days. Use opened vials within 30 days. Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A. Made in India Code No.: AP/DRUGS/103/97 MI:573:10C:R1        PRINCIPAL DISPLAY PANEL NDC 67457-574-10 Rocuronium Bromide Injection 100 mg/10 mL (10 mg/mL) For Intravenous Use Only http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNS “PREMIERPro™Rx” is a trademark of Premier, Inc., used under license. Drugs.com Print Version WARNING: Rocuronium Bromide may cause respiratory depression. Facilities for artificial respiration must be immediately available. Rx only     10 x 10 mL Multi-Dose Vials Sterile. Non-pyrogenic. Each mL contains: 10 mg rocuronium bromide, 2 mg sodium acetate. Adjusted to isotonicity with sodium chloride (3.10 mg/mL) and a pH of 4 with acetic acid and/or sodium hydroxide. Usual Dosage: See enclosed full prescribing information. Store refrigerated at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use within 60 days. Use opened vials within 30 days. Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A. Made in India Code No.: AP/DRUGS/103/97 MI:574:10C:R1 ROCURONIUM BROMIDE  Rocuronium Bromide Injection Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:67457-228 Route of Administration INTRAVENOUS DEA Schedule      http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNT “PREMIERPro™Rx” is a trademark of Premier, Inc., used under license. Drugs.com Print Version Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ROCURONIUM BROMIDE (ROCURONIUM) ROCURONIUM BROMIDE 10 mg  in 1 mL Inactive Ingredients Ingredient Name Strength SODIUM ACETATE 2 mg  in 1 mL SODIUM CHLORIDE   ACETIC ACID   SODIUM HYDROXIDE   Packaging # Item Code Package Description 1 NDC:67457-228-05 10 VIAL, MULTI-DOSE in 1 CARTON 1 NDC:67457-228-00 5 mL in 1 VIAL, MULTI-DOSE 2 NDC:67457-228-10 10 VIAL, MULTI-DOSE in 1 CARTON 2 NDC:67457-228-99 10 mL in 1 VIAL, MULTI-DOSE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date ANDA ANDA079199 04/24/2013 Marketing End Date ROCURONIUM BROMIDE  Rocuronium Bromide Injection Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:67457-573 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ROCURONIUM BROMIDE (ROCURONIUM) ROCURONIUM BROMIDE 10 mg  in 1 mL Inactive Ingredients Ingredient Name Strength SODIUM ACETATE 2 mg  in 1 mL SODIUM CHLORIDE   ACETIC ACID   SODIUM HYDROXIDE   Packaging # Item Code Package Description 1 NDC:67457-573-05 10 VIAL, MULTI-DOSE in 1 CARTON 1 NDC:67457-573-00 5 mL in 1 VIAL, MULTI-DOSE http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNU Product Information Drugs.com Print Version Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date ANDA ANDA079199 09/29/2014 Marketing End Date ROCURONIUM BROMIDE  Rocuronium Bromide Injection Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:67457-574 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ROCURONIUM BROMIDE (ROCURONIUM) ROCURONIUM BROMIDE 10 mg  in 1 mL Inactive Ingredients Ingredient Name Strength SODIUM ACETATE 2 mg  in 1 mL SODIUM CHLORIDE   ACETIC ACID   SODIUM HYDROXIDE   # Item Code Package Description 1 NDC:67457-574-10 10 VIAL, MULTI-DOSE in 1 CARTON 1 NDC:67457-574-00 10 mL in 1 VIAL, MULTI-DOSE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date ANDA ANDA079199 09/29/2014 Marketing End Date Labeler - Mylan Institutional LLC (790384502) Revised: 05/2014   http://www.drugs.com/pro/rocuronium-bromide-injection.html?printable=1[12/2/2014 2:54:13 PM] Mylan Institutional LLC t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSNV Packaging 668  ASHP Therapeutic Guidelines Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient Neuromuscular Junction in Health and Disease The neuromuscular junction consists of a motor nerve terminus, the neurotransmitter acetylcholine, and the postsynaptic muscle endplate (Figure 1). The impulse of an action potential causes the release of acetylcholine from synaptic vesicles (each containing about 10,000 molecules of acetylcholine) diffusing across the 20-nm gap to the postsynaptic endplate. The motor endplate contains specialized ligand-gated, nicotinic acetylcholine receptors (nAChRs), which convert the chemical signal (i.e., binding of two acetylcholine molecules) into electrical signals (i.e., a transient permeability change and depolarization in the postsynaptic membrane of striated muscle). There are depolarizing and nondepolarizing NMBAs. Depolarizing NMBAs physically resemble acetylcholine and, therefore, bind and activate acetylcholine receptors. Succinylcholine is currently the only available depolarizing NMBA and is not used for long-term use in ICUs. Nondepolarizing NMBAs also bind acetylcholine receptors but do not activate them—they are competitive antagonists. The difference in the mechanism of action also accounts for different effects in certain diseases. If there is a long-term decrease in acetylcholine release, the number of acetylcholine receptors within the muscle increases. This upregulation causes an increased response to depolarizing NMBAs but a resistance to nondepolarizing NMBAs (i.e., more receptors must be blocked). Conditions in which there are fewer acetylcholine receptors (e.g., myasthenia gravis) lead to an increase in sensitivity to nondepolarizing NMBAs. Adult skeletal muscle retains an ability to synthesize both the mature adult nAChR as well as an immature nAChR variant in which a gamma subunit is substituted for the normal epsilon subunit. Synthesis of immature (fetal) receptors may be triggered in the presence of certain diseases (e.g., Guillain-Barré syndrome, stroke) and other conditions producing loss of nerve function. These immature nAChRs are distinguished by three features. First, immature receptors are not localized to the muscle endplate but migrate across the entire membrane surface.2 Second, the immature receptors are metabolically short-lived (<24 hours) and more ionically active, having a 2- to 10-fold longer channel “open time.” Lastly, these immature receptors are more sensitive to the depolarizing effects of such drugs as succinylcholine and more resistant to the effects of competitive antagonists, such as pancuronium. This increase in the number of immature acetylcholine receptors may account for the tachy­ phylaxis seen with NMBAs and some of the complications associated with their use. For the remainder of this document, only nondepolarizing NMBAs will be discussed. Pharmacology of NeuromuscularReceptor Blockers Aminosteroidal Compounds. The aminosteroidal compounds include pancuronium, pipecuronium, vecuronium, and rocuronium (Tables 1 and 2).3–11 Pancuronium. Pancuronium, one of the original NMBAs used in ICUs, is a long-acting, nondepolarizing compound that is effective after an intravenous bolus dose of 0.06–0.1 mg/kg for up to 90 minutes. Though it is commonly given as an i.v. bolus, it can be used as a continuous infusion12 by adjusting the dose to the degree of neuromuscular blockade that is desired (Table 1). Pancuronium is vagolytic (more than 90% of ICU patients will have an increase in heart rate of ≥10 beats/ min), which limits its use in patients who cannot tolerate an increase in heart rate.12 In patients with renal failure or cirrhosis, pancuronium’s neuromuscular blocking effects are prolonged because of its increased elimination half-life and the decreased clearance of its 3-hydroxypancuronium metabolite that has one-third to one-half the activity of pancuronium. Pipecuronium. Pipecuronium is another long-acting NMBA with an elimination half-life of about two hours, similar to pancuronium’s. Khuenl-Brady and colleagues13 conducted an open-label evaluation of pipecuronium compared with pancuronium in 60 critically ill patients to determine the minimum doses required for ventilatory management. The administration of 8 mg of either drug followed by intermittent boluses of 4–6 mg when needed resulted in optimal paralysis. Patients were paralyzed for a mean duration of 62.6 hours (45–240 hours) and 61.5 hours (46–136 hours) with pancuronium and pipecuronium, respectively. No adverse effects were attributed to either drug. Perhaps because of this lack of difference and because there are no recent studies examining pipecuronium’s use in the ICU, most clinicians continue to use the more familiar drug, pancuronium. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOM The decision to treat a patient in the intensive care unit (ICU) with neuromuscular blocking agents (NMBAs) (for reasons other than the placement of an endotracheal tube) is a difficult one that is guided more commonly by individual practitioner preference than by standards based on evidence-based me­dicine. Commonly cited reasons for the use of NMBAs in the ICU are to facilitate mechanical ventilation or different modes of mechanical ventilation and to manage patients with head trauma or tetanus. Independent of the reasons for using NMBAs, we emphasize that all other modalities to improve the clinical situ­ ation must be tried, using NMBAs only as a last resort. In 1995 the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM) published guidelines for the use of NMBAs in the ICU. The present document is the result of an attempt to reevaluate the literature that has appeared since the last guidelines were published and, based on that review, to update the recommendations for the use of NMBAs in the ICU. Appendix A summarizes our recommendations. Using methods previously described to evaluate the literature and grade the evidence, the task force reviewed the physiology of the neuromuscular receptor, the pharmacology of the NMBAs currently used in the ICU, the means to monitor the degree of blockade, the complications associated with NMBAs, and the economic factors to consider when choosing a drug. ASHP Therapeutic Guidelines  669 Vecuronium. Vecuronium is an intermediate-acting NMBA that is a structural analogue of pancuronium and is not vagolytic. An i.v. bolus dose of vecuronium 0.08–0.1 mg/kg, produces blockade within 60–90 seconds that typically lasts 25–30 minutes. After an i.v. bolus dose, vecuronium is given as a 0.8–1.2-μg/kg/min continuous infusion, adjusting the rate to the degree of blockade desired. Because up to 35% of a dose is renally excreted, patients with renal failure will have decreased drug requirements. Similarly, because up to 50% of an injected dose is excreted in bile, patients with hepatic insufficiency will also have decreased drug requirements to maintain adequate blockade. The 3-desacetylvecuronium metabolite has 50% of the pharmacologic activity of the parent compound, so patients with organ dysfunction may have increased plasma concentrations of both the parent compound and the active metabolite, which contributes to the prolongation of blockade if the dose is not adjusted. Vecuronium has been reported to be more commonly associated with prolonged blockade once discontinued, compared with other NMBAsa. Members of the task force believe that vecuronium is being used with decreased frequency in the ICU. Vecuronium has been studied in open-label prospective trials.14,15 In one of these studies, the mean infusion rate for vecuronium was 0.9 ± 0.1 μg/kg/min for a mean duration of 80 ± 7 hours. Recovery of a train-of-four (TOF) ratio of ≥0.7 was significantly longer than with cisatracurium.15 Recovery time averaged 1–2 hours but ranged from ≤30 minutes to more than 48 hours. Although Rudis, et al.14 observed no difference in the incidence of prolonged blockade between patients receiving vecuronium with and without concomitant administration of corticosteroids, the opinion of the task force was that patients receiving vecuronium and corticosteroids were at increased risk of prolonged weakness once the drug was discontinued. Rocuronium. Rocuronium is a newer nondepolarizing NMBA with a monoquaternary steroidal chemistry that has an intermediate duration of action and a very rapid onset. When given as a bolus dose of 0.6–1 mg/kg, blockade is almost always achieved within two minutes, with maximum blockade occurring within three minutes. Continuous infusions are begun at 10 μg/kg/min.8 Rocuronium’s metabolite, 17-des-acetylrocuronium, has only 5–10% activity compared with the parent compound. Sparr, Khuenl-Brady, and colleagues8,9 studied the dose requirements, recovery times, and pharmacokinetics of rocuronium in 32 critically ill patients, 27 of whom were given intermittent bolus doses, and 5 received a continuous infusion. The median duration of drug administration was 29 hours and 63.4 hours in the bolus dose and infusion groups, respectively. The mean dose of rocuronium required to maintain 80% blockade was 0.34 mg/kg, and the median infusion rate required to maintain one twitch of the TOF was 0.54 mg/kg/hr. The median time from the last bolus dose to the appearance of TOF response was 100 minutes; in the infusion group, the TOF response returned 60 minutes after the infusion was stopped. Rapacuronium. Rapacuronium, a propionate analogue of vecuronium, was marketed as a nonde polarizing NMBA as an alternative to succinylcholine. It was withdrawn from the market on March 27, 2001, because of reports of morbidity (bronchospasm) and mortality associated with its use. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSON Figure 1. Neuromuscular Junction. Schematic model of the organization and structure of the neuromuscular junction, with focus and enlargement on the postsynaptic membrane. Agrin is the nerve-derived protein that triggers receptor clustering during synapse formation. Receptor aggregation appears to occur in distinct steps, however, initiated with acetylcholine receptors (AChR) localized together by rapsyn. Meanwhile, D-dystroglycan, the extracellular component of dystrophin-associated glycoprotein complex (DGC), is the agrin receptor which transduces final AChR clustering. This process utilizes the structural organization of additional proteins like utrophin, which stabilize the mature, immobile domains by interaction with the underlying cytoskeleton (actin). When completed, this process concentrates AChR density 1000-fold compared to typical muscle membrane. ACh = acetylcholine, MuSK = muscle-specific-receptor kirase, MASC = MuSK-accessory specificity component. (Reprinted with permission, from Wall MH, Prielipp RC. Monitoring the neuromuscular junction. In: Lake C, Blitt CD, Hines RL, eds. Clinical Monitoring: Practical Applications for Anesthesia and Critical Care. Philadelphia: W.B. Saunders, 2000, Figure 10-3.) 670  ASHP Therapeutic Guidelines Table 1. Selected Neuromuscular Blocking Agentsa for ICU Use Benzylisoquinolinium Drugs Cisatracurium (Nimbex) d-Turbocurarine Variable (Curare) Atracurium (Tracrium) Doxacurium (Nuromax) Mivacurium (Mivacron) Introduced (yr) ED95b dose (mg/kg) Initial dose (mg/kg) Duration (min) Infusion described Infusion dose (μg/kg/min) Recovery (min) % Renal excretion 1942 0.51 0.1–0.2 80 . . . . . . 1995 0.05 0.1–0.2 45–60 Yes 2.5–3 1983 0.25 0.4–0.5 25–35 Yes 4–12 1991 0.025–0.03 0.025–0.05 120–150 Yes 0.3–0.5 1992 0.075 0.15–0.25 10–20 Yes 9–10 80–180 40-45 90 Hofmann elimination 120–180 70 10–20 Inactive metabolites Renal failure % Biliary excretion Increased duration 10–40 No change Hofmann elimination Increased duration Insufficient data Increased duration . . . Hepatic failure Minimal change to mild increased effect No Minimal to no change 40–60 5–10 (uses Hofmann elimination) No change Minimal (uses Hofmann elimination) Minimal to no change . . . Increased duration No . . . No Marked No No Minimal No No, but can accumulate laudanosine Minimal but dose dependent No No Minimal but dose dependent No Marked No Minimal to none No No . . . Rare Rare Insufficient data Insufficient data Active metabolites Histamine release hypotension Vagal block tachycardia Ganglionic blockade hypotension Prolonged ICU block Aminosteroidal Drugs Pipecuronium (Arduan) Rocuronium (Zemuron) Introduced (yr) ED95b dose (mg/kg) Initial dose (mg/kg) Duration (min) Infusion described Infusion dose (μg/ kg/min) Recovery (min) % Renal excretion Renal failure 1972 0.05 0.06–0.1 90–100 Yes 1–2 1984 0.05 0.08–0.1 35–45 Yes 0.8–1.2 1991 0.05 0.085–0.1 90–100 No 0.5–2 1994 0.3 0.6–1 30 Yes 10–12 120–180 45–70 Increased effect 55–160 50+ Increased duration 20–30 33 Minimal % Biliary excretion Hepatic failure 10–15 Mild increased effect 45–60 50 Increased effect, especially metabolites 35–50 Variable, mild Minimal Minimal <75 Moderate Active metabolites Yes, 3-OH and 17-OHpancuronium No Yes, 3-desacetyl– vecuronium No Insufficient data No No No Modest to marked No No No No No Some at higher doses No Yes Yes Insufficient data Insufficient data Histamine release hypotension Vagal block tachycardia Ganglionic blockade hypotension Prolonged ICU block a Based on drugs for use in a 70-kg man. Modified with permission from Prielipp and Coursin. Reference 3. ED95 = effective dose for 95% of patients studied. b Benzylisoquinolinium Compounds. The benzylisoquino­ linium compounds include D-tubocuranine, atracurium, cisatracurium, doxacurium, and mivacurium (Tables 1 and 3).12,15,16,31 d-Tubocurarine. Tubocurarine was the first nondepolarizing NMBA to gain acceptance and usage in the ICU. This long-acting benzylisoquinolinium agent is rarely used in ICUs because it induces histamine release and autonomic t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOO Vecuronium (Norcuron) Pancuronium (Pavulon) ASHP Therapeutic Guidelines  671 Table 2. ICU Studies of Aminosteroidal Drugsa Patients Reference Type of Study 4 30 5 Prospective, observational, cohort Prospective, open-label 6 Prospective, open-label 6 7 Survey . . . 8 Prospective, open-label 30 SICU 9 Prospective, open-label 32 10 Prospective, randomized, controlled 20 CABG 11 Prospective, open-label 12 ICU 25 PICU Level of Evidence Results Median time to recovery with pancuronium was 3.5 hr in infusion group vs. 6.3 hr in the bolus dose group. Increased infusion requirements for pancuronium with anticonvulsants. Vecuronium clearance increased in 3 and decreased in 2 patients. VD did not change. Neuromuscular blockade monitored clinically with only 8.3% using TOF. All respondents indicated concomitant use of sedatives and/or opioids (75%). 25 trauma patients received rocuronium 50-mg i.v. bolus dose followed by maintenance doses of 25 mg whenever TOF = 2, five patients were on continuous infusion at 25 mg/hr. Duration 1–5 days, recovery approximately 3 hr, and plasma clearance similar between groups. An initial dose of rocuronium 50 mg followed by maintenance doses of 25 mg with TOF = 2 (n = 27) or by continuous infusion to maintain TOF (n = 5). Pharmacokinetic data tabulated. Crossover with patients reported by Khuenl-Brady, et al.8 Pancuronium (n = 10) was compared to rocuronium (n = 10). Incidence of residual block higher with pancuronium than rocuronium. No effect on time to extubation. 12 patients, 4 with MODS. Patients given 0.6-mg/kg bolus dose of rocuronium followed by repeated bolus (n = 2) or continuous infusion (n = 10) started at 10–12 μg/kg/min and adjusted to TOF = 1–4. No evidence of prolonged blockade. 3 3 3 5 3 3 2 3 a PICU = pediatric intensive care unit, SICU = surgical intensive care unit, CABG = coronary artery bypass grafting, ICU = intensive care unit, TOF = train-of-four, VD = volume of distribution, MODS = multiple organ dysfunction syndrome. Table 3. ICU Studies of Benzylisoquinolinium Drugsa 16 17 18 Type of Study Patients Dose Review Prospective, open-label, controlled . . . . . . 14 with Cisatracurium 0.1-mg/ hepatic kg i.v. bolus dose failure vs. 11 controls Prospective, Cisatracurium (n = 12) 20 ICU randomized, 0.25 mg/kg/hr single-blind Atracurium (n = 8) 0.62 mg/kg/hr Level of Evidence Results Review of pharmacokinetics VD greater in liver patients but no differences in elimination t½ or in duration of action 5 5 Similar mean recovery time 2 19 Prospective, 12 ICU randomized Cisatracurium 0.1-mg/kg bolus dose + 0.18-mg/ kg/hr infusion Atracurium: 0.5 mg/kg + 0.6mg/kg/hr infusion Measured VD, Cl, T½. Laudanosine concentration was lower in patients on cisatracurium 2 20 Randomized, open-label Cisatracurium (n = 26) 0.1mg/kg bolus, followed by an infusion of 3 μg/ kg/min; 14 pts infusion only 118 ± 19 min recovery no change in HR, BP, and ICP with bolus 3 61 ICU Atracurium (n = 18) 0.5 mg/kg bolus followed by an infusion of 10 μg/kg/min; 3 pts infusion only Infusion adjusted to one twitch (Continued on Next Page) t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOP Reference 672  ASHP Therapeutic Guidelines Table 3 (continued) Type of Study Patients Dose Results Recovery profiles were significantly different with more prolonged recovery noted for vecuronium. TOF monitoring could not eliminate prolonged recovery and myopathy 15 Prospective, randomized, double-blind, multicenter 58 ICU Cisatracurium 2.5-μg/kg/ min Vecuronium 1-μg/kg/min 21 Prospective, blinded, cross-over 14 with brain injury Cisatracurium 0.15 mg/kg No change in ICP, CPP, CBF, MAP, ETCO2, and HR and no histamine-related symptoms, with 3×ED95 bolus cisatracurium. With 3×ED95 tracurium, ICP, CPP, Atracurium 0.75 mg/kg CBF, and MAP decreased within 2–4 min. Five bolus patients had typical histamine reaction; excluding these five patients, there was no difference in any variable compared with cisatracurium 22 Observational, prospective, open-label 24 with brain injury 0.1 or 0.2-mg/kg cisatracurium bolus dose No change from baseline in ICP, CPP, MAP, ETCO2, HR, and CBF velocity in both groups Level of Evidence 1 2 5 23 Case . . . . . . . . . 4 24 Case . . . . . . . . . 4 25 Review Editorial . . . . . . . . . 4 26 . . . . . . . . . 4 27 Review . . . . . . . . . 5 . . . 28 Review . . . . . . 12 Multicenter, prospective, double-blind, randomized 40 critically ill No difference in adverse reactions or onset of Doxacurium 0.04-mg/kg blockade; pancuronium had a more prolonged and bolus dose, 0.025variable recovery time mg/kg maintenance; pancuronium: 0.07 mg/ kg bolus dose, 0.05mg/kg maintenance 29 Prospective, open-label Doxacurium: 0.03-mg/kg 8 mechanical load; 0.03-mg/kg/hr ventilated infusion ICU with HD monitoring and pHi <7.35 30 Prospective, open-label study 8 ICU with traumatic head injury 31 Case report 4 with atracurium Doxacurium 0.25–0.75 tachyphylaxis μg/kg/min Doxacurium 0.05 mg/kg then 0.25 μg/kg/min 5 1 DO2 + VO2 decreased, pHi increased; VO2 is decreased and pHi increased. NMBA causes redistribution of blood flow to splanchnic beds 5 No significant effect in HR, BP, ICP. No adverse effects 5 No tachyphylaxis noted 5 a ICU = intensive care unit, TOF = train-of-four, VD = volume of distribution, HR = heart rate, BP = blood pressure, ICP = intracranial pressure, CPP = cerebral perfusion pressure, CBF = cerebral blood flow, MAP = mean arterial pressure, NMBA = neuromuscular blocking agent, ETCO2 = end tidal carbon dioxide, ED95 = effective dose for 95% of patients studied, HD = hemodynamic flow, pHi = gastric mucosal pH, DO2 = oxygen delivery, VO2 = oxygen consumption, CBF = cerebral blood flow. ganglionic blockade. Hypotension is rare, however, when the agent is administered slowly in appropriate dosages (e.g., 0.1–0.2 mg/kg). Metabolism and elimination are affected by both renal and hepatic dysfunction. Atracurium.Atracurium is an intermediate-acting NMBA with minimal cardiovascular adverse effects and is associated with histamine release at higher doses. It is inactivated in plas­ma by ester hydrolysis and Hofmann elimination so that renal or hepatic dysfunction does not affect the duration of blockade. Laudanosine is a breakdown product of Hofmann elimination of atracurium and has been associated with central nervous system excitation. This has led to concern about the possibility of precipitating seizures in patients who have received extremely high doses of atracurium or who are in hepatic failure (laudanosine is metabolized by the liver). There has been only one report of a surgical patient who had a seizure while receiving atracurium.32 Atracurium has been administered to various critically ill patient populations, including those with liver failure,17 brain injury,21 or multiple organ dysfunction syndrome (MODS), to facilitate mechanical ventilation. In these reports, atracurium infusion rates varied widely, but they typically ranged from 10 to 20 μg/kg/min with doses adjusted to clinical endpoints or by TOF monitoring. Infusion durations ranged from ≤24 hours to >200 hours. Recovery of normal neuromuscular activity usually occurred within one to two hours after stopping the infusions and was independent of organ function. Long–term infusions have been associated with the development of toler­ ance, necessitating significant dose increases or conversion to other NMBAs.31,33 Atracurium has been associated with persis­ tent neuromuscular weakness as have other NMBAs.34–38 Cisatracurium. Cisatracurium, an isomer of atracurium, is an intermediate-acting benzyliso-quinolinium NMBA that is increasingly used in lieu of atracurium. It produces few, if any, cardiovascular effects and has a lesser tendency to produce mast cell degranulation than atracurium. Bolus doses of 0.1–0.2 mg/kg result in paralysis in an average of 2.5 minutes, and recovery begins at approximately 25 minutes; maintenance infusions should be started at 2.5–3 μg/kg/min. Cisatracurium is also metabolized by ester hydrolysis and Hofmann elimination, so the duration of blockade should not be affected by renal or hepatic dysfunction. Prolonged weakness has been reported following the use of cisatracurium.38 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOQ Reference ASHP Therapeutic Guidelines  673 Indications NMBAs are indicated in a variety of situations (Table 4).8,9,12– There have been no studies randomizing patients who are considered candidates for NMBAs to a placebo versus an NMBA. We therefore reviewed many studies comparing one NMBA to another to assess the clinical indications for enrolling patients in these studies. The most common indications for long-term administration of NMBAs included facilitation of mechanical ventilation, control of ICP, ablation of muscle spasms associated with tetanus, and decreasing oxygen consumption (Figure 2). NMBAs are often used to facilitate ventilation and ablate muscular activity in patients with elevated ICP or seizures but have no direct effect on either condition. Patients who are being treated for seizures who also take NMBAs should have electroencephalographic monitoring to ensure that they are not actively seizing while paralyzed. With the exception of atracurium and cisatracurium, which need to be given continuously because of their short half-lives, bolus administration of NMBAs offers potential advantages for controlling tachyphylaxis; monitoring for 15,17–21,30,39,42 accumulation, analgesia, and amnesia; and limiting complications related to prolonged or excessive blockade; and improving economics. However, in many ICUs, NMBAs are administered continuously, achieving adequate paralysis and faster recovery with TOF monitoring. Facilitate Mechanical Ventilation. Numerous reports have described the use of NMBAs to facilitate mechanical venti­ lation. Most of the reports are limited to case studies, small prospective open-label trials, and small randomized openlabel and double-blind trials enrolling a wide variety of critically ill patients to whom NMBAs were given to prevent respiratory dysynchrony, stop spontaneous respiratory efforts and muscle movement, improve gas exchange, and facilitate inverse ratio ventilation. However, none of these reports compared NMBAs to placebos. Manage Increased ICP. The data supporting the use of NMBAs to control ICP are limited to a case report and an open-label trial. Prielipp30 evaluated doxacurium use in eight patients with severe head injury in an open-label prospective study. NMBAs were given to facilitate ventilation or to manage brain injuries. Patients received an initial bolus injection of doxacurium 0.05 mg/kg followed by a continuous infu­ sion of 0.25 μg/kg/min adjusted to maintain one twitch of the TOF. Doxacurium had no effect on ICP, heart rate, or blood pressure. Infusion rates were similar at the beginning (1 ± 0.1 mg/hr) and at the end (1.3 ± 0.2 mg/hr) of the study. TOF responses returned at 118 minutes; a TOF ratio of 0.7 was measured at 259 ± 24 minutes. No adverse events were reported. McClelland, et al.40 treated three patients with atracurium for four to six days to manage increased ICP. patients could undergo a neurologic examination within minutes after discontinuing atracurium. No adverse events were reported. There have been no controlled studies evaluating the role of NMBAs in the routine management of increased ICP. Treat Muscle Spasms. Case studies describe the use of NMBAs in the treatment of muscle contractures associated with tetanus, drug overdoses, and seizures; many were published before 1994. Anandaciva and Koay41 administered a continuous rocuronium infusion to control muscle tone in patients with tetanus. Muscle spasms recurred at an infusion rate of 8 μg/ kg/min, and neither administering a bolus dose of 0.9 mg/ kg nor increasing the infusion rate to 10 μg/kg/min controlled the muscle contractures but did increase heart rate. Switching to a different NMBA could control the spasms. Decrease Oxygen Consumption. Freebairn, et al.42 evaluated the effects of vecuronium on oxygen delivery, oxygen consumption, oxygen extraction ratios, and gastric intramuco­ sal pH in a randomized, placebo-controlled crossover trial in 18 critically ill patients with severe sepsis. Although the infusion of vecuronium achieved an adequate level of paralysis and improved respiratory compliance, it did not alter intramucosal pH, oxygen consumption, oxygen delivery, or oxygen extraction ratios. Recommended Indications There are no prospective, randomized, controlled trials assigning patients to an NMBA versus a placebo with a goal t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOR Cisatracurium has been compared with atracurium and vecuronium for facilitating mechanical ventilation in sev­ eral open-label prospective trials.15,18–21 Cisatracurium infu­ sion rates ranged from 2 to 8 μg/kg/min and were adjusted to clinical endpoints or to TOF count. Infusion durations varied from 4 to 145 hours. Recovery of a TOF ratio >0.7 occurred within 34–85 minutes after drug discontinuation and was independent of organ function. These recovery times are similar to those seen with atracurium18,21 and less than those observed with vecuronium.15 Doxacurium. Doxacurium, a long-acting benzylisoquinolinium agent, is the most potent NMBA currently available. Doxacurium is essentially free of hemodynamic adverse effects. Initial doses of doxacurium 0.05–0.1 mg/kg may be given with maintenance infusions of 0.3–0.5 μg/kg/ min and adjusted to the degree of blockade desired. An initial bolus dose lasts an average of 60–80 minutes. Doxacurium is primarily eliminated by renal excretion. In elderly patients and patients with renal dysfunction, a significant prolongation of effect may occur. Murray and colleagues12 conducted a prospective, randomized, controlled, multicenter comparison of intermittent doses of doxacurium and pancuronium in 40 critically ill patients requiring neuromuscular blockade to optimize mechanical ventilation or to lower intracranial pressure (ICP). Patients were given another bolus dose based on TOF monitoring and were paralyzed for a mean duration of 2.6 days with doxacurium or 2.2 days with pancuronium. There was a clinically significant increase in heart rate after the initial bolus dose of pancuronium compared with baseline (120 ± 23 versus 109 ± 22 beats/min, respectively) without any differences after the initial dose of doxacurium (107 ± 21 versus 109 ± 21 beats/min, respectively). Once the drugs were discontinued, the pancuronium group had a more prolonged and variable recovery time (279 ± 229 min) than the doxacurium group (135 ± 46 min). Mivacurium. Mivacurium is one of the shortest-acting NMBAs currently available. It consists of multiple stereoisomers and has a half-life of approximately two minutes, allowing for rapid reversal of the blockade. There are little data to support its use as a continuous infusion in the ICU. Agents (n) Multiple trauma and/or blunt brain trauma Prospective, open-label Case report Prospective, open-label Case report Case report Prospective, randomized, controlled, cross-over Rocuronium (30) Vecuronium and atracurium (1) Doxacurium (8) Atracurium (4) Rocuronium (1) Vecuronium (18) t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOS 42 41 Tetanus Severe sepsis and septic shock 40 30 39 8 Severe head injury Severe head injury Respiratory failure in a kidney/pancreas transplant patient Respiratory failure, multiple trauma, blunt brain trauma Prospective, open-label 2 5 5 3 5 3 3 3 13 Head injury, multiple trauma, sepsis, multiorgan failure 9 2 12 2 15 Prospective, randomized, double-blind Prospective, open-label 2 19 Head trauma, intracranial hemorrhage, trauma, ARDS, sepsis, hepatic or renal failure, tetanus Not reported Randomized, double-blind 2 2 Level of Evidence 18 20 Reference Cisatracurium (28), vecuronium (30) Doxacurium (19), pancuronium (21) Pipecuronium (30), pancuronium (30) Rocuronium (32) Randomized, open-label Cardiac arrest, respiratory failure, postneurosurgery, trauma, multiorgan failure, asthma, cardiogenic shock Multiple Randomized, single-blind Underlying Diseases Hepatic failure, sepsis, cardiogenic shock, ARDS Study Design Randomized, open-label ARDS = acute respiratory distress syndrome, ICP = intracranial pressure. a Optimize mechanical ventilation, increase ICP Facilitate mechanical ventilation Facilitate mechanical ventilation; dose-finding pharmacokinetic study Facilitate mechanical ventilation; dose-finding pharmacokinetic study Deterioration in gas exchange Control ICP Facilitate mechanical ventilation and/or management of traumatic brain injury Control ICP Control Muscle Spasms Control tetanospasms Decrease Oxygen Consumption Determine effect on oxygen delivery, consumption, and gastric intramucosal pH Facilitate management Facilitate Mechanical Ventilation Facilitate management Cisatracurium (40), atracurium (21) Beneficial to management Cisatracurium (12), atracurium (8) Cisatracurium (6), Facilitate management atracurium (6) Indication Table 4. Indications for the Long-Term Use of Neuromuscular Blocking Agents in Critically III Patientsa 674  ASHP Therapeutic Guidelines ASHP Therapeutic Guidelines  675 that is based on interpretation of the severity of the patient’s underlying cardiovascular disease. For example, a patient with a history of atrial fibrillation now in sinus rhythm and otherwise hemodynamically stable might better tolerate pancuronium than a patient who is hospitalized with cardiogenic pulmonary edema and managed with mechanical ventilation. The clinician should choose an NMBA on the basis of other patient characteristics. Any benzylisoquino­ linium compound or aminosteroidal compound could be substituted for pancuronium in these circumstances. There are no ideal PRCTs that support this recommendation, but there are data suggesting that patients recover more quickly following administration of cisatracurium or atracurium compared with patients receiving other NMBAs if they have evidence of hepatic or renal disease. Figure 2. Use of neuromuscular blocking agents (NMBAs) in the ICU. Recommendations: The majority of patients in an ICU who are pre­scribed an NMBA can be managed effectively with pancuronium. (Grade of recommendation = B) a Monitor train-of-four ratio, protect eyes, position patient to protect pressure points, and address deep venous thrombosis prophylaxis. Reassess every 12–24 hours for continued NMBA indication. Recommendation: NMBAs should be used for an adult patient in an ICU to manage ventilation, manage increased ICP, treat muscle spasms, and decrease oxygen consumption only when all other means have been tried without success. (Grade of recommendation = C) Recommended Drugs There has, in essence, been no study since the last guidelines were published that questions the use of pancuronium for the majority of patients in an ICU. Those prospective, randomized, controlled trials (PRCTs) that have been conducted do not clearly show the benefits of using newer agents or any other agents instead of pancuronium. There are no well-designed studies with sufficient power to make this a level A recommendation, but there is evidence in the literature that patients on pancuronium fare as well as or better than patients receiving any other NMBA. The two adverse effects of pancuronium that are commented on frequently are vagolysis and an increase in heart rate. Therefore, patients who would not tolerate an increase in heart rate, i.e., those with cardiovascular disease, should probably receive an NMBA other than pancuronium. The indications for the use of an NMBA must outweigh the risk of tachycardia, and Because of their unique metabolism, cisatracurium or atracurium is recommended for patients with significant hepatic or renal disease. (Grade of recommendation = B) Monitoring Monitoring neuromuscular blockade is recommended (Table 5).12,14,43–55 Monitoring the depth of neuromuscular blockade may allow use of the lowest NMBA dose and may minimize adverse events. No PRCT has reported that reducing the dose of an NMBA can prevent persistent weakness. Despite this lack of evidence and the lack of a standardized method of monitoring, assessment of the depth of neuromuscular blockade in ICU patients is recommended.43 Visual, tactile, or electronic assessment of the patient’s muscle tone or some combination of these three is commonly used to monitor the depth of neuromuscular blockade. Observation of skeletal muscle movement and respiratory effort forms the foundation of clinical assessment; electronic methods include the use of ventilator software allowing plethysmographic recording of pulmonary function to detect spontaneous ventilatory efforts and “twitch monitoring,” i.e., the assessment of the muscular response by visual, tactile, or electronic means to a transcutaneous delivery of electric current meant to induce peripheral nerve stimulation (PNS). t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOT of documenting if such patients could be managed by means other than NMBA therapy. For patients for whom vagoly­ sis is contraindicated (e.g., those with cardiovascular disease), NMBAs other than pancuronium may be used. (Grade of recommendation = C) 676  ASHP Therapeutic Guidelines Table 5. Monitoring the Degree of Neuromuscular Blockadea Study Design Monitoring Method Reference Level of Evidence TOF vs. clinical assessment to guide dosing Prospective, randomized, single-blind 14 2 TOF vs. clinical assessment to compare depth of neuromuscular blockade Complications with various monitoring methods Use of TOF in comparing NMBAs Methods of monitoring NMBAs Methods of monitoring NMBAs Comparison of common NMBAs/pharmacology Frequency of NMBA monitoring methods Comparison of NMBA monitoring methods Comparison of NMBA monitoring methods Comparison of NMBA monitoring methods Technical aspects and problems in NMBA monitoring Technical problems with NMBAs monitoring Technical problems with NMBA monitoring Methods of assessing depth of NMBA Patient assessment during NMBA use Prospective, nonrandomized 43 4 Retrospective, nonrandomized cohort Multicenter, double-blind, PRCT Editorial Review Review Nonrandomized, historic, descriptive Editorial Expert opinion Expert opinion Review Review Review Prospective, randomized, blinded Review 44 12 45 46 25 47 48 49 50 51 52 53 54 55 4 2 6 6 6 4 6 6 6 6 6 5 2 6 TOF = train-of-four, NMBA = neuromuscular blocking agent, PRCT = prospective, randomized, controlled trial. Since the last practice guidelines were published, only two studies have examined the best method of monitoring the depth of neuromuscular blockade, and none have compared the efficacy or accuracy of specific techniques. The first study was a prospective, randomized, single-blinded trial of 77 patients in a medical ICU who were administered vecuronium based on either clinical parameters (patient breathed above the preset ventilatory rate) or TOF monitoring, with a goal of one of four twitches.44 PNS resulted in a significantly lower total dose and lower mean infusion rate of NMBA as well as a faster time to recovery of neuromuscular function and spontaneous ventilation. A second study sought to compare the depth of blockade induced by atracurium either by “best clinical assessment” (i.e., maintenance of patient-ventilator synchrony and prevention of patient movement) or TOF monitoring (with a goal of three of four twitches). Analysis of the 36 medical ICU patients in this prospective, nonrandomized trial revealed no difference in the total dose, mean dose, or the mean time to clinical recovery.43 This may have been due to sample size or study design. An additional study examining the results of the implementation of a protocol using PNS to monitor the level of blockade in patients receiving a variety of NMBAs found a reduction in the incidence of persistent neuromuscular weakness.49 Other methods of electronic monitoring of the depth of blockade are fraught with difficulties; TOF monitoring of PNS remains the easiest and most reliable method avail­ able,43,44,46–50 despite its shortcomings and technical pit­ falls.51–53 Currently, there is no universal standard for twitch monitoring. The choice of the number of twitches necessary for “optimal” blockade is influenced by the patient’s overall condition and level of sedation. The choice of the “best” nerve for monitoring may be influenced by site accessibility, risk of false positives, considerations for the effect of stimulation on patient visitors, and whether faint twitches should be included in the assessment of blockade.54–56 Despite these gaps in research-generated knowledge, evidence-based prac­ tice appears to be influencing the increasing frequency with which PNS is utilized.47 The low correlation of blockade measured peripherally compared with that of the phrenic nerve and diaphragm underscores the importance of three issues: (1) more than one method of monitoring should be utilized, (2) poor technique in using any device will invariably produce inaccurate results, and (3) more clinical studies are necessary to determine the best techniques. Recommendations for Monitoring Degree of Blockade Even though the patient may appear quiet and “comfortable,” experienced clinicians understand the indications and therapeutic limits of NMBAs. Despite multiple admonitions that NMBAs have no analgesic or amnestic effects, it is not uncommon to find a patient’s degree of sedation or comfort significantly overestimated or even ignored. It is difficult to assess pain and sedation in the patient receiving NMBAs, but patients must be medicated for pain and anxiety, despite the lack of obvious symptoms or signs. In common practice, sedative and analgesic drugs are adjusted until the patient does not appear to be conscious and then NMBAs are administered. There have been no studies of the use of electrophysiologic monitoring in assessing adequacy of sedation or analgesia. In a phenomenological study of 11 critically ill adult trauma patients who required therapeutic NMBA, patients compared their feelings of vagueness to dreaming.56 Few patients recalled pain or painful procedures. Family members understood the rationale for the use of the drugs and remembered being encouraged to touch and talk with patients. The use of effective pain and sedation protocols and a liberalized visiting policy may have affected the findings. Recommendations: Patients receiving NMBAs should be assessed both clinically and by TOF monitoring (Grade of recommendation = B), with a goal of adjusting the degree of neuromuscular blockade to achieve one or two twitches. (Grade of recommendation = C) t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOU a ASHP Therapeutic Guidelines  677 Complications Skeletal muscle weakness in ICU patients is multifactorial, producing a confusing list of names and syndromes, including acute quadriplegic myopathy syndrome (AQMS), floppy man syndrome, critical illness polyneuropathy (CIP), acute myopathy of intensive care, rapidly evolving myopathy, acute myopathy with selective lysis of myosin filaments, acute steroid myopathy, and prolonged neurogenic weakness (Table 6).57,58 There are probably two adverse events related to prolonged paralysis following discontinuation of NMBAs. We define the first, “prolonged recovery from NMBAs,” as an increase (after cessation of NMBA therapy) in the time to recovery of 50–100% longer than predicted by pharmacologic parameters. This is primarily due to the accumulation of NMBAs or metabolites. By comparison, the second, AQMS, presents with a clinical triad of acute paresis, myonecrosis with increased creatine phosphokinase (CPK) concentration, and abnormal electromyography (EMG). The latter is characterized by severely reduced compound motor action potential (CMAP) amplitudes and evidence of acute denervation. In the beginning, these syndromes are characterized by neuronal dysfunction; later (days or weeks), muscle atrophy and necrosis may develop.59 Prolonged Recovery from NMBAs. The steroid-based NMBAs are associated with reports of prolonged recovery and myopathy.57,60 This association may reflect an increased risk inferred by these NMBAs or may reflect past practice patterns in which these drugs may have been more commonly used.61 Steroid-based NMBAs undergo extensive hepatic metabolism, producing active drug metabolites. For instance, vecuronium produces three metabolites: 3-des-, 17-des-, and 3,17-desacetyl vecuronium.62 The 3-desacetyl Table 6. Weakness in ICU Patients: Etiologies and Syndromesa 1. Prolonged recovery from NMBAs (secondary to parent drug, drug metabolite, or drug–drug interaction) 2. Myasthenia gravis 3. Lambert-Eaton syndrome 4. Muscular dystrophy 5. Guillain-Barré syndrome 6. Central nervous system injury or lesion 7. Spinal cord injury 8. Steroid myopathy 9. Mitochondrial myopathy 10. HIV-related myopathy 11. Acute myopathy of intensive care 12. Disuse atrophy 13. Critical illness polyneuropathy 14. Severe electrolyte toxicity (e.g., hypermagnesemia) 15. Severe electrolyte deficiency (e.g., hypophosphatemia) a ICU = intensive care unit, NMBAs = neuromuscular blocking agents, HIV = human immunodeficiency virus. metabolite is estimated to be 80% as potent as the parent compound. The 3-desacetyl vecuronium metabolite is poorly dialyzed, minimally ultrafiltrated, and accumulates in patients with renal failure because hepatic elimination is decreased in patients with uremia. Thus, the accumulation of both 3– desacetyl vecuronium and its parent compound, vecuronium, in patients with renal failure contributes to a prolonged recovery by this ICU subpopulation. Other explanations have been proposed. One suggests that the basement membrane of the neuromuscular junction acts as a reservoir of NMBAs, maintaining NMBAs at the nAChRs long after the drug has disappeared from the plasma.63 Drug–drug interactions that potentiate the depth of motor blockade (Table 7) may also prolong recovery. The specific interaction of NMBAs and exogenous corticoste­ roids is discussed later.57,62–65 Physiologic changes of the nAChRs are enhanced when patients are immobilized or denervated secondary to spinal cord injury, and perhaps during prolonged NMBA drug-induced paralysis. The nAChRs may be triggered to re­ vert to a fetal–variant structure (Figure 3), characterized by an increase in total number, frequent extrajunctional proliferation, and resistance to nondepolarizing NMBAs. The proliferation and distribution of these altered receptors across the myomembrane may account for tachyphylaxis and the neuromuscular blocking effects of these drugs. AQMS. AQMS, also referred to as postparalytic quadriparesis, is one of the most devastating complications of NMBA therapy and one of the reasons that indiscriminate use of NMBAs is discouraged (Table 8).65,66 This entity must be differentiated from other neuromuscular pathologies (Table 6) seen in an ICU and requires extensive testing. Reports of AQMS in patients receiving NMBAs alone are quite limited; no experimental model has been able to produce the histopathology of this syndrome by administering NMBAs. Afflicted patients demonstrate diffuse weakness that persists long after the NMBA is discontinued and the drug and its active metabolites are eliminated. Neurologic examination reveals a global motor deficit affecting muscles in both the upper and lower extremities and decreased motor reflexes. However, extraocular muscle function is usually preserved. This myopathy is characterized by low-amplitude CMAPs, and muscle fibrillations but normal (or nearly normal) sensory nerve conduction studies.63,67 Muscle biopsy shows prominent vacuol­ization of muscle fibers without inflammatory infiltrate, patchy type 2 muscle fiber atrophy, and sporadic myofiber necrosis.64 Modest CPK increases (0 to 15-fold above normal range) are noted in approximately 50% of patients and are probably dependent on the timing of enzyme measurements and the initiation of the myopathic process. Thus, there may be some justification in screening patients with serial CPK determinations during infusion of NMBAs, particularly if the patients are concurrently treated with corticosteroids. Also, since AQMS develops after prolonged exposure to NMBAs, there may be some rationale to daily “drug holidays” (i.e., stopping the drugs for a few to several hours and restarting them only when necessary). However, no one has demonstrated that drug holidays decrease the frequency of AQMS. Other factors that may contribute to the development of the syndrome include nutritional deficiencies, concurrent drug administration with aminoglycosides or cyclosporine, hyperglycemia, renal and hepatic dysfunction, fever, and severe metabolic or electrolyte disorders. Evidence supports, but occasionally refutes,14 the association of concurrent administration of NMBAs and cor- t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSOV Before initiating neuromuscular blockade, patients should be medicated with sedative and analgesic drugs to provide adequate sedation and analgesia in accordance with the physician’s clinical judgment to optimize therapy. (Grade of recommendation = C) 678  ASHP Therapeutic Guidelines Table 7. Drug–Drug Interactions of Neuromuscular Blocking Agents (NMBAs) Drugs that Antagonize the Actions of Nondepolarizing NMBAs Phenytoin Carbamazepine Theophylline Ranitidine Recommendations: For patients receiving NMBAs and corticosteroids, every effort should be made to discontinue NMBAs as soon as possible. (Grade of recommendation = C) Figure 3. Acetylcholine Receptor. The mature nicotinic acetylcholine receptor (AChR) (left) with its glycoprotein subunits arranged around the central cation core. Two molecules of acetylcholine bind simultaneously to the two alpha subunits to convert the channel to an open state. The immature, or fetal-variant, receptor is shown on the right, with a single subunit substitution which follows major stress such as burns or denervation. These immature receptors are characterized by 10-fold greater ionic activity, rapid metabolic turnover, and extrajunctional proliferation. (Reprinted, with permission, from Martyn JAJ, White DA, Gronert GA, et al. Upand-down regulation of skeletal muscle acetylcholine receptors. Anesthesiology. 1992; 76:825.) ticosteroids with AQMS.59,63,68,69 The incidence of myopathy may be as high as 30% in patients who receive corticoste­ roids and NMBAs. While no period of paralysis is risk free, NMBA administration beyond one or two days increases the risk of myopathy in this setting.63 Similarly, there is an inconsistent correlation with the dose of corticosteroids, but total doses in excess of 1 g of methylprednisolone (or equivalent) probably increase the risk. Afflicted patients manifest an acute, diffuse, flaccid weakness and an inability to wean from mechanical ventilation. Sensory function is generally preserved.63 Muscle biopsy shows extensive type 2 fiber atrophy, myonecrosis, disarray of sarcomere architecture, and an extensive, selective loss of myosin. Experimental evidence in animals shows that denervation for ≥24 hours induces profound negative nitrogen balance and increases expression of steroid receptors in muscle. Such denervation sensitizes muscle to even normal corticosteroid concentrations, and evidence suggests that the combination of denervation and high-dose corticosteroids precipitates myosinolysis. Drug holidays (i.e., stopping NMBAs daily until forced to restart them based on the patient’s condition) may decrease the incidence of AQMS. (Grade of recommendation = C) Other nerve and muscle disorders have been recognized in the last decade in ICU patients (Table 6). For instance, CIP is a sensory and motor polyneuropathy iden­ tified in elderly, septic patients or those with MODS.58,66,70 EMG testing reveals decreased CMAP, fibrillation potentials, and positive sharp waves.60,63,64 CIP is primarily an axonopathy and may be related to microvascular ischemia of the nerve but is not directly related to the use of NMBAs. Recovery from ICU myopathy requires a protracted (weeks or months) hospitaliza­tion. One economic analysis of 10 patients who developed AQMS showed the median additional hospital charge to be $66,000 per patient.65 As for any critically ill patient, particularly immobilized patients, deep venous thrombosis (DVT) prophylaxis and physical therapy to maintain joint mobility are important. Patients receiving NMBAs are also at risk of developing keratitis and corneal abrasion. Prophylactic eye care is highly variable and recommendations may include methylcellulose drops, ophthalmic ointment, taping the eyelids shut to ensure complete closure, or eye patches. In a study of 69 paralyzed or heavily sedated patients by Lenart and Garrity,71 there was strong evidence that the use of an artificial tear ointment prevented corneal exposure. In this randomized study, patients served as their own controls. Myositis Ossificans (Heterotopic Ossification). Myositis ossificans can develop in patients who are paralyzed for long periods of time, but inflammation is not characteristic of the ailment. The name is misleading be cause the process involves connective tissue (not muscle). The name originates from the ossification that occurs within the connective tissue of muscle but may also be seen in ligaments, tendons, fascia, aponeuroses, t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPM Drugs that Potentiate the Action of Nondepolarizing NMBAs Local anesthetics Lidocaine Antimicrobials (aminoglycosides, polymyxin B, clindamycin, tetracycline) Antiarrhythmics (procainamide, quinidine) Magnesium Calcium channel blockers β-Adrenergic blockers Immunosuppresive agents (cyclophospha­ mide, cyclosporine) Dantrolene Diuretics Lithium carbonate Acute myopathy in ICU patients is also reported after administration of the benzylisoquinolinium NMBAs (i.e., atracurium, cisatracurium, doxacurium).24,34,69 Common to all these reports is the coadministration of benzyliso-quinolinium NMBAs and large doses of corticosteroids, aminoglycosides, or other drugs that affect neuromuscular transmission. ASHP Therapeutic Guidelines  679 medication-related cost savings were found when voluntary prescribing guidelines for NMBAs Complications and Contraindications of General Complications Associated with were initiated in the operating room Succinylcholine in the ICU NMBAs in the ICU of a university hospital.73 In another Awake, paralyzed patient–anxiety and Loss of airway study that involved randomization to panic one of three NMBAs, there were no Hyperkalemia Risk of ventilator disconnect or airway significant cost differences between mishap atracurium, vecuronium, and roPlasma pseudocholinesterase Autonomic and cardiovascular effects (i.e., curonium for surgeries lasting two deficiency vagolytic) hours or less, but vecuronium and Decreased lymphatic flow rocuronium were economically adRisk of generalized deconditioning vantageous if the duration of surgery Skin breakdown Peripheral nerve injury was two to four hours.74 In a third Corneal abrasion, conjunctivitis retrospective study, long-acting Myositis ossificans NMBAs (e.g., D-tubocurarine and Risk of prolonged muscle weakness, AQMS pancuronium) were associated with Potential central nervous system toxicity prolonged postoperative recovery a compared with shorter-acting agents NMBA = neuromuscular blocking agent, AQMS = acute quadriplegic myopathy syndrome. (e.g., atracurium, mivacurium, and vecuronium). The authors noted in the discussion section and joint capsules. The acquired form of the disease may occur of the paper that based on intrainstitutional recovery room at any age in either sex, especially around the elbows, thighs, costs, delays in recovery times seen with the longerand buttocks. The basic defect is the inappropriate differentiaacting agents offset the expected savings in drug costs.75 tion of fibroblasts into osteoblasts and is usually triggered by For patients transferred to the ICU, this may not be a major trauma and muscle injury, paraplegia or quadriplegia, tetanus, problem. and burns. Treatment consists of promoting an active range of Two pharmacoeconomic investigations involving motion around the affected joint and surgery when necessary. NMBAs in the ICU evaluated the costs associated with prolonged recovery following discontinuation of nondepolarizing Tachyphylaxis. For reasons mentioned earlier, tachyphyNMBAs. In one study, overall costs were lower when TOF laxis to NMBAs can and does develop. monitoring was employed.76 In another study, patients who Coursin and colleagues31 administered doxacurium to had prolonged motor weakness after discontinuing NMBAs four patients who developed tolerance to atracurium infusions were compared with a control group77; ICU and hospital (range, 16 to 40 μg/kg/min). Patients were successfully blocked costs were substantially higher in the patients with prowith infusion rates of doxacurium 0.25–0.75 μg/kg/min. longed weakness. Tschida, et al.72 described a patient whose atracurium A study involving 40 academic medical centers with requirement escalated from 5 to 30 μg/kg/min over 10 days. patients undergoing coronary artery bypass graft surgery The patient was successfully blocked with a pancuronium found no significant differences in duration of intubation infusion of 10–50 μg/kg/min for a period of five days. or duration of ICU or hospital stay among patients who reFish and Singletary33 describe a patient who was inadceived pancuronium (n = 732), vecuronium (n = 130), or equately blocked with a 60-μg/kg/min infusion of atracurium both (n = 242) agents.78 It is unknown if these results pertain but adequately paralyzed for seven days with 2.3-mg/kg/hr to subgroups of patients, such as those with renal or hepatic infusion of vecuronium. Tachyphylaxis then developed to ve­ dysfunction. If the results of this study are confirmed, the curonium which prompted discontinuation of NMBAs. Two choice of agent could be based solely on cost minimization days later, 50–μg/kg/min atracurium infusions were required using medication purchase cost information and equipotent with high-dose midazolam and fentanyl infusions to achieve dosage regimens. adequate oxygenation and acceptable airway pressures. A prospective, randomized trial comparing TOF to standard clinical assessment showed decreased NMBA usRecommendations: Patients receiving NMBAs age and faster return of spontaneous ventilation with TOF should have prophylactic eye care (Grade of recommonitoring.14 TOF has the potential to decrease costs associmendation = B), physical therapy (Grade of recomated with NMBA use in ICUs. mendation = C), and DVT prophylaxis. (Grade of Appendix B describes the basic steps involved in recommendation = C) conducting a cost-effectiveness analysis of the NMBAs. Consequently, intrainstitutional data and assumptions Patients who develop tachyphylaxis to one NMBA can be used to perform the analysis along with local should try another drug if neuromuscular blockade is value judgments involved in selecting the appropriate still required. (Grade of recommendation = C) agent(s). Economics There have been few formal pharmacoeconomic evalua­ tions of NMBAs. In one of these economic evaluations, Recommendations: Institutions should perform an economic analysis using their own data when choosing NMBAs for use in an ICU. (Grade of recommendation = C) t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPN Table 8. Potential Complications of Neuromuscular Blockade Use in the ICUa References 1. Society of Critical Care Medicine and American Society of Health–System Pharmacists. Sedation, analgesia, and neuromuscular blockade of the critically ill adult: revised clinical practice guidelines for 2002. Am J Health-Syst Pharm. 2002; 59:147–9. 2. 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Oxygen delivery, oxygen consumption, and gastric intramucosal pH are not improved by a computer-controlled, closedloop, vecuronium infusion in severe sepsis. Crit Care Med. 1997; 25:72–7. 43. Strange C, Vaughan L, Franklin C, et al. Comparison of train–of–four and best clinical assessment during continuous paralysis. Am J Resp Crit Care Med. 1997; 156:1556–61. 44. Frankel H, Jeng J, Tilly E, et al. The impact of implementation of neuromuscular blockade monitoring standards in a surgical intensive care unit. Am Surg. 1996; 62:503–6. 45. Sladen RN. Neuromuscular blocking agents in the intensive care unit: a two-edged sword. Crit Care Med. 1995; 23:423–8. 46. Ford EV. Monitoring neuromuscular blockade in the adult ICU. Am J Crit Care. 1995; 4:122–30. 47. Kleinpell R, Bedrosian C, McCormick L. Use of peripheral nerve stimulators to monitor patients with neuromuscular blockade in the ICU. Am J Crit Care. 1996; 5:449–54. 48. Murray MJ. 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Effect of prescribing guidelines on the use of neuromuscular blocking agents. Am J Health-Syst Pharm. 1995; 52:1900–4. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPP ASHP Therapeutic Guidelines  681 682  ASHP Therapeutic Guidelines Appendix A—Summary of Recommendations 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. NMBAs should be used for an adult patient in an ICU to manage ventilation, manage increased ICP, treat muscle spasms, and decrease oxygen consumption only when all other means have been tried without success.1 (Grade of recommendation = C) The majority of patients in an ICU who are prescribed an NMBA can be managed effectively with pan­ curonium. (Grade of recommendation = B) For patients for whom vagolysis is contraindicated (e.g., those with cardiovascular disease), NMBAs other than pancuronium may be used. (Grade of recommendation = C) Because of their unique metabolism, cisatracurium or atracurium is recommended for patients with significant hepatic or renal disease. (Grade of recommendation = B) Patients receiving NMBAs should be assessed both clinically and by TOF monitoring (Grade of recommendation = B), with a goal of adjusting the degree of neuromuscular blockade to achieve one or two twitches. (Grade of recommendation = C) Before initiating neuromuscular blockade, patients should be medicated with sedative and analgesic drugs to provide adequate sedation and analgesia in accordance with the physician’s clinical judgment to optimize therapy. (Grade of recommendation = C) For patients receiving NMBAs and corticosteroids, every effort should be made to discontinue NMBAs as soon as possible. (Grade of recommendation = C) Drug holidays (i.e., stopping NMBAs daily until forced to restart them based on the patient’s condition) may decrease the incidence of AQMS. (Grade of recommendation = C) Patients receiving NMBAs should have prophylactic eye care (Grade of recommendation = B), physical therapy (Grade of recommendation = C), and DVT prophylaxis. (Grade of recommendation = C) Patients who develop tachyphylaxis to one NMBA should try another drug if neuromuscular blockade is still required. (Grade of recommendation = C) 11. Institutions should perform an economic analysis using their own data when choosing NMBAs for use in an ICU. (Grade of recommendation = C) Appendix B—Determination of Cost Effectiveness Using Intrainstitutional Dataa 1. For each adverse effect (e.g., prolonged recovery) of any given neuromuscular blocking agent (NMBA), add all associated costs together and multiply this figure by the probability of the occurrence of the adverse effect. If adverse effects A, B, and C are associated with an NMBA, then (Drug cost + cost Al) (probability of occurrence expressed as a decimal) = $U (Drug cost + cost B1) (probability of occurrence expressed as a decimal) = $V (Drug cost + cost C1) (probability of occurrence expressed as a decimal) = $W 2. Calculate the product of the drug cost multiplied by the probability of occurrence of no adverse effects expressed as a decimal; add this product to the cost multiplied by the probability factor for each adverse effect calculated in step 1. (Drug cost) (probability of occurrence of no ad­verse effects) + $U + $V + $W = average cost of all pathways for agent Note: The probabilities of all adverse effects plus the probability of no adverse effects associated with the NMBA must add up to 1. 3. Determine the cost effectiveness of the agent by dividing the total costs associated with the agent by the probability of occurrence of no adverse effects expressed as a decimal. Example using pancuronium: a. [$224 (drug cost for 4 days of therapy) + $1000 (estimated cost of 1 extra day of ICU stay due to prolonged paralysis resulting from renal dysfunction)] [0.07 (estimated probability of renal dysfunction)] = $85.68 [$224 (drug cost for 4 days of therapy) + $1000 (estimated cost of 1 extra day of ICU (intensive care unit) stay due to prolonged paralysis resulting from hepatic dysfunction)] [0.04 (estimated probability of hepatic dysfunction)] = $48.96 b. [$224 (drug cost for 4 days of therapy, assuming no adverse effects) × 0.89 (estimated probability of no adverse effects)] + $85.68 + $48.96 = $334.00 c. Cost effectiveness of pancuronium = 334.00/0.89 (probability of no adverse effects) = $375.28 a Note that the term “adverse effects” includes problems such as prolonged paralysis resulting from decreased medication elimination due to impaired organ function. If a neuromuscular blocking agent is eliminated by more than one organ (e.g., kidney and liver), prolonged paralysis may result from impaired elimination due to a combination of organ problems. For example, one adverse effect may be prolonged paralysis associated with renal dysfunction, while another adverse effect may be prolonged paralysis associated with hepatic dysfunction, while a third adverse effect may be prolonged paralysis associated with combined renal and hepatic dysfunction. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPQ 74. Loughlin KA, Weingarten CM, Nagelhout J, et al. A pharmacoeconomic analysis of neuromuscular blocking agents in the operating room. Pharmacotherapy. 1996; 16:942–50. 75. Ballantyne JC, Chang Y. The impact of choice of muscle relaxant on postoperative recovery time: a retrospective study. Anesth Analg. 1997; 85:476–82. 76. Zarowitz BJ, Rudis MI, Lai K, et al. Retrospective pharmacoeconomic evaluation of dosing vecuronium by peripheral nerve stimulation versus standard clinical assessment in critically ill patients. Pharmacotherapy. 1997; 17:327–32. 77. Rudis MI, Guslits BJ, Peterson EL, et al. Economic impact of prolonged motor weakness complicating neuromuscular blockade in the intensive care unit. Crit Care Med. 1996; 24:1749–56. 78. Butterworth J, James R, Prielipp RC, et al. Do shorteracting neuromuscular blocking drugs or opioids as­ sociate with reduced intensive care unit or hospital length of stay after coronary artery bypass grafting? Anesthesiology. 1998; 88:1437–46. ASHP Therapeutic Guidelines  683 Members of the 2001–2002 Commission on Therapeutics are William  L. Greene, Pharm.D., BCPS, FASHP, Chair; Mary Lea GoraHarper, Pharm.D., BCPS, Vice Chair; Kate Farthing, Pharm.D.; Charles W. Ham, Pharm.D., M.B.A.; Rita K. Jew, Pharm.D.; Rex S. Lott, Pharm.D.; Keith M. Olsen, Pharm.D., FCCP; Joseph J. Saseen, Pharm.D., BCPS; Beth A. Vanderheyden, Pharm.D., BCPS; Amy M. Blachere, R.Ph., Student Member; Jill E. Martin, Pharm.D., FASHP, Board Liaison; Dennis Williams, Pharm.D., FASHP, FCCP, FAPHA, BCPS, Liaison Section of Clinical Specialist; and Cynthia L. LaCivita, Pharm.D., Secretary. Members of the Neuromuscular Blockade Task Force are Michael J. Murray, M.D., Ph.D., FCCM, Chair, Professor and Chair of Anesthesiology, and Dean, Mayo School of Health Sciences, Mayo Clinic Jacksonville, FL; Stanley Nasraway, Jr., M.D., FCCM, Exec­ utive Director of Task Force, Associate Professor, Surgery, Medicine, and anesthesia, Tufts-New England Medical Center, Boston, MA; Jay Cowen, M.D., Director, Medical Intensive Care Unit, LeHigh Valley Hospital, Allentown, PA; Heidi F. DeBlock, M.D., Department of Surgery, Albany Medical Center, Albany, NY; Brian L. Erstad, Pharm.D., FCCM, Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ; Anthony W. Gray, Jr., M.D., FCCM, Section of Pulmonary and Critical Care, Medicine and Surgical Critical Care, Lahey Clinic Medical Center, Burlington, MA; Judith Jacobi, Pharm.D., FCCM, BCPS, Critical Care Pharmacy Specialist, Methodist Hospital–Clarian Health Partners, Indianapolis, IN; Philip D. Lumb, M.B., B.S., FCCM, Professor and Chairman, Department of Anesthesiology, Keck School of Medicine of USC, Los Angeles, CA; William T. McGee, M.D., M.H.A., Critical Care Division, Departments of Medicine & Surgery, Baystate Medical Center, Springfield, MA; William T. Peruzzi, M.D., FCCM, Associate Professor of Anesthesiology, Northwestern University School of Medicine, Chief, Section of Critical Care Medicine, Northwestern Memorial Hospital, Chicago, IL; Richard C. Prielipp, M.D., FCCM, Section Head, Critical Care and Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC; Greg Susla, Pharm.D., FCCM, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD; Ann N. Tescher, R.N., Clinical Nurse Specialist, Mayo Clinic, Rochester, MN; Cynthia L. LaCivita, Pharm.D., Clinical Affairs Associate, ASHP Staff Liaison; Deborah L. McBride, Director of Publications, SCCM Staff Liaison. Reviewers: American College of Chest Physicians; American Academy of Neurology; American Association of Critical Care Nurses; American Nurses Association; American Pharmaceutical Association; American College of Clinical Pharmacy; Joe Dasta, Pharm.D.; Doug Fish, Pharm.D.; Erkan Hassan, Pharm.D.; H. Mathilda Horst, M.D.; Carlayne E. Jackson, M.D.; Karen Kaiser, R.N.; Kathleen M. Kelly, M.D.; Carl Schoenberger, M.D.; Lori Schoonover, R.N.; and Gayle Takaniski, Pharm.D. The recommendations in this document do not indicate an exclusive course of treatment to be followed. Variations, taking into account individual circumstances, may be appropriate. Copyright © 2002, American Society of Health-System Pharmacists, Inc. and the Society of Critical Care Medicine. All rights reserved. The bibliographic citation is as follows: Society of Critical Care Medicine and American Society of Health-System Pharmacists. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Am J Health Syst Pharm. 2002; 59:179–95. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPR Developed through the Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), in collaboration with the American Society of HealthSystem Pharmacists (ASHP), and in alliance with the American College of Chest Physicians; and approved by the Board of Regents of ACCM and the Council of SCCM on November 15, 2001 and the ASHP Board of Directors on November 17, 2001. Drugs.com Print Version Print   Close Thiopental Sodium Class: Barbiturates VA Class: CN202 Chemical Name: 5-Ethyl-dihydro-5-(1-methylbutyl)-2-thioxo-4,6(1H,5H)-pyrimidinedione monosodium salt Molecular Formula: C11H17N2NaO2S CAS Number: 71-73-8 Brands: Pentothal Introduction Barbiturate anesthetic.1 2 3 7 24 Uses for Thiopental Sodium Induction and Maintenance of Anesthesia Induction of general anesthesia prior to administration of other anesthetic agents or as the sole anesthetic agent for short (≤15 minutes) surgical procedures.1 2 3 4 7 12 Induction results in dose-related hypnotic effects (progressing from light sleep to unconsciousness) and anterograde amnesia, but not analgesia.1 2 12 As the hypnotic component of balanced anesthesia (e.g., IV hypnotic and/or inhalation anesthetic, analgesic, skeletal muscle relaxant).1 2 3 7 12 Seizures Management of seizures occurring during or after administration of local or inhalation anesthetics and seizures attributed to various etiologies.1 2 3 6 7 12 23 47 78 110 Control of generalized tonic-clonic status epilepticus refractory to conventional anticonvulsants† in intubated and mechanically ventilated patients.3 6 47 Increased Intracranial Pressure Management of increased intracranial pressure associated with neurosurgical procedures when adequate ventilation is maintained.1 2 3 7 12 13 58 Has been used to induce coma3 12 26 85 86 87 88 89 90 105 in the management of cerebral ischemia† and increased intracranial pressure associated with head trauma injury†/3 27 86 87 88 89 stroke†,3 85 Reye’s 3 3 90 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPS Adjunct to regional anesthesia (also called block anesthesia or conduction anesthesia).1 2 Drugs.com Print Version syndrome†, or hepatic encephalopathy†; however, pentobarbital is the most commonly used barbiturate.26 89 Safety and efficacy for the management of increased intracranial pressure associated with neurotraumas are controversial 26 85 86 87 88 105 and are not established.26 85 88 105 Narcoanalysis Hypnotic agent for narcoanalysis in psychiatric conditions; use historically misnomered as “truth serum.”1 2 104 106 123 124 Sedation in Children To provide sedation† when administered as extemporaneously prepared rectal suspensions, solutions, or suppositories prior to diagnostic procedures (e.g., computed tomography [CT scan], magnetic resonance imaging [MRI]).27 28 29 30 31 108 Thiopental Sodium Dosage and Administration General Test Dose Prior to initiation of therapy, the manufacturers recommend administration of a 25- to 75-mg test dose (1–3 mL of a 2.5% solution) followed by observation of the patient for ≥60 seconds to detect unusual sensitivity and assess tolerance.1 2 12 Reduce dosage in particularly sensitive patients.12 If unexpectedly deep anesthesia or respiratory depression occurs, consider factors other than sensitivity (e.g., excessive premedication, unintended use of a more concentrated solution).1 2 Premedication Administration IV Administration For solution and drug compatibility, see Compatibility under Stability. Administer by IV injection or continuous IV infusion.1 2 3 To decrease pain at the injection site, administer thiopental by slow injection into large veins (rather than into small hand veins); may also administer a local anesthetic or an opiate agonist prior to induction to minimize pain.12 Avoid extravasation and intra-arterial administration.1 2 (See Local Effects under Cautions.) Prior to IV infusion, check placement of the IV catheter to ensure that it is in the vein.1 2 Observe strict aseptic technique in preparing and handling thiopental solutions as commercially available thiopental sodium for injection contains no preservatives.1 2 Reconstituted solutions should not be sterilized by heat.1 2 Use promptly and discard any unused portion after 24 hours.1 2 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPT The manufacturers state that patients may receive premedication with other drugs (e.g., benzodiazepines [to relieve anxiety and produce anterograde amnesia], other barbiturates [to relieve anxiety and provide sedation]) prior to administration of thiopental for induction of anesthesia.1 2 12 Anticholinergic agents (e.g., atropine, scopolamine) also have been used (to suppress vagal reflexes and inhibit secretions).1 2 Peak effects of these drugs should be reached shortly before IV induction.1 2 Drugs.com Print Version Reconstitution for Intermittent IV Injection For intermittent IV administration, reconstitute powder for injection with sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to a concentration of 2–5% (usually 2 or 2.5%).1 2 A 3.4% solution of thiopental sodium in sterile water for injection is isotonic.1 2 Do not use sterile water for injection for preparing solutions with concentrations <2%, since use of the resulting hypotonic solutions will cause hemolysis.1 2 Use 2.5- or 5-g vials when preparing solutions for several patients.1 2 Preparation of 2% Thiopental Sodium Solution12 Amount of Thiopental Sodium (g in vial) Volume of Diluent 0.4 g 20 mL 1g 50 mL 2.5 g 125 mL 5g 250 mL Preparation of 2.5% Thiopental Sodium Solution12 Amount of Thiopental Sodium (g in vial) Volume of Diluent 0.25 g 10 mL 0.5 g 20 mL 1g 40 mL 2.5 g 100 mL 5g 200 mL Amount of Thiopental Sodium (g in vial) Volume of Diluent 1g 20 mL 5g 100 mL Reconstitution for IV Infusion For continuous IV infusion, reconstitute thiopental sodium powder for injection with 0.9% sodium chloride injection, 5% dextrose injection, or Normosol-R (pH 7.4) to a concentration of 0.2–0.4%.1 2 A 3.4% solution of thiopental sodium in sterile water for injection is isotonic.1 2 Do not use sterile water for injection for preparing solutions with concentrations <2%, since use of the resulting hypotonic solutions will cause hemolysis.1 2 Preparation of Thiopental for IV Infusion12 Desired Concentration of Final Solution Amount of Thiopental Sodium (g in vial) http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] Volume of Diluent t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPU Preparation of 5% Thiopental Sodium Solution12 Drugs.com Print Version 0.2% 1g 500 mL 0.4% 1g 250 mL 0.4% 2g 500 mL Rate of Administration IV injection: Administer slowly (see Dosage) to minimize respiratory depression and the possibility of overdosage.1 2 120 Depth of anesthesia is controlled by rate of IV infusion.1 2 Clinical assessment of the depth of anesthesia is based on responses to verbal commands and surgical stimulation, EEG changes, autonomic signs, eyelash reflex, and movement.4 7 12 119 120 121 122 Rectal Administration Preparations for rectal† use no longer commercially available in the US; extemporaneous rectal formulations have been prepared7 27 28 29 30 using commercially available thiopental sodium for injection.28 108 Dosage Available as thiopental sodium; dosage expressed in terms of the salt.1 2 Individual response to thiopental is variable; therefore, adjust dosage according to individual requirements and response, age, weight, gender, physical and clinical status, underlying pathologic conditions (e.g., shock, intestinal obstruction, malnutrition, anemia, burns, advanced malignancy, ulcerative colitis, uremia, alcoholism), and the type and amount of premedication or concomitant medication(s).1 2 7 12 Pediatric Patients Pediatric patients require relatively larger doses than middle-aged and geriatric adults.1 2 11 12 120 121 Induction and Maintenance of Anesthesia IV Induction of anesthesia in infants: 7–8 mg/kg administered over 20–30 seconds is recommended by some clinicians; however, this dosage is estimated for healthy individuals and should be titrated to clinical effect.4 12 Induction of anesthesia in children: 5–6 mg/kg administered over 20–30 seconds is recommended by some clinicians; however, this dosage is estimated for healthy individuals and should be titrated to clinical effect.4 12 Seizures IV Initial loading dose of 1 mg/kg followed by continuous IV infusion of 10–120 mcg/kg per minute has been used.6 A limited number of children receiving conventional anticonvulsants have received thiopental infusions for 3–5 days.7 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSPV Reduce dosage in neonates (because of decreased protein binding11 and reduced clearance).11 18 Drugs.com Print Version Increased Intracranial Pressure Increased Intracranial Pressure Associated with Trauma† IV Children 3 months to 15 years of age: Initial dose of 5–10 mg/kg followed by continuous IV infusion of 1–4 mg/kg per hour.7 A more rapid IV infusion rate of up to 7–12 mg/kg per hour has been maintained for 8–10 days.7 Sedation† Rectal 25–50 mg/kg.27 28 29 31 In one study, dosage was based on both the child’s weight and age.29 Thiopental Sodium Dosage for Sedation Based on Child’s Weight and Age29 Age of Child Dosage <6 months 50 mg/kg 6 months to 1 year 35 mg/kg >1 year 25 mg/kg (maximum 700 mg) Adults Younger patients require relatively larger doses than middle-aged and geriatric adults.1 2 11 12 120 121 Some clinicians estimate that dosage requirements decrease by 10% per decade over the age range of 20– 80 years.7 Adult males usually require higher dosages than adult females.1 2 11 12 120 121 Induction and Maintenance of Anesthesia Moderately slow induction of anesthesia: Initially, 50–75 mg (2–3 mL of a 2.5% solution), usually administered at intervals of 20–40 seconds, based on patient response.1 2 Additional doses of 25–50 mg may be given as necessary when patient movements indicate lightening of anesthesia.1 2 Alternatively, some clinicians suggest induction doses administered over 20–30 seconds of 3–5 mg/kg in young adults or 2–4 mg/kg in older adults; however, these dosages are estimated for healthy individuals and should be titrated to clinical effect.4 12 Rapid induction as a component of balanced anesthesia: Initially, 210–280 mg (3–4 mg/kg) given in 2– 4 divided doses in an average 70-kg adult.1 2 Maintenance of anesthesia: Intermittent injections or continuous IV infusion of a 0.2 or 0.4% solution may be used without additional anesthetic agents for short (≤15-minute) surgical procedures.1 2 Seizures IV 75–125 mg (3–5 mL of a 2.5% solution) administered as soon as possible after seizures develop.1 2 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQM IV Drugs.com Print Version Seizures following Administration of Local Anesthesia IV 125–250 mg administered over 10 minutes;1 2 121 dosage depends on the amount of the local anesthetic used and its seizure characteristics.1 2 Generalized Tonic-Clonic Status Epilepticus IV Initial loading dose of 5 mg/kg followed in 30 minutes by continuous IV infusion of 1–3 mg/kg per hour for ≥12 hours after seizures abate is recommended by some clinicians.3 Alternatively, an initial loading dose of 250–1000 mg followed by continuous IV infusion of 80–120 mg per hour has been used for up to 13 days.47 Increased Intracranial Pressure Increased Intracranial Pressure Associated with Neurosurgical Procedures IV 1.5–3.5 mg/kg by intermittent IV infusion.1 2 Alternatively, an initial loading dose of 20 mg/kg administered over 1 hour, followed by a second loading dose of 10 mg/kg per hour over 6 hours and subsequently followed by a continuous IV maintenance infusion of 3 mg/kg per hour, has been used.117 118 120 Dosage was adjusted to maintain blood concentrations of 20–40 mcg/mL.117 Increased Intracranial Pressure Associated with Head Injury† IV Low-dosage IV infusion (0.5–3 mg/kg per hour) administered in combination with other therapeutic agents (e.g., dihydroergotamine, metoprolol, clonidine) has been used.86 87 Narcoanalysis Patients usually receive an anticholinergic agent prior to a test dose of thiopental.1 2 Administer at a rate of 100 mg/minute (4 mL/minute of a 2.5% solution) while the patient counts backward from 100.1 2 Shortly after the counting becomes confused but before actual sleep occurs, discontinue thiopental, allowing the patient to return to a semidrowsy state under which conversation is coherent.1 2 Alternatively, administer as a 0.2% solution by continuous IV infusion at a rate ≤50 mL/minute (100 mg/minute).1 2 Some clinicians have used an initial IV loading dose of 25 mg followed by continuous IV infusion of 0.5 mg/kg per hour.104 123 Special Populations Hepatic Impairment Generally not recommended for use; however, if used, reduce dosage and rate of administration.1 2 96 121 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQN IV Drugs.com Print Version Renal Impairment Generally not recommended for use; however, if used, reduce dosage and rate of administration.1 2 96 121 Geriatric Patients Reduce initial dosage.1 2 12 Some clinicians estimate that dosage requirements decrease by 10% per decade over the age range of 20–80 years.7 Obese Patients Dosage requirements are proportional to body weight.1 2 Obese patients may require larger doses than relatively lean patients of the same weight;1 2 however, some clinicians suggest that dosage used in anesthesia7 should be based on lean body weight.7 12 120 Other Populations Reduce dosage and administer slowly in patients with severe cardiovascular disease, hypotension or shock, status asthmaticus, and conditions that might prolong or intensify the hypnotic effect (e.g., excessive premedication, Addison’s disease, myxedema, increased blood urea concentrations, severe anemia, asthma, myasthenia gravis).1 2 Cautions for Thiopental Sodium Contraindications Known hypersensitivity to barbiturates.1 2 Patients in whom a suitable vein is not accessible for IV administration.1 2 History of acute intermittent porphyria or porphyria variegata,1 2 since thiopental interferes with porphyrin metabolism.12 Relative Contraindications (See Other Populations under Dosage and Administration): Severe cardiovascular disease.1 2 Status asthmaticus.1 2 Conditions that might prolong or intensify the hypnotic effect (e.g., excessive premedication, Addison’s disease, hepatic or renal impairment, myxedema, increased blood urea concentrations, severe anemia, asthma, myasthenia gravis).1 2 Warnings/Precautions Warnings Respiratory and Cardiovascular Effects Possible respiratory depression.1 2 3 4 7 12 13 14 May depress ventilatory response to carbon dioxide stimulation12 or cause decreases in tidal volume.12 Apnea and hypoventilation may result from unusual responsiveness or overdosage.1 2 Laryngospasm may occur during light anesthesia at intubation or, in the absence of intubation, it may be associated with irritation caused by foreign matter or secretions in the respiratory tract.1 2 7 Laryngospasm or bronchospasm is more likely caused by premature insertion of oral airways or http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQO Hypotension or shock.1 2 Drugs.com Print Version endotracheal tubes in inadequately anesthetized patients by airway reactivity.12 Manufacturers state that laryngeal and bronchial vagal reflexes may be suppressed and secretions minimized by premedication with an anticholinergic agent (e.g., atropine, scopolamine) and administration of a barbiturate or an opiate agonist.1 2 121 Possible myocardial depression (proportional to the amount of drug that is in direct contact with the heart),1 2 33 36 38 cardiac arrhythmias (occurring rarely in patients with adequate ventilation),1 2 increased heart rate,12 circulatory depression,7 vasodilation,12 and hypotension (especially in hypovolemic patients).3 7 38 These effects may be particularly severe in patients with impaired vascular homeostatic mechanisms.1 2 7 12 13 120 Appropriate resuscitative equipment for prevention and treatment of anesthetic emergencies must be readily available.1 2 Facilities for intubation, assisted respiration, and administration of oxygen must be available whenever the drug is used.1 2 Supervised Administration Should be administered only by individuals qualified in the use of IV anesthetics.1 2 Local Effects Local reactions at the injection site reported; 12 33 36 38 IV administration has caused pain,12 36 38 venous thrombosis,33 phlebitis,33 and thrombophlebitis.33 Extravasation can cause chemical irritation of perivascular tissues (possibly associated with high alkalinity [pH 10–11] of the injection);120 121 local reactions can vary from slight tenderness to venospasm, extensive necrosis, and sloughing.1 2 Inadvertent intra-arterial injection may cause arteriospasm and severe pain along the affected artery; the resulting necrosis can progress to gangrene.1 2 Increased risk of intra-arterial administration if aberrant arteries are present (especially at the medial aspect of the antecubital fossa).1 2 Decrease pain at the injection site by slow injection into large veins (rather than into small hand veins) and by administration of a local anesthetic or an opiate agonist prior to induction.12 In a conscious patient, the first manifestation of intra-arterial injection may be a complaint of fiery burning that roughly follows the distribution path of the injected artery with blanching of the arm and fingers; stop the injection immediately and assess the situation.1 2 Treatment of extravasation or inadvertent intra-arterial injection includes application of moist heat and administration of a 1% procaine injection at the affected site.1 2 120 The most appropriate therapy for inadvertent intra-arterial injection has not been fully established; efforts aimed at prevention are important; consult the manufacturers’ labeling for suggested therapies that may be beneficial.1 2 Sensitivity Reactions Hypersensitivity Reactions Anaphylactic or anaphylactoid and other serious hypersensitivity reactions (e.g., urticaria,1 2 flushing and/or rash [on the face, neck, and/or upper chest],12 33 42 bronchospasm,1 2 42 45 61 vasodilation,1 2 hypotension,42 44 edema,1 2 44 angioedema,42 cardiovascular collapse,45 shock,12 death1 2 3 12 33 34 40 41 42 43 44 61 ) reported rarely.1 2 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQP IV solutions in concentrations >2.5% appear to be associated with an increased incidence of local adverse effects;33 severe tissue injury may occur when solutions of these concentrations are injected sub-Q or intra-arterially.12 Drugs.com Print Version Allergic reactions often appear to be immediate type I IgE-mediated hypersensitivity reactions,33 34 40 41 42 43 44 45 although some reactions may result from direct histamine release.33 34 42 43 46 Hypersensitivity reactions are most likely to occur in patients with asthma33 34 61 or urticaria42 and in those with a history of atopy34 40 42 43 61 or allergies to other drugs and/or food.33 40 42 43 44 45 General Precautions Postoperative Shivering Postoperative shivering (manifested by facial muscle twitching and occasionally by tremor of arms, head, shoulder, and body) reported in up to 65% of patients receiving general anesthesia.1 2 56 57 120 Shivering may lead to increased oxygen demand with increases in minute ventilation and cardiac output.56 57 Management includes administration of chlorpromazine or methylphenidate, raising room temperature to 22°C, and covering patient with blankets.1 2 Concomitant Medical Conditions Use with caution in patients with advanced cardiac disease, increased intracranial pressure, ophthalmoplegia plus, asthma, myasthenia gravis, and endocrine disorders (e.g., pituitary, thyroid, adrenal, pancreas).1 2 Specific Populations Pregnancy Category C.1 Usual anesthesia induction doses have been used safely in women undergoing cesarean section.12 Use in pregnant women only when clearly needed.1 2 Lactation Many clinicians state that nursing women undergoing surgery may receive usual anesthetic induction doses of thiopental;12 51 52 however, since trace amounts of the drug may be present in milk, drowsiness of nursing infants may occur on the day of the procedure.12 Pediatric Use Safety and efficacy not established in children.1 2 120 121 Pharmacology of thiopental in infants and children is similar to that in adults; however, pharmacokinetics may be different in neonates and young infants because of their immature organs of elimination (see Distribution and also Elimination, under Pharmacokinetics).7 12 Induction doses tend to be higher (relative to weight) in children.12 (See Pediatric Patients under Dosage and Administration.) Used rectally to provide sedation.27 28 29 30 31 108 However, 1 manufacturer does not recommend such use, because the high alkalinity of thiopental may result in local irritation.121 Geriatric Use Possible reduced clearance and prolonged drug-associated effects.12 120 121 (See Special Populations under Dosage and Administration.) Hepatic Impairment http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQQ Distributed into colostrum7 20 50 and milk.1 2 50 Drugs.com Print Version Hypnotic effect may be prolonged.1 2 (See Hepatic Impairment under Dosage and Administration.) Renal Impairment Hypnotic effect may be prolonged.1 2 (See Renal Impairment under Dosage and Administration.) Common Adverse Effects Respiratory depression, myocardial depression, cardiac arrhythmias, prolonged somnolence and recovery, sneezing, coughing, bronchospasm, laryngospasm, shivering.1 2 Interactions for Thiopental Sodium Protein-bound Drugs Potential for thiopental to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.3 7 67 Specific Drugs Interaction Comments Aminophylline Administration of low-dose (e.g., 2 mg/kg) IV aminophylline after surgery may partially reverse thiopental-induced sedation in the early phase of recovery1 2 82 83 Aspirin Thiopental theoretically could be displaced from binding sites by, or could displace from binding sites, aspirin3 7 67 Potentiation of hypnotic effect reported3 Clonidine IV administration of clonidine 2.5 or 5 mg prior to induction of anesthesia with thiopental reduced thiopental dosage requirements by about 25 or 37%, respectively12 94 Some clinicians recommend reduction of thiopental dosage when clonidine is administered as an adjunct to anesthesia94 CNS depressants (e.g., sedatives, hypnotics, opiates, nitrous oxide, alcohol) Thiopental may be additive with or potentiate the effects of other CNS depressants;1 2 3 71 65 75 92 premedication with other CNS depressants may potentiate hypnotic effect of thiopental3 71 Possible reduction of antinociceptive effect of opiate analgesics1 2 71 Adjustment of thiopental dosage may be required with concomitant use3 71 Chronic use of CNS depressants (e.g., alcohol) may increase thiopental dosage required to achieve the desired anesthetic effect3 75 Diazoxide Hypotension reported during induction of anesthesia with thiopental in patients undergoing surgery for insulinoma who were receiving oral diazoxide (a highly protein-bound drug) for several days prior to surgery1 2 84 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQR Drug Drugs.com Print Version Ketamine Additive anesthetic effects reported in 1 study;70 76 in another study, increased thiopental doses required to achieve unconsciousness70 76 Meprobamate Thiopental theoretically could be displaced from binding sites by, or could displace from binding sites, meprobamate3 7 67 Possible potentiation of hypnotic effects7 Metoclopramide Administration of metoclopramide prior to induction of anesthesia with thiopental can reduce thiopental dosage requirements64 Midazolam Possible potentiation of hypnotic effect3 71 Reduce thiopental dosages for induction of anesthesia by about 15% in patients receiving premedication with IM midazolam69 Phenothiazines Possible potentiation of hypnotic effects;68 concomitant use of thiopental in patients (e.g., chlorpromazine, receiving chlorpromazine reported to prolong sleep time and reduce thiopental dosage promethazine) requirements by 60%68 Possible increased excitatory effects of thiopental3 72 Probenecid Thiopental theoretically could be displaced from Reduction of thiopental binding sites by, or could displace from binding dosage may be necessary73 81 3 7 67 sites, probenecid Possible prolongation of hypnotic effects (possibly through competition for protein-binding sites)3 67 81 Sulfisoxazole Thiopental theoretically could be displaced from binding sites by, or could displace from binding sites, sulfisoxazole3 7 67 Potentiation of hypnotic effects reported7 Thiopental Sodium Pharmacokinetics Absorption Bioavailability Rectal absorption may be unpredictable when using a suspension rather than a solution of the drug.3 Onset Following IV administration of usual induction doses (2.5–5 mg/kg) in adults, hypnosis1 2 or unconsciousness3 4 7 occurs within 10–40 seconds,1 2 3 4 7 11 16 with maximal effects occurring in about 1 minute.7 16 Following rectal administration in children, onset of sedation generally occurs within 3–15 minutes.27 28 29 30 31 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQS Possible increased hypotension3 72 Drugs.com Print Version Duration Following IV administration of usual induction doses (2.5–5 mg/kg) in adults, duration of anesthesia persists for 5–8 minutes.1 2 3 4 7 11 13 16 Duration of action is variable;7 13 16 the duration of single doses usually is determined by redistribution of the drug from the CNS rather than by the rate of elimination.7 13 16 However, the anesthesia effect is prolonged following repeated injections or continuous infusion because of drug accumulation in adipose tissue.1 2 4 7 16 Following rectal administration in children, sedation generally persists for about 0.5–5 hours.27 28 29 30 31 Distribution Extent Following IV administration, thiopental is rapidly distributed to all tissues and fluids, with high concentrations in brain and liver.4 7 Penetrates the blood-brain barrier rapidly; rate of entry into the brain is limited only by the rate of cerebral blood flow.7 16 24 Readily crosses the placenta1 2 4 7 19 20 49 53 55 and is distributed into fetal blood and umbilical vein blood at delivery.1 2 7 19 20 49 53 Distributed into milk;7 20 50 colostrum-to-plasma ratios of 0.67–0.68 reported at 4 and 9 hours after induction of anesthesia.7 20 Plasma Protein Binding Approximately 80%1 2 3 7 11 (mainly albumin).7 11 Special Populations Elimination Metabolism Metabolized mainly in the liver by the CYP enzyme system and to a lesser extent in other organs and tissues (e.g., kidneys, brain).1 2 3 4 7 Undergoes desulfuration to form pentobarbital, an active metabolite.7 13 Both thiopental and pentobarbital undergo oxidation and hydroxylation to form the corresponding carboxylic acid metabolites and alcohols, respectively;7 all detected metabolites are pharmacologically inactive.1 2 7 Elimination Route Excreted mainly in urine as inactive metabolites,1 2 7 with small amounts as unchanged drug.7 Half-life Following small IV doses, concentrations appear to decline in a monoexponential (first-order) fashion, with an elimination half-life of about 3–22 hours.1 2 7 11 14 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQT Plasma protein binding may be decreased in neonates.11 Drugs.com Print Version Following rapid IV (“bolus”) injection, pharmacokinetics described by a triexponential equation;3 24 the drug appears to undergo rapid and slow distribution phases followed by a terminal elimination phase.24 In the rapid distribution phase, thiopental rapidly distributes into highly perfused organs (CNS, viscera);7 16 in the slow distribution phase, the drug equilibrates between highly perfused organs and adipose tissue.7 16 In adults, the mean plasma half-lives in the initial distribution phase and slow distribution phase are about 1.7–13.2 and 39.5–161.4 minutes, respectively.7 At high therapeutic concentrations, pharmacokinetics characterized by Michaelis-Menten kinetics,7 11 with a first-order elimination half-life of 9.7–49.4 hours.7 Special Populations In pediatric patients 5 months to 13 years of age, elimination half-life is about one-half the elimination half-life in adults (about 6 hours).7 11 59 In neonates, elimination half-life is increased by 2-fold compared with their mothers’ (about 15 hours).7 11 59 Stability Storage Parenteral Powder for Injection 15–30°C.1 2 Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Solution CompatibilityHID Compatible Alcohol 5%, dextrose 5% Dextran 6% in dextrose 5% Dextran 6% in sodium chloride 0.9% Dextrose 2.5% in sodium chloride 0.45 or 0.9% Dextrose 5% in sodium chloride 0.225 or 0.45% Dextrose 2.5 or 5% in water Multielectrolyte solution Normosol R http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQU Incompatible with acidic solutions or drugs.1 2 12 Drugs.com Print Version Sodium chloride 0.45 or 0.9% Sodium lactate (1/6) M Incompatible Dextrose–Ringer’s injection combinations Dextrose–Ringer’s injection, lactated, combinations Dextrose 5% in Ringer’s injection, lactated Dextrose 10% in sodium chloride 0.9% Dextrose 10% in water Fructose 10% in sodium chloride 0.9% Fructose 10% solutions Fructose 10% in water Invert sugar 5 and 10% in sodium chloride 0.9% Invert sugar 5 and 10% in water Ionosol products Normosol solutions (except R) Ringer’s injection Ringer’s injection, lactated Variable Dextrose 5% in sodium chloride 0.9% Admixture CompatibilityHID Compatible Chloramphenicol sodium succinate Hydrocortisone sodium succinate Oxytocin Pentobarbital sodium Phenobarbital sodium Potassium chloride Sodium bicarbonate Incompatible Amikacin sulfate http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSQV Drug Compatibility Drugs.com Print Version Dimenhydrinate Diphenhydramine HCl Hydromorphone HCl Insulin, regular Meperidine HCl Metaraminol bitartrate Morphine sulfate Norepinephrine bitartrate Penicillin G potassium Prochlorperazine edisylate Promethazine HCl Succinylcholine chloride Variable Ephedrine sulfate Y-Site CompatibilityHID Compatible Bivalirudin Fentanyl citrate Furosemide Hetastarch in lactated electrolyte injection (Hextend) Milrinone lactate Mivacurium chloride Nitroglycerin Propofol Ranitidine HCl Remifentanil HCl Incompatible Alfentanil HCl Ascorbic acid injection http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRM Heparin sodium Drugs.com Print Version Atracurium besylate Atropine sulfate Diltiazem HCl Dobutamine HCl Dopamine HCl Ephedrine sulfate Epinephrine HCl Fenoldopam mesylate Hydromorphone HCl Labetalol HCl Lidocaine HCl Midazolam HCl Nicardipine HCl Norepinephrine bitartrate Pancuronium bromide Phenylephrine HCl Succinylcholine chloride Sufentanil citrate Vecuronium bromide Variable Morphine sulfate Actions CNS effects appear to be related, at least partially, to thiopental’s ability to enhance the activity of GABA by altering inhibitory synaptic transmissions that are mediated by GABAA receptors.10 13 14 Capable of producing all levels of CNS depression—from mild sedation to hypnosis to deep coma to death.12 Is a poor skeletal muscle relaxant, has no analgesic activity, and may increase the reaction to painful stimuli at subanesthetic doses.4 7 13 Exhibits anticonvulsant activity.1 2 3 6 7 12 23 47 78 110 May reduce cerebral metabolic rate (measured by cerebral metabolic rate for oxygen; CMRO2) in a dose-dependent manner;13 26 105 decreases in CMRO2 may result in decreased cerebral blood flow and intracranial pressure.13 http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRN Lorazepam Drugs.com Print Version Advice to Patients Importance of informing patients that their ability to perform activities requiring mental alertness (e.g., driving, operating machinery) may be impaired for some time after undergoing general anesthesia or sedation.b Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2 Importance of women informing clinicians if they are or plan to become pregnant or plan to breastfeed.1 2 Importance of informing patients of other important precautionary information.1 2 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.1 2 * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Thiopental Sodium Dosage Forms Strengths Brand Names Manufacturer Parenteral For 250 mg injection, for IV use Pentothal ( C-III; with 10 mL sterile water for injection or sodium chloride 0.9% injection; available with a disposable syringe and needle) Hospira 400 mg Pentothal ( C-III; with 20 mL sterile water for injection or sodium chloride 0.9% injection; available with a disposable syringe and needle) Hospira 500 mg* Pentothal ( C-III; with 20 mL sterile water for injection or sodium chloride 0.9% injection; available with or without a disposable syringe and needle) Hospira Thiopental Sodium ( C-III; with 20 mL sodium chloride 0.9% injection; available with a disposable syringe and needle) Baxter Anesthesia Penthothal ( C-III; with 40 or 50 mL sterile water for injection) Hospira Thiopental Sodium ( C-III; with 40 mL sodium chloride 0.9% injection; available with transfer spikes) Baxter Pentothal ( C-III; with 100 or 150 mL sterile water for injection) Hospira 1 g* 2.5 g* http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRO Routes Drugs.com Print Version 5 g* Thiopental Sodium ( C-III; with 100 mL sterile water for injection; available with transfer spikes) Baxter Pentothal ( C-III; with 200 or 250 mL sterile water for injection) Hospira Thiopental Sodium ( C-III; with 200 mL sterile water for injection; available with transfer spikes) Baxter AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. † Use is not currently included in the labeling approved by the US Food and Drug Administration. References 1. Abbott. Pentothal thiopental sodium for injection prescribing information. North Chicago, IL; 1993 Nov. 2. Baxter. Thiopental Sodium for injection prescribing information. Deerfield, IL; 1998 Sep. 3. Martindale: the complete drug reference. 32nd ed. Parfitt K, ed. London: Pharmaceutical Press, 1999:1233-4. 4. Carmichael FJ, Haas DA. General Anesthetics. In: Kalant H and Roschlau WHE, eds. Principles of Medical Pharmacology. 6th edition. New York: Oxford University Press; 1998:278-92. 5. Budavari S ed. The Merck Index. 12th ed. Whitehouse Station, NJ: Merck & CO., Inc. 1996:1595. 7. Russo H, Bressolle F. Pharmacodynamics and pharmacokinetics of thiopental. Clin Pharmacokinet. 1998; 35:95-134. [PubMed 9739479] 8. Newton DW. Introduction: physiochemical determinants of incompatibility and instability drugs for injection and infusion. In: Trissel LA. Handbook on injectable drugs. 3rd ed. Bethesda, MD: American Society of Hospital Pharmacists, Inc; 1983:xi-xxi. 9. (unused reference number) 10. Hales TG, Olsen RW. Basic pharmacology of intravenous induction agents. In: Bowdle TA, Horita A, Kharasch ED, eds. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:295-306. 11. Henthorn TK. Pharmacokinetics of intravenous induction agents. In: Bowdle TA, Horita A, Kharasch ED, eds. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:307-18. 12. Fragen RJ. Clinical pharmacology and applications of intravenous anesthetic induction agents. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:319-36. http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRP 6. Lohr A Jr, Werneck LC. [Comparative non-randomized study with midazolam versus thiopental in children with refractory status epilepticus.] (Portuguese; with English abstract.) Arq Neuropsiquiatr. 2000; 58:282-7. Drugs.com Print Version 13. Witzum JL. Evers AS, Crowder CM. General Anesthetics. In: Hardman JG, Gilman AG, Limbird LE, eds. Goodman and Gilman’s The pharmacological basis of therapeutics. 10th ed. McGraw-Hill; 2001: 337-44. 14. Donnelly AJ, Shafer AL. Perioperative care. In: Young LL, Koda- Kimble MA, eds. Applied Therapeutics: The clinical use of drugs. 6th ed. Vancouver WA: Applied Therapeutics, Inc.; 1995:8-1-8-24. 15. Tanelian DL, Kosek P, Mody I et al. The role of the GABAA receptor/chloride channel complex in anesthesia. Anesthesiology. 1993; 78:757-76. [IDIS 316350] [PubMed 8385426] 16. 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Henthorn TK. Emerging concepts in pharmacokinetics. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:741-54. 24. Burch PG, Stanski DR. The role of metabolism and protein binding in thiopental anesthesia. Anesthesiology. 1983; 58:146-52. [IDIS 165879] [PubMed 6824168] 25. Morgan DJ, Blackman GL, Paull JD et al. Pharmacokinetics and plasma binding of thiopental. I: studies in surgical patients. Anesthesiology. 1981; 54:468-73. [IDIS 133050] [PubMed 7235274] 26. Anon. The use of barbiturates in the control of intracranial hypertension. J Neurotrauma. 1996; 13:711-4. [PubMed 8941890] 27. De Boer AG, De Leede LGJ, Breimer DD. Drug absorption by sublingual and rectal routes. Br J Anaesth. 1984; 56:69-82. [IDIS 182485] [PubMed 6140933] 28. Nahata MC. Sedation in pediatric patients undergoing diagnostic procedures. Drug Intell Clin Pharm. 1988; 22:711-5. [IDIS 245367] [PubMed 3063482] 29. Alp H, Güler I, Orbak Z et al. 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[IDIS 292816] [PubMed 1545098] 41. Fisher MM, Baldo BA, Silbert BS. Anaphylaxis during anesthesia: use of radioimmunoassays to determine etiology and drugs responsible in fatal cases. Anesthesiology. 1991; 75:1112-5. [IDIS 2295232] [PubMed 1741501] 42. Moscicki RA, Sockin SM, Corsello BF. Anaphylaxis during induction of general anesthesia: subsequent evaluation and management. J Allergy Clin Immunol. 1990; 86:325-32. [IDIS 274725] [PubMed 2212407] 43. Moudgil GC. Anaesthesia and allergic drug reactions. Can Anaesth Soc J. 1986; 33:400-14. [IDIS 216200] [PubMed 3521800] 44. Dolovich J, Evans S, Rosenbloom D et al. Anaphylaxis due to thiopental sodium anesthesia. Can Med Assoc J. 1980; 123:2924. [PubMed 6167340] 45. Moneret-Vautrin DA, Widmer S, Gueant JL et al. Simultaneous anaphylaxis to thiopentone and a neuromuscular blocker: a study of two cases. Br J Anesth. 1990; 64:743-5. http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRR 39. Jensen NF, Fiddler DS, Striepe V. Anesthetic considerations in porphyrias. Anesth Analg. 1995; 80:591-9. [IDIS 343295] [PubMed 7864431] Drugs.com Print Version 46. Levy JH. Anaphylactic reaction to thiopental. JAMA. 1993; 270:2503. 47. Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant effects of anesthetics (Part II). Anesth Analg. 1990; 70:433-44. [IDIS 267841] [PubMed 2180345] 48. Leach AA. An unusual complication of thiopentone administration. Anaesthesia. 1986; 46:762. 49. Jorgensen NP, Walstad RA, Molne K. The concentrations of ceftazidime and thiopental in maternal plasma, placental tissue and amniotic fluid in early pregnancy. Acta Obstet Gynecol Scand. 1987; 66:29-33. [PubMed 3300134] 50. Andersen LW, Qvist T, Hertz J et al. Concentrations of thiopentone in mature breast milk and colostrum following an induction dose. Acta Anaesthesiol Scand. 1987; 31:30-2. [PubMed 3825473] 51. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001; 108:776-89. [IDIS 468574] [PubMed 11533352] 52. Anderson PO. Drug use during breast-feeding. Clin Pharm. 1991; 10:594-624. [IDIS 283187] [PubMed 1934918] 53. Datta S, Alper MH. Anesthesia for cesarean section. Anesthesiology. 1980; 53:142-60. [IDIS 118575] [PubMed 6998326] 54. Ong BY, Cohen MM. Anesthesia for cesarean section—Effects on neonates. Anesth Analg. 1989; 68:270-5. [IDIS 252266] [PubMed 2919765] 55. Clark RB. Anesthesia in obstetrics. Postgrad Med. 1973; 53:158-62. [PubMed 4571934] 56. Singh P, Harwood R, Cartwright DP et al. A comparison of thiopentone and propofol with respect to the incidence of postoperative shivering. Anaesthesia. 199; 49:996-8. 58. Shapiro BA, Warren J, Egol AB et al. Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Crit Care Med. 1995; 23:1596-1600. [IDIS 354085] [PubMed 7664563] 59. Gaspari F, Marraro G, Penna GF et al. Elimination kinetics of thiopentone in mothers and their newborn infants. Eur J Clin Pharmacol. 1985; 28:321-25. [IDIS 201405] [PubMed 4007037] 60. Backer RC, Caplan YH, Duncan CE. Thiopental suicide – case report. Clin Toxicol. 1975; 8:283-7. [PubMed 1175345] 61. Dundee JW, Assem ESK, Gaston JM et al. Sensitivity to intravenous anaesthetics: a report of three cases. Br Med J. 1974; 1:63-5. [PubMed 4272996] 62. Sulfisoxazole (Gantrisin) interactions: thiopental (pentothal). In: Hansten PD, Horn JR. Hansten and Horn’s drug interactions analysis and management. Vancouver, WA: Applied Therapeutics, Inc; 1997:466-7. 63. Probenecid (Benemid) interactions: thiopental (pentothal). In: Hansten PD, Horn JR. Hansten and Horn’s drug interactions http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRS 57. Cheong KF, Chen FG, Yau GHM. Postanaesthetic shivering—A comparison of thiopentone and propofol. Ann Acad Med Singapore. 1998; 27:729-32. [PubMed 9919351] Drugs.com Print Version analysis and management. Vancouver, WA: Applied Therapeutics, Inc; 1997:444-5. 64. Mehta D, Bradley EL, Kissin I. Metoclopramide decreases thiopental hypnotic requirements. Anesth Analg. 1993; 77:784-7. [IDIS 321297] [PubMed 8214666] 65. Lichtor JL, Zacny JP, Coalson DW et al. The interaction between alcohol and the residual effects of thiopental anesthesia. Anesthesiology. 1993; 79:28-35. [IDIS 317760] [PubMed 8342825] 66. Fassoulaki A, Sarantopoulos C, Papilas K. Flumazenil reduces the duration of thiopentone but not propofol anaesthesia in humans. Can J Anaesth. 1993; 40:10-12. [IDIS 308606] [PubMed 8425236] 67. Wood M. Plasma drug binding: implications for anesthesiologists. Anesth Analg. 1986; 65:786-804. [IDIS 217629] [PubMed 3087239] 68. Janowsky EC, Risch C, Janowsky DS. Effects of anesthesia on patients taking psychotropic drugs. J Clin Psychopharmacol. 1981; 1:14-20. [PubMed 6117578] 69. Roche Laboratories. Versed (midazolam hydrochloride) injection prescribing information (dated 2000 Jun). In: Physicians’ desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:3027-33. 70. Barbiturate Anesthetics/Ketamine. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St Louis: JB Lippincott Co; 1999(Jul):111c. 71. Barbiturate Anesthetics/Narcotic Analgesics. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St Louis: JB Lippincott Co; 1996(Apr):112. 72. Barbiturate Anesthetics/Phenothiazines. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St Louis: JB Lippincott Co; 1990(Jan):113. 74. Barbiturate Anesthetics/Sufonamides. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St Louis: JB Lippincott Co; 1990(Jan):115. 75. Ethanol/Barbiturates. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St Louis: JB Lippincott Co; 1994(Apr):324. 76. G, Valenti S, Vincenti E et al. Interaction between thiopentone and subhypnotic doses of ketamine. Eur J Anesthesiol. 1992; 9:43-7. 77. Roytblat L, Katz J, Rozentsveig V et al. Anaesthetic interaction between thiopentone and ketamine. Eur J Anaesthesiol. 1992; 9:307-12. [PubMed 1628634] 78. Pourrat X, Serekian JM, Antier D et al. [Generalized tonic-clonic status epilepticus: therapeutic strategy.] (French; with English abstract.) Presse Med.2001; 30:1031-6. 79. (unused reference number) http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRT 73. Barbiturate Anesthetics/Probenecid. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St Louis: JB Lippincott Co; 1990(Jan):114. Drugs.com Print Version 80. Roelofse JA. Anaesthesia and diazoxide. S Afr Med J. 1984; 137:794. 81. Kaukinen S, Eerola M, Ylitalo P. Prolongation of thiopentone anaesthesia by probenecid. Br J Anaesth. 1980; 52:603-6. [IDIS 115978] [PubMed 7000105] 82. Chen YC, Chan KH, Tsou MY et al. The reversal effect of low dose aminophylline on thiopental-induced sedation. Chung Hua I Hsueh Tsa Chih (Taipei). 1993; 52:145-8. 83. Krintel JJ, Wegmann F. Aminophylline reduces the depth and duration of sedation with barbiturates. Acta Anaesthesiol Scand. 1987; 31:352-4. [PubMed 3296607] 84. Burch PG, McLeskey CH. Anesthesia for patients with insulinoma treatment with oral diazoxide. Anesthesiology. 1981; 55:472475. [IDIS 166391] [PubMed 6271026] 85. Schwab S, Spranger M, Schwartz S et al. Barbiturate coma in severe hemispheric stroke: useful or obsolete? Neurology. 1997; 48:1608-13. 86. Naredi S, Edén E, Zäll S et al. A standardized neurosurgical/neurointensive therapy directed toward vasogenic edema after severe traumatic brain injury: clinical results. Intensive Care Med. 1998; 24:446-51. [IDIS 409134] [PubMed 9660259] 87. Eker C, Ásgeirsson B, Grande PO et al. Improved outcome after severe head injury with a new therapy based on principles for brain volume regulation and preserved microcirculation. Crit Care Med. 1998; 26:1881-6. [IDIS 418847] [PubMed 9824083] 88. Stover JF, Stocker R. Barbiturate coma may promote reversible bone marrow suppression in patients with severe isolated traumatic brain injury. Eur J Pharmacol. 1998; 54:529-34. 89. Boucher BA, Phelps SJ. Acute management of the head injury patient. In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy: a pathophysiologic approach. 4th ed. Stamford, CT: Appleton & Lange; 1999:991-7. 91. Bullock R, Chestnut RM, Clifton G et al. Guidelines for the management of severe head injury. Eur J Emerg Med. 1996; 2:10927. 92. Wilder-Smith OH, Ravussin PA, Decosterd LA et al. Midazolam premedication and thiopental induction of anaesthesia: interactions at multiple end-points. Br J Anaesth. 1999; 83:590-5. [IDIS 435322] [PubMed 10673875] 93. Kissin I. A concept for assessing interactions of general anesthetics. Anesth Analg. 1997; 85:204-10. [IDIS 389617] [PubMed 9212148] 94. Leslie K, Mooney PH, Silbert BS. Effect of intravenous clonidine on the dose of thiopental required to induce anesthesia. Anesth Analg. 1992; 75:530-5. [IDIS 302489] [PubMed 1530166] 95. Bass NM, Williams RL. Guide to drug dosage in hepatic disease. Clin Pharmacokinet. 1988; 15:396-420. [IDIS 249947] [PubMed 3072141] http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRU 90. Forbes A, Alexander GJ, O’Grady JG et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology. 1989; 10:306-10. [PubMed 2759548] Drugs.com Print Version 96. Bennet WM. Guide to drug dosage in renal failure. Clin Pharmacokinet. 1988; 15:326-54. [IDIS 250553] [PubMed 3060292] 97. Wada DR, Björkman S, Ebling WF et al. Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans. Anesthesiology. 1997; 87:884-99. [IDIS 396580] [PubMed 9357892] 98. Lzar ER, Jolly DT, Tam YK. Propofol and thiopental in a 1:1 volume mixture is chemically stable. Anesth Analg. 1998; 86:422-6. [IDIS 400789] [PubMed 9459260] 99. Pankerd RJ, Jones RD. Physiochemical compatibility of propofol with thiopental sodium. Am J Health-Syst Pharm. 1996; 53:2606-10. [IDIS 374425] [PubMed 8913389] 100. Chernin EL, Stewar JT, Smiler B. Stability of thiopental sodium and propofol in polypropylene syringes at 23 and 4˚C. Am J Health-Syst Pharm. 1996; 53:1576-9. [IDIS 367724] [PubMed 8809279] 101. Crowther J, Hrazdil J, Jolly DT. Growth of microorganisms in propofol, thiopental, and a 1:1 mixture of propofol and thiopental. Anesth Analg. 1996; 82:475-8. [IDIS 361758] [PubMed 8623946] 102. Cernin EL, Smiler B. Propofol-thiopental combination: implications for cost savings and clinical use. Am J Anesthesiology. 1997; 24:251-3. 103. Trissel LA. Handbook on injectable drugs. 11th ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 1998:1219-26. 104. Simon EP, Dahl LF. The sodium penthotal hypnosis interview with follow-up treatment for complex regional pain syndrome. J Pain Symptom Management. 1999; 18:132-6. 105. Stover JF, Pleines UE, Morganti-Kossmann MC et al. Thiopental attenuates energetic impairment but fails to normalize cerebrospinal fluid glutamate in brain-injured patients. Crit Care Med. 1999; 27:1351-7. [IDIS 432495] [PubMed 10446831] 107. (unused reference number) 108. Nguyen MT, Greenberg SB, Fitzhugh KR et al. Pediatric Imaging: Sedation with an injection formulation modified for rectal administration. Radiology. 2001; 221:760-2. [IDIS 473792] [PubMed 11719673] 109. Neville BGR. Epilepsy in childhood. Br Med J. 1997; 315:924-30. 110. Chapman MG, Smith M, Hirsch NP. Status epilepticus. Anaesthesia. 2001; 56:648-59. [IDIS 467143] [PubMed 11437765] 111. Rantala H, Saukkonen AL, Remes M et al. Efficacy of five days’ barbiturate anesthesia in the treatment of intractable epilepsies in children. Epilepsia. 1999; 40:1775-79. [IDIS 440993] [PubMed 10612343] 112. Mayersohn M, Calkins JM, Perrier DG et al. Thiopental kinetics in obese surgical patients. Anesthesiology. 1981; 55(Suppl): A178. http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSRV 106. Smith JW, Lemere F, Dunn RB. Pentothal interviews in the treatment of alcoholism. Psychosomatics. 1971; 12:330-1. [PubMed 5172949] Drugs.com Print Version 113. Jung D, Mayersohn M, Perrier D et al. Thiopental disposition in lean and obese patients undergoing surgery. Anesthesiology. 1982; 56:269-74. [IDIS 149322] [PubMed 7065435] 114. Potyk DK, Raudaskoski P. Overview of anesthesia for primary care physicians. West J Med. 1998; 168:517-21. [PubMed 9655993] 115. Beattie C. History and principles of anesthesiology. In: Hardman JG, Gilman AG, Limbird LE, eds Goodman and Gilman’s The pharmacological basis of therapeutics. 10th ed. McGraw-Hill; 2001: 321-35. 116. Cordato DJ, Mather LE, Gross AS et al. Pharmacokinetics of thiopental enantiomers during and following prolonged high-dose therapy. Anesthesiology.1999: 91:1693-1702. 117. Quandt C, de los Reyes RA, Diaz FG. Barbiturate-induced coma for the treatment of cerebral ischemia: review of outcome. Clin Pharm. 1982; 1:549-50. [IDIS 161403] [PubMed 7185542] 118. Quandt CM, De Los Reyes RA. Pharmacologic management of acute intracranial hypertension. Drug Intell Clin Pharm. 1984; 18:105-12. [IDIS 181290] [PubMed 6697873] 119. Glass PS, Bloom M, Kearse L et al. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology. 1997; 86:836-47. [IDIS 384520] [PubMed 9105228] 120. Reviewers’ comments (personal observations). 121. Abbott Laboratories, Abbott Park, IL: Personal communication. 122. Reviewers’ comments (personal observations) on Propofol 28:04. 124. Taher Y, Fakhr-El-Islam M, El-Sherif A et al. The effect of pentothal as a “truth serum”: a controlled study. J Egypt Med Assoc. 1969; 52:75-81. [PubMed 5350189] HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1541-8. b. AHFS Drug Information 2004. McEvoy GK, ed. Barbiturate General Statement . Bethesda, MD: American Society of HealthSystem Pharmacists; 2004:2363-6. http://www.drugs.com/monograph/thiopental-sodium.html?printable=1[12/2/2014 2:52:02 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSM 123. Russo MB, Brooks FR, Fontenot JP et al. Sodium pentothal hypnosis: a procedure for evaluating medical patients with suspected psychiatric co-morbidity. Military Medicine. 1997; 162:215-8. [IDIS 383920] [PubMed 9121671] Drugs.com Print Version Print   Close Vecuronium Bromide Class: Neuromuscular Blocking Agents VA Class: MS200 Chemical Name: 1-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(1-piperidinyl) androstan-16-yl]-1methylpiperidinium bromide Molecular Formula: C34H57N2O4•Br CAS Number: 50700-72-6 Brands: Norcuron Warning(s) Should be administered only by individuals experienced in the use of neuromuscular blocking agents.1 Introduction Nondepolarizing neuromuscular blocking agent.1 3 4 5 Uses for Vecuronium Bromide Production of skeletal muscle relaxation during surgery after general anesthesia has been induced.1 Facilitation of endotracheal intubation;1 15 16 30 39 40 41 46 54 63 68 71 77 80 113 117 124 129 131 142 however, succinylcholine generally is preferred in emergency situations where rapid intubation is required.110 111 112 141 145 A single dose should not be used in place of succinylcholine for rapid sequence induction of anesthesia (“crash intubation”).141 Treatment to increase pulmonary compliance during assisted or controlled respiration after general anesthesia has been induced.1 Has been used for facilitation of mechanical ventilation in intensive care setting.1 186 187 188 189 190 191 192 193 Vecuronium Bromide Dosage and Administration General Adjust dosage carefully according to individual requirements and response.1 2 Assess neuromuscular blockade and recovery in patients undergoing anesthesia; a peripheral http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSN Skeletal Muscle Relaxation Drugs.com Print Version nerve stimulator is recommended to accurately monitor the degree of muscle relaxation and to minimize the possibility of overdosage.1 To avoid patient distress, administer only after unconsciousness has been induced.141 Facilitation of Endotracheal Intubation Endotracheal intubation for nonemergency surgical procedures generally can be performed within 2.5–3 minutes following administration of 0.08- to 0.1-mg/kg dose.1 61 75 (See Onset and also Duration under Pharmacokinetics.) Maintenance of Neuromuscular Blockade Repeated administration of maintenance doses appears to have little, if any, cumulative effect on duration of neuromuscular blockade.1 16 17 40 51 62 71 72 80 93 143 Rate of spontaneous recovery from neuromuscular blockade following discontinuance of maintenance infusion usually is comparable to that following administration of a single IV injection.1 Close monitoring recommended to avoid excessive dosage when continuous infusion is employed.30 33 39 113 Reversal of Neuromuscular Blockade To reverse neuromuscular blockade, administer a cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium), usually in conjunction with an antimuscarinic (e.g., atropine, glycopyrrolate) to block adverse muscarinic effects of the cholinesterase inhibitor.1 2 11 16 17 18 19 28 39 40 41 43 44 45 46 47 88 137 143 Administration Administer IV only;1 do not administer IM.144 IV Administration For solution and drug compatibility information, see Compatibility under Stability. Consult specialized references for specific procedures and techniques of administration.HID Do not mix in the same syringe or administer through the same needle as an alkaline solution.1 Reconstitution Reconstitute vial containing 10 or 20 mg of vecuronium bromide with 10 or 20 mL of bacteriostatic water for injection, respectively, to provide a solution containing 1 mg/mL.1 2 Use within 5 days.1 When reconstituted with other compatible solutions (see Solution Compatibility under Stability), use within 24 hours and discard unused portions.1 Dilution For continuous IV infusion, dilute the reconstituted solution to the desired concentration (usually 0.1 or 0.2 mg/mL) in a compatible IV solution (see Solution Compatibility under Stability).1 2 30 80 113 Use within 24 hours.1 http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSO Administer initial (intubating) dose by rapid IV injection;1 administer maintenance dosage for prolonged surgical procedures by intermittent IV injection or continuous IV infusion.1 Drugs.com Print Version Dosage Available as vecuronium bromide; dosage expressed in terms of the salt.1 Pediatric Patients Skeletal Muscle Relaxation Initial (Intubating) Dosage IV Children 7 weeks to 1 year of age may receive dosages recommended for adults.27 148 (See Adults under Dosage and Administration.) Children 1–9 years of age may require slightly higher initial doses than adults.1 2 27 28 (See Adults under Dosage and Administration.) Children >10 years of age should receive dosages recommended for adults.1 2 (See Adults under Dosage and Administration.) Maintenance Dosage Intermittent IV Injection Children 7 weeks to 1 year of age may receive doses recommended for adults; however, less frequent administration may be necessary.27 148 (See Adults under Dosage and Administration and also see Pediatric Use under Cautions.) Children 1–9 years of age may require more frequent doses than adults.1 2 28 (See Adults under Dosage and Administration.) Children >10 years of age should receive dosages recommended for adults.1 2 (See Adults under Dosage and Administration.) Continuous IV Infusion Adults Skeletal Muscle Relaxation Initial (Intubating) Dosage IV 0.08–0.1 mg/kg.1 2 (See Onset and also Duration under Pharmacokinetics.) Reduce initial dosage by about 15% (i.e., to 0.06–0.085 mg/kg) when administered >5 minutes after administration of enflurane, isoflurane, or halothane has been initiated or after steady-state anesthesia has been achieved.1 2 See Interactions: Specific Drugs. If larger initial dose is required, 0.15–0.28 mg/kg has been administered in patients undergoing halothane anesthesia with minimal adverse cardiovascular effects as long as ventilation was adequately maintained.1 2 If administering following succinylcholine, reduce dosage to 0.05–0.06 mg/kg with balanced anesthesia or 0.04–0.06 mg/kg with inhalation anesthesia.1 2 http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSP Dosage recommendations not established; administration by continuous IV infusion not adequately studied.1 Drugs.com Print Version Maintenance Dosage Intermittent IV Injection 0.01–0.015 mg/kg, administered as necessary, in patients receiving balanced anesthesia.1 2 0.008–0.012 mg/kg, administered as necessary, in patients receiving inhalation anesthesia.144 Increase dose (i.e., to >0.01–0.015 mg/kg) if longer intervals between doses are desirable.1 Administer first maintenance dose generally 25–45 minutes after the initial dose in patients undergoing balanced or inhalation anesthesia.1 2 Administer repeat maintenance doses at relatively regular intervals (i.e., from 12–15 minutes in patients undergoing balanced anesthesia or at slightly longer intervals in those undergoing enflurane or isoflurane anesthesia).1 2 Continuous IV Infusion Initially, 1 mcg/kg per minute.1 Adjust infusion rate to maintain 90% neuromuscular blockade; 0.8–1.2 mcg/kg per minute usually maintains continuous neuromuscular blockade in most patients.1 39 Initiate continuous IV infusion only after early spontaneous recovery from initial IV dose is evident (approximately 20–40 minutes after rapid IV administration of initial dose1 30 33 39 76 80 113 118 ).1 Required infusion rates decrease progressively and become relatively constant within 30–50 minutes.30 39 113 May need to reduce infusion rate by about 25–60% approximately 45–60 minutes following initial IV dose if steady-state anesthesia has been induced with enflurane or isoflurane.1 Reduction in infusion rate may not be necessary if steady-state anesthesia has been induced with halothane.1 Special Populations Hepatic Impairment Renal Impairment Usual initial and maintenance doses recommended for patients with renal failure who are optimally prepared with dialysis prior to surgery; monitor carefully to determine interval between doses.141 149 (See Renal Impairment under Cautions.) Manufacturer recommends consideration of decreased initial dose if emergency surgery is necessary in patients with severe renal failure (i.e., Clcr <10 mL/minute) who are not optimally prepared with dialysis;1 2 however, most clinicians believe that usual initial dose may be given.141 Adjust maintenance doses carefully according to patient’s response.141 Geriatric Patients Dosage necessary to maintain steady-state neuromuscular blockade30 32 33 may be decreased. Burn Patients Substantially increased doses may be required due to development of resistance.175 (See Burn Patients under Cautions.) http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSQ Data currently insufficient for specific dosage recommendations.1 Some clinicians suggest usual initial dose;141 151 others suggest a reduced initial dose.141 Adjust maintenance dosing (probably with reduced doses) carefully according to patient’s response.141 151 (See Hepatic Impairment under Cautions.) Drugs.com Print Version Intensive Care Setting Dosage recommendations not established for prolonged, continuous IV infusions during mechanical ventilation in intensive care settings.1 (See Intensive Care Setting under Cautions.) Patients with Neuromuscular Disease Administer small test dose (e.g., 0.005–0.02 mg/kg)141 144 and monitor response.1 (See Neuromuscular Disease under Cautions.) Other Populations Patients in whom substantial histamine release would be particularly hazardous (e.g., patients with clinically important cardiovascular disease) or patients with any history suggesting a greater risk of histamine release (e.g., a history of severe anaphylactoid reactions or asthma): Administer slowly over 1–2 minutes or longer; discontinue administration if any signs of histamine release occur.141 144 (See Hypersensitivity Reactions under Cautions.) Cautions for Vecuronium Bromide Contraindications Known hypersensitivity to vecuronium bromide or any ingredient in the formulation.144 Warnings/Precautions Warnings Respiratory Effects Should be used only by individuals experienced in the use of neuromuscular blocking agents and in the maintenance of an adequate airway and respiratory support.1 2 Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be immediately available.1 IV cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium) should be readily available.1 18 19 39 40 41 44 88 (See Reversal of Neuromuscular Blockade under Dosage and Administration.) Use with caution in patients with pulmonary impairment or respiratory depression.b Neuromuscular Disease Possible exaggerated neuromuscular blockade in patients with neuromuscular disease (e.g., myasthenia gravis, Eaton-Lambert syndrome).1 Administer small test dose; monitor response carefully with a peripheral nerve stimulator.1 141 144 Sensitivity Reactions Hypersensitivity Reactions Histamine-like hypersensitivity reactions (e.g., bronchospasm, flushing, redness, hypotension, and tachycardia) are not likely to occur.1 12 18 48 143 http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSR Potential for severely compromised respiratory function and respiratory paralysis.1 110 111 127 128 Drugs.com Print Version General Precautions Burn Patients Resistance to therapy can develop in burn patients,169 170 172 173 174 175 particularly those with burns over 25– 30% or more of body surface area.175 Resistance becomes apparent ≥1 week after the burn,169 170 171 172 173 174 175 peaks ≥2 weeks after the burn,170 171 172 174 persists for several months or longer,170 172 and decreases gradually with healing.169 170 172 174 Consider possible need for substantially increased doses.175 Cardiovascular Effects Exhibits minimal cardiovascular effects;1 3 5 6 19 143 therefore, will not counteract the bradycardia induced by many anesthesia agents1 21 59 (e.g., high-dose fentanyl)122 143 or by vagal stimulation.141 Intensive Care Setting Possible prolonged paralysis and/or muscle weakness and atrophy.1 Continuous monitoring of neuromuscular transmission recommended during neuromuscular blocking agent therapy in intensive care setting.1 Do not administer additional doses before there is a definite response to nerve stimulation tests.1 If no response is elicited, discontinue administration until response returns.1 Impaired Circulation Possible delayed onset of action and delayed maximum effect in patients with impaired circulation or in those with cardiovascular disease or edema (vecuronium volume of distribution may be increased).1 2 141 Larger-than-usual initial doses are not recommended; caution advised when administering a subsequent dose before the maximum effect of the initial dose is attained.141 Electrolyte Disturbances Carefully monitor the degree of neuromuscular blockade with a peripheral nerve stimulator in patients with severe electrolyte disturbances (i.e., hypermagnesemia, hypokalemia, hypocalcemia)141 or diseases that result in electrolyte disturbances (e.g., adrenocortical insufficiency).141 Malignant Hyperthermia Malignant hyperthermia is rarely associated with use of neuromuscular blocking agents and/or potent inhalation anesthetics.b Insufficient data to determine whether vecuronium is capable of initiating the development of this condition.1 Be vigilant for possible development of malignant hyperthermia and prepared for its management in any patient undergoing general anesthesia.168 Carcinomatosis Carefully monitor the degree of neuromuscular blockade with a peripheral nerve stimulator.1 Obesity Use with caution in severely obese patients; maintenance of adequate airway and ventilation support http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSS Possible prolonged paralysis in patients with electrolyte disturbances (e.g., increased plasma magnesium concentrations) or acid-base imbalances.186 187 189 190 Drugs.com Print Version prior to, during, and following administration of neuromuscular blocking agents may require particular care.1 Debilitated Patients Carefully monitor the degree of neuromuscular blockade with a peripheral nerve stimulator in patients with severe debilitation.1 Specific Populations Pregnancy Category C.1 Lactation Not known whether vecuronium is distributed into milk.1 141 Caution advised if used in nursing women.1 141 Pediatric Use Safety and efficacy not established in children <7 weeks of age.1 144 Has been used safely and effectively in children >7 weeks of age who were undergoing surgery.27 28 Children 7 weeks–1 year of age may be more sensitive than adults to the neuromuscular blocking effects and generally require 50% longer to recover from neuromuscular blockade.1 2 27 148 Vecuronium bromide that has been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates.1 163 164 165 166 167 Geriatric Use Possible increased time to onset of neuromuscular blockade31 and decreased rate of recovery compared with younger adults.30 32 33 Hepatic Impairment Use with caution; careful monitoring with a peripheral nerve stimulator recommended.1 Renal Impairment Onset and duration of and rate of recovery from neuromuscular blockade not substantially altered by renal dysfunction;1 74 84 149 however, possible prolonged duration of blockade in patients with severe renal impairment who have not undergone dialysis prior to surgery.1 2 Careful monitoring with a peripheral nerve stimulator recommended to avoid inadvertent overdosage; consider reduced initial dose.1 Common Adverse Effects Skeletal muscle weakness.1 Interactions for Vecuronium Bromide Specific Drugs http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSST Prolonged duration of and rate of recovery from neuromuscular blockade.1 38 79 90 Drugs.com Print Version Drug Interaction Comments Acylaminopenicillins (e.g., mezlocillin, piperacillin) Prolonged neuromuscular blockade158 159 Use with caution158 159 Anesthetics, general (enflurane, halothane, isoflurane) Increased potency and prolonged duration of neuromuscular blockade1 2 3 13 Reduced vecuronium dosage may be required1 2 14 23 89 (See Dosage under Dosage and Administration) 14 18 23 73 89 129 143 Anti-infective agents (aminoglycosides, bacitracin, clindamycin, lincomycin, polymyxins, tetracyclines) Possible prolonged duration of neuromuscular blockade1 2 3 13 Calcium-channel blocking agents (e.g., verapamil) Possible prolonged duration of neuromuscular blockade43 Dantrolene Possible prolonged duration of neuromuscular blockade157 Magnesium salts Increased neuromuscular blockade;1 141 154 155 reversal may be impeded1 141 155 Use with caution; reduce dosage as necessary1 141 154 155 Neuromuscular blocking agents, nondepolarizing Possible increased neuromuscular blockade1 Concomitant administration not recommended1 Quinidine Possible recurrence of paralysis1 Succinylcholine Possible increased potency and prolonged duration of neuromuscular blockade1 2 3 21 18 156 33 62 124 131 132 Administer vecuronium in reduced dosage after effects of succinylcholine begin to dissipate1 Absorption Bioavailability Poorly absorbed from the GI tract.b Onset Time to maximum neuromuscular blockade decreases as the dose increases.1 2 17 18 26 46 69 70 87 Following IV administration of 0.08–0.1 mg/kg, neuromuscular blockade begins within 1 minute and is maximal at 3–5 minutes.1 2 Duration Duration of neuromuscular blockade increases as the dose increases.1 2 17 47 70 80 87 Duration of clinically sufficient neuromuscular blockade induced by initial dose of 0.08–0.1 mg/kg under http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSU Vecuronium Bromide Pharmacokinetics Drugs.com Print Version balanced or halothane anesthesia is about 25–30 or 30–40 minutes, respectively.2 Spontaneous recovery to about 25% of baseline generally occurs within 25–40 minutes under balanced anesthesia and is usually 95% complete 45–65 minutes after administration.1 The time necessary for 25–75% recovery from neuromuscular blockade following doses of 0.08–0.1 mg/kg under balanced or halothane anesthesia is about 15–25 minutes;1 144 recovery time following initial doses appears to be dose dependent.17 141 Special Populations Hepatic dysfunction (i.e., cirrhosis, cholestasis) may prolong duration of and rate of recovery from neuromuscular blockade.1 38 79 90 In patients with severe renal impairment who have not undergone dialysis prior to surgery, duration of neuromuscular blockade may be prolonged.1 2 In geriatric patients, increased time of onset31 and decreased rate of recovery from neuromuscular blockade.30 32 33 In patients undergoing cardiopulmonary bypass surgery under induced hypothermia, duration of neuromuscular blockade may be prolonged.152 Distribution Extent Appears to rapidly distribute into extracellular space.2 100 Undergoes rapid and extensive hepatic extraction.116 Crosses the placenta minimally;94 95 96 97 not known whether distributed into milk.144 Plasma Protein Binding Approximately 60–90%.1 2 57 99 In children <1 year of age, volume of distribution is increased.148 In geriatric patients, volume of distribution may be decreased.100 In patients with renal failure, volume of distribution may be slightly increased.74 84 104 Elimination Metabolism Metabolic fate not fully characterized in humans.1 2 3 106 116 143 In vitro, vecuronium undergoes spontaneous deacetylation to form hydroxy derivatives.9 Elimination Route Excreted principally in feces via biliary elimination;1 38 79 90 143 also excreted in urine.1 2 106 116 Half-life Biphasic;1 3 18 26 38 84 94 95 98 104 terminal elimination half-life averages 65–75 minutes.1 Special Populations http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSSV Special Populations Drugs.com Print Version In patients with cirrhosis, half-life averages 84 minutes.38 In patients with renal failure, half-life not substantially altered;84 104 potential for high plasma concentrations of 3-desacetyl vecuronium (neuromuscular blocking activity is ≥50% of that of vecuronium).186 187 189 190 84 104 During late pregnancy, half-life decreases to about 35–40 minutes.1 2 94 95 Stability Storage Parenteral Powder for Injection 15–30°C; protect from light.1 2 Following reconstitution with bacteriostatic water for injection containing benzyl alcohol, 2–8°C or room temperature (<30°C) for 5 days.1 Following reconstitution with sterile water for injection or other compatible solution (see Solution Compatibility under Stability), 2–8°C for 24 hours.1 Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Unstable in the presence of bases.10 11 Solution CompatibilityHID Dextrose 5% in sodium chloride 0.9% Dextrose 5% in water Ringer's injection, lactated Sodium chloride 0.9% Drug Compatibility Admixture CompatibilityHID Compatible Ciprofloxacin Y-Site CompatibilityHID Compatible Alprostadil http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTM Compatible Drugs.com Print Version Aminophylline Amiodarone HCl Cefazolin sodium Cefuroxime sodium Co-trimoxazole Dexmedetomidine HCl Diltiazem HCl Dobutamine HCl Dopamine HCl Epinephrine HCl Esmolol HCl Fenoldopam mesylate Fentanyl citrate Fluconazole Gentamicin sulfate Heparin sodium Hetastarch in lactated electrolyte injection (Hextend) Hydrocortisone sodium succinate Hydromorphone HCl Labetalol HCl Linezolid Lorazepam Midazolam HCl Milrinone lactate Morphine sulfate Nicardipine HCl Nitroglycerin Norepinephrine bitartrate Palonosetron HCl Propofol http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTN Isoproterenol HCl Drugs.com Print Version Ranitidine HCl Sodium nitroprusside Vancomycin HCl Incompatible Amphotericin B cholesteryl sulfate complex Diazepam Etomidate Furosemide Micafungin sodium Actions Produces skeletal muscle relaxation by causing a decreased response to acetylcholine (ACh) at the myoneural (neuromuscular) junction of skeletal muscle.b Exhibits high affinity for ACh receptor sites and competitively blocks access of ACh to motor endplate of myoneural junction; may affect ACh release.b Blocks the effects of both the small quantities of ACh that maintain muscle tone and the large quantities of ACh that produce voluntary skeletal muscle contraction; does not alter the resting electrical potential of the motor end-plate or cause muscular contractions.b Exhibits minimal cardiovascular effects.1 3 5 6 19 145 Appears to have little histamine-releasing activity.1 4 12 18 19 48 49 50 52 143 147 A less potent stimulator of histamine release than atracurium or pancuronium.52 147 Importance of women informing clinicians if they are or plan to become pregnant or plan to breastfeed.1 Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, neuromuscular disease).1 Importance of informing patients of other important precautionary information.1 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Vecuronium Bromide Routes Dosage Forms Strengths Brand Names http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] Manufacturer t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTO Advice to Patients Drugs.com Print Version Parenteral For injection, for IV use only 10 mg* Vecuronium Bromide for Injection 20 mg* Vecuronium Bromide for Injection AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 6, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. References 1. Organon Inc. Norcuron (vecuronium bromide) for injection prescribing information. West Orange, NJ; 1998 Feb. 2. Organon Inc. Product information form for American Hospital Formulary Service on Norcuron. West Orange, NJ; 1984 May. 3. Durant NN. Norcuron, a new nondepolarizing neuromuscular blocking agent. Semin Anesth. 1982; 1:47-56. 4. AMA Division of Drugs. AMA drug evaluations. 5th ed. Chicago: American Medical Association; 1983:419-44. 5. Miller RD. Is atracurium an ideal neuromuscular blocking drug? Anesth Analg (Cleveland). 1982; 61:721-2. Editorial. (IDIS 157359) 6. Savarese JJ. The new neuromuscular blocking drugs are here. Anesthesiology. 1981; 55:1-3. [IDIS 136052] [PubMed 6113792] 7. Bowman WC. New neuromuscular blocking drugs in anaesthetic practice. Pharm Int. 1983; 4:131-4. 8. Booij LHDJ, Vree TB, Crul JF. Org-NC45: a new steroidal non-depolarizing muscle relaxant. Pharm Weekbl Sci Ed. 1982; 1-4. 9. Savage DS, Sleigh T, Carlyle I. The emergence of Org NC 45, 1-[(2β,3α,5α,16β,17β)-3, 17 bis(acetyloxy)-2-(1-piperidinyl) androstan-16-yl]-1-methylpiperidinium bromide, from the pancuronium series. Br J Anaesth. 1980; 52(Suppl 1):3-9S. 10. Torda TA. Drug interactions with vecuronium and other competitive neuromuscular blockers. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:72-8. 11. Baraka A, Noueihed R, Sinno H et al. Succinylcholine-vecuronium (Org NC 45) sequence for cesarean section. Anesth Analg. 1983; 62:909-13. [IDIS 176143] [PubMed 6137170] 12. Robertson EN, Booij LHDJ, Fragen RJ et al. Clinical comparison of atracurium and vecuronium (Org NC 45). Br J Anaesth. 1983; 55:125-9. [IDIS 165994] [PubMed 6131682] 13. Richardson FJ, Agoston S. Muscle relaxants. In: Dukes MNG, ed. Side effects of drugs. Annual 6. New York: Elsevier/North Holland Inc.; 1982:128-34. 14. Rupp SM, Miller RD, Gencarelli PJ. Vecuronium-induced neuromuscular blockade during enflurane, insoflurane, and halothane anesthesia in humans. Anesthesiology. 1984; 60:102-5. [IDIS 182089] [PubMed 6141748] http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTP (IDIS 145892) Drugs.com Print Version 15. Gramstad L, Lilleaasen P. Dose-response relation for atracurium, Org NC 45 and pancuronium. Br J Anaesth. 1982; 54:647-51. [IDIS 152105] [PubMed 6123339] 16. Buzello W, Nöldge G. Repetitive administration of pancuronium and vecuronium (Org NC 45, Norcuron) in patients undergoing long lasting operations. Br J Anaesth. 1982; 54:1151-7. [IDIS 161115] [PubMed 6128011] 17. Fahey MR, Morris RB, Miller RD et al. Clinical pharmacology of Org NC 45 (Norcuron): a new nondepolarizing muscle relaxant. Anesthesiology. 1981; 55:6-11. [IDIS 136054] [PubMed 6113794] 18. Hilgenberg JC. Comparison of the pharmacology of vecuronium and atracurium with that of other currently available muscle relaxants. Anesth Analg. 1983; 62:524-31. [IDIS 170170] [PubMed 6132564] 19. Richardson FJ, Agoston SA. Muscle relaxants. In: Dukes MNG, ed. Side effects of drugs. Annual 7. New York: Elsevier/North Holland Inc; 1983:144-6. 20. Gramstad L, Lilleaasen P, Minsaas B. Comparative study of atracurium, vecuronium (Org NC 45) and pancuronium. Br J Anaesth. 1983; 55(Suppl 1):95-6S. [IDIS 172724] [PubMed 6687551] 21. Booij LHDJ, Robertson EN. Clinical comparison between vecuronium bromide and atracurium di-besylate. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:38-45. 22. Booij LHDJ, Crul JF. A comparison of vecuronium with the hypothetical ideal neuromuscular blocking drug. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:3-8. 23. Foldes FF, Bencini A, Newton D. Influence of halothane and enflurane on the neuromuscular effects of Org NC 45 in man. Br J Anaesth. 1980; 52(Suppl 1):64-5S. 25. Robertson EN, Fragen RJ, Booij LHDJ et al. Some effects of diisopropyl phenol (ICI 35 868) on the pharmacodynamics of atracurium and vecuronium in anaesthetized man. Br J Anaesth. 1983; 55:723-8. [IDIS 175149] [PubMed 6136286] 26. Bevan DR. Neuromuscular blocking drugs. Can Anaesth Soc J. 1983; 30(3: Part 2):S56-61. 27. Fisher DM, Miller RD. Neuromuscular effects of vecuronium (Org NC 45) in infants and children during N2O, halothane anesthesia. Anesthesiology. 1983; 58:519-23. [IDIS 172082] [PubMed 6134483] 28. Goudsouzian NG, Martyn JJA, Liu LMP et al. Safety and efficacy of vecuronium in adolescents and children. Anesth Analg. 1983; 62:1083-8. [IDIS 178917] [PubMed 6139963] 29. Savage DS. The discovery of vecuronium bromide. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:1-6. 30. d’Hollander A, Massaux F, Nevelsteen M et al. Age-dependent dose-response relationship of Org NC 45 in anaesthetized http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTQ 24. Hughes R, Payne JP. Clinical assessment of atracurium using the single twitch and tetanic responses of the adductor pollicis muscles. Br J Anaesth. 1983; 55(Suppl 1):47-52S. Drugs.com Print Version patients. Br J Anaesth. 1982; 54:653-7. [IDIS 152106] [PubMed 6123340] 31. d’Hollander AA, Nevelsteen M, Barvais L et al. Effect of age on the establishment of muscle paralysis induced in anaesthetized adult subjects by Org NC 45. Acta Anaesthesiol Scand. 1983; 27:108-10. [PubMed 6132514] 32. d’Hollander A, Barvais L, Massaut J et al. Vecuronium in geriatric patients. In: Agoston S, Bowman WC, Miller RD, VibyMogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:1714. 33. d’Hollander A, Bomblet JP, Esselen M. Administration of vecuronium bromide by intravenous infusion during long-lasting operations. Effects of age, and interaction with suxamethonium chloride. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:85-91. 34. Crul JF. General discussion. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:196-8. 35. Brandom BW, Rudd GD, Cook DR. Clinical pharmacology of atracurium in paediatric patients. Br J Anaesth. 1983; 55(Suppl 1):117-21S. 36. Funk DI, Crul JF, vd Pol FM. Effects of changes in acid-base balance on neuromuscular blockade produced by Org-NC 45. Acta Anaesthesiol Scand. 1980; 24:119-24. [PubMed 6104411] 37. Gencarelli PJ, Swen J, Koot HWJ et al. The effects of hypercarbia and hypocarbia on pancuronium and vecuronium neuromuscular blockades in anesthetized humans. Anesthesiology. 1983; 59:376-80. [IDIS 178100] [PubMed 6139044] 38. Lebrault C, Berger JL, d’Hollander AA et al. Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis. Anesthesiology. 1985; 62:601-5. [IDIS 199487] [PubMed 2859815] 39. Newton DEF. Vecuronium—continuous infusion in general clinical practice. In: Agoston S, Bowman WC, Miller RD, Viby- 40. Clarke RSJ. Intubating conditions and neuromuscular effects following administration of vecuronium bromide. Comparison with suxamethonium chloride and pancuronium bromide. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:60-8. 41. Thomas B, Rolly G, Huylenbroek G et al. Clinical use of vecuronium bromide in balanced anesthesia. Comparison with pancuronium bromide. In: Agoston S, ed. Clinical experiences with Norcuron(Org NC 45, vecuronium bromide). Amsterdam: Excerpta Media; 1983:76-84. 42. Fragen RJ, Shanks CA. Neuromuscular recovery after laparoscopy. Anesth Analg. 1984; 63:51-4. [IDIS 180534] [PubMed 6140885] 43. van Poorten JF, Dhasmana KM, Kuypers RSM et al. Verapamil and reversal of vecuronium neuromuscular blockade. Anesth Analg. 1984; 63:155-7. [IDIS 180674] [PubMed 6140886] 44. Gencarelli PJ, Miller RD. Antagonism of Org NC 45 (vecuronium) and pancuronium neuromuscular blockade by neostigmine. Br J Anaesth. 1982; 54:53-6. [IDIS 146255] [PubMed 6119998] http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTR Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:10914. Drugs.com Print Version 45. Baird WLM, Bowman WC, Kerr WJ. Some actions of Org NC 45 and of edrophonium in the anaesthetized cat and in man. Br J Anaesth. 1982; 54:375-85. [IDIS 149545] [PubMed 6121569] 46. Krieg N, Mazur L, Booij LHDJ et al. Intubation conditions and reversibility of a new non-depolarizing neuromuscular blocking agent, Org NC 45. Acta Anaesthesiol Scand. 1980; 24:423-5. [PubMed 6110303] 47. Mirakhur RK, Ferres CJ, Clarke RSJ et al. Clinical evaluation of Org NC 45. Br J Anaesth. 1983; 55:119-24. [IDIS 165993] [PubMed 6131681] 48. Crul JF, Booij LHDJ. First clinical experiences with Org NC 45. Br J Anaesth. 1980; 52(Suppl 1):49-52S. [IDIS 123596] [PubMed 6769450] 49. Marshall IG, Agoston S, Booij LHDJ et al. Pharmacology of Org NC 45 compared with other nondepolarizing neuromuscular blocking drugs. Br J Anaesth. 1980; 52(Suppl 1):11-9S. [IDIS 123593] [PubMed 6990947] 50. Basta SA, Savarese JJ. Comparative histamine-releasing properties of vecuronium, atracurium, tubocurarine and metocurine. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:183-4. 51. Foldes FF, Nagashima H, Boros M et al. Muscular relaxation with atracurium, vecuronium and Duador under balanced anaesthesia. Br J Anaesth. 1983; 55(Suppl 1):97-103S. [IDIS 165990] [PubMed 6600929] 52. Booij LHDJ, Krieg N, Crul JF. Intradermal histamine releasing effect caused by Org-NC 45: a comparison with pancuronium, metocurine and d-tubocurarine. Acta Anaesthesiol Scand. 1980; 24:393-4. [PubMed 6162354] 53. Vilardi V, Sanfilippo M, Pelaia P et al. The effect of vecuronium on intraocular pressure during general anesthesia. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:163-6. 55. Bowman WC. Preclinical pharmacology of vecuronium bromide. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:7-19. 56. Bowman WC. Non-relaxant properties of neuromuscular blocking drugs. Br J Anaesth. 1982; 54:147-60. [IDIS 157231] [PubMed 6174134] 57. Foldes FF, Deery A. Protein binding of atracurium and other short-acting neuromuscular blocking agents and their interaction with human cholinesterases. Br J Anaesth. 1983; 55(Suppl 1):31-4S. 58. Lienhart A, Desnault H, Guggiari M et al. Vecuronium bromide: dose-response curve and haemodynamic effects in anaesthetized man. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:46-53. 59. Crul JF. Conclusions. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:96-7. http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTS 54. Sia RL, Rashkovsky OM. Org NC 45 and intraocular pressure during anesthesia. Acta Anaesthesiol Scand. 1981; 25:219-21. [PubMed 6119868] Drugs.com Print Version 60. Lienhart A, Guggiari M, Maneglia R et al. Cardiovascular effects of vecuronium in man. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:150-5. 61. Nagashima H, Kaplan R, Radnay P et al. Relaxation with Org-NC45 during neurolept anesthesia. Anesthesiology. 1981; 55:A200. 62. Krieg N, Crul JF, Booij LHDJ. Relative potency of Org NC 45, pancuronium, alcuronium and tubocurarine in anaesthetized man. Br J Anaesth. 1980; 52:783-8. [IDIS 123646] [PubMed 6107097] 63. Barnes PK, Smith GB, White WD et al. Comparison of the effects of Org NC 45 and pancuronium bromide on heart rate and arterial pressure in anaesthetized man. Br J Anaesth. 1982; 54:435-9. [IDIS 149552] [PubMed 6121570] 64. Gencarelli PJ, Roizen MF, Miller RD et al. ORG NC45 (Norcuron) and pheochromocytoma: a report of three cases. Anesthesiology. 1981; 55:690-3. [IDIS 167110] [PubMed 6118079] 65. Morris RB, Cahalan MK, Miller RD et al. The cardiovascular effects of vecuronium (ORG NC45) and pancuronium in patients undergoing coronary artery bypass grafting. Anesthesiology. 1983; 58:438-40. [IDIS 170742] [PubMed 6132568] 66. Durant NN, Marshall IG, Savage DS et al. The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues, in the cat. J Pharm Pharmacol. 1979; 31:831-6. [PubMed 43368] 67. Marshall IG, Gibb AJ, Durant NN. Neuromuscular and vagal blocking actions of pancuronium bromide, its metabolites, and vecuronium bromide (Org NC 45) and its potential metabolites in the anaesthetized cat. Br J Anaesth. 1983; 55:703-14. [PubMed 6136285] 68. Kerr WJ, Baird WLM. Clinical studies on Org NC 45: comparison with pancuronium. Br J Anaesth. 1982; 54:1159-65. [IDIS 161116] [PubMed 6128012] 70. Crul JF. Depolarising and nondepolarising muscle relaxants for endotracheal intubation. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:54-9. 71. Nöldge G, Bischoff G, Buzello W. Clinical characteristics of the new muscle relaxant vecuronium bromide. Comparison with pancuronium bromide. In: Agoston S, ed. Clinical experiences with Norcuron(Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:69-75. 72. Ali HH, Savarese JJ, Basta SJ et al. Evaluation of cumulative properties of three new nondepolarizing neuromuscular blocking drugs BW A444U, atracurium and vecuronium. Br J Anaesth. 1983; 55(Suppl 1):107-11S. 73. Agoston S. Clinical pharmacology of vecuronium: a preliminary report on a multicentre study in 800 patients. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:99-108. 74. Miller RD, Rupp SM, Fahey MR et al. Pharmacokinetics of vecuronium in patients with kidney disease. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTT 69. Crul JF. Initial clinical experiences with vecuronium bromide. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:20-4. Drugs.com Print Version Excerpta Medica; 1983:124-6. 75. Nagashima H, Kaplan R, Yun H et al. Clinical pharmacology of vecuronium: a comparison with pancuronium. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:127-31. 76. Gramstad L, Lilleaasen P. Clinical comparison of vecuronium, atracurium and pancuronium: a short communication. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:140-4. 77. Clarke RSJ, Mirakhur RK. Intubating conditions after vecuronium: a study with three doses and a comparison with suxamethonium and pancuronium. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:145-9. 78. Goudsouzian NG. Vecuronium in pediatric anesthesia. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:167-70. 79. Duvaldestin P, Lebrault C, Terestchenko MC et al. Vecuronium in patients with liver disease. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:180-2. 80. Agoston S, Salt P, Newton D et al. The neuromuscular blocking agent of Org NC 45, a new pancuronium derivative, in anaesthetized patients. A pilot study. Br J Anaesth. 1980; 52(Suppl 1):53-9S. 81. Fisher DM, Fahey MR, Cronnelly R et al. Potency determination for vecuronium (Org NC45): comparison of cumulative and single-dose techniques. Anesthesiology. 1982; 57:309-10. [IDIS 158360] [PubMed 6127044] 82. Gramstad L, Lilleaasen P, Minsaas B. Onset time and duration of action for atracurium, Org NC45 and pancuronium. Br J Anaesth. 1982; 54:827-30. [IDIS 156472] [PubMed 6125161] 84. Fahey MR, Morris RB, Miller RD et al. Pharmacokinetics of Org NC45 (Norcuron) in patients with and without renal failure. Br J Anaesth. 1981; 53:1049-53. [IDIS 167708] [PubMed 6117300] 85. Schaer H, Hossli G. Preliminary clinical observations with Org NC 45. Br J Anaesth. 1980; 52(Suppl 1):65S. [IDIS 123601] [PubMed 6107111] 86. Williams A, Gyasi H, Melloni C et al. Clinical experience with Org NC45 (Norcuron) as the sole muscle relaxant. Can Anaesth Soc J. 1982; 29:567-72. [IDIS 162968] [PubMed 6128068] 87. Engbaek J, Ording H, Viby-Mogensen J. Neuromuscular blocking effects of vecuronium and pancuronium during halothane anaesthesia. Br J Anaesth. 1983; 55:497-500. [IDIS 171881] [PubMed 6134535] 88. Foldes FF, Yun H, Radnay PA et al. Antagonism of the NM effect of Org-NC45 by edrophonium. Anesthesiology. 1981; 55:A201. http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSTU 83. Baird WLM, Herd D. A new neuromuscular blocking drug, Org NC 45. Br J Anaesth. 1980; 52(Suppl 1):61-2S. [IDIS 123598] [PubMed 7378231] Drugs.com Print Version 89. Duncalf D, Nagashima H, Hollinger I et al. Relaxation with Org-NC45 during enflurane anesthesia. Anesthesiology. 1981; 55:A203. 90. Duvaldestin P, Berger JL, Videcoq M et al. Pharmacokinetics and pharmacodynamics of Org NC 45 in patients with cirrhosis. Anesthesiology. 1982; 57:A238. 91. Katz RL. General discussion. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:156-60. 92. Bencini A, Agoston S, Ket J. Use of the human “isolated arm” preparation to indicate qualitative aspects of a new neuromuscular blocking agent, Org NC 45. Br J Anaesth. 1980; 52(Suppl 1):43-7S. 93. Buzello W, Bischoff G, Kuhls E et al. The new non-depolarizing muscle relaxant Org NC 45 in clinical anaesthesia: preliminary results. Br J Anaesth. 1980; 52(Suppl 1):62-4S. 94. Dailey PA, Fisher DM, Shnider SM et al. Pharmacokinetics, placental transfer, and neonatal effects of vecuronium and pancuronium administered during cesarean section. Anesthesiology. 1984; 60:569-74. [IDIS 186741] [PubMed 6145374] 95. Dailey PA, Fisher DM, Shnider SM et al. Pharmacokinetics, placental transfer and neonatal effects of vecuronium and pancuronium administered during cesarean delivery. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. 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Bethesda, MD: American Society of Health-System Pharmacists; 2004:1303-6. http://www.drugs.com/monograph/vecuronium-bromide.html?printable=1[12/2/2014 2:56:52 PM] CURRICULUM VITAE Name: Roswell Lee Evans, Jr., Pharm.D., FASHP, FCCP, BCPP Business Address: Auburn University Harrison School of Pharmacy 2316 Walker Building Auburn University, Alabama 36849-5501 Office: 334/844-8348 E-Mail: evansrl@auburn.edu Personal Data: Spouse: Brenda Yates Evans Children: Kenneth Lee Heather Michelle Present Positions: Dean Auburn University Harrison School of Pharmacy Auburn University, Alabama 36849-5501 Professor Department of Clinical Pharmacy Practice Auburn University Harrison School of Pharmacy Auburn University, Alabama 36849-5501 Pharm.D. University of Tennessee College of Pharmacy Memphis, Tennessee June 1972-1973 B.S. (Pharm.) University of Georgia Athens, Georgia June 1968-1971 Residency: American Society of Hospital Pharmacists Accredited Medical University Hospital Medical University of South Carolina Charleston, South Carolina Preceptor: Max D. Ray, M.S.Ph., Pharm.D. 1971-1972 Pharmacy Licensure: Georgia Missouri Board Certified: Board Certified Psychiatric Pharmacist, 1997 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSUS Education: University Experience: 1987-1994 Dean Harrison School of Pharmacy Auburn University Professor and Chairman Division of Pharmacy Practice School of Pharmacy University of Missouri-Kansas City 1979-1987 Associate Professor of Clinical Pharmacy Head, Section of Ambulatory Care Instruction Division of Pharmacy Practice School of Pharmacy University of Missouri-Kansas City 1987-1994 Professor of Medicine Department of Psychiatry School of Medicine University of Missouri-Kansas City 1979-1987 Associate Professor of Medicine Department of Psychiatry School of Medicine University of Missouri-Kansas City 1975-1979 Assistant Professor of Clinical Pharmacy Ambulatory Care Instruction School of Pharmacy University of Missouri-Kansas City 1973-1975 Assistant Professor of Clinical Pharmacy College of Pharmacy University of Tennessee Professional Experience: 1978-1994 Psychopharmacy Specialist and Consultant Western Missouri Mental Health Center Kansas City, Missouri 1986 Acting Director of Pharmacy Western Missouri Mental Health Center Kansas City, Missouri (April-June) 1974-1975 Clinical Pharmacy Coordinator Veterans Administration Medical Center Memphis, Tennessee 2 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSUT 1994- 1973-1974 Psychopharmacy Specialist Consultant Jackson Mental Health Center Jackson, Tennessee 1973-1974 Coordinator of Community Mental Health Center Contracted Pharmacy Services Memphis and Shelby County Mental Health Center Tennessee Psychiatric Hospital and Institute University of Tennessee College of Pharmacy Memphis, Tennessee 1972-1973 Clinical Assistant in Psychopharmacy College of Pharmacy University of Tennessee 1971-1972 Hospital Pharmacy Resident Medical University Hospital Medical University of South Carolina 1968-1970 Pharmacy Intern St. Mary's Hospital Athens, Georgia Alabama Pharmaceutical Association Alabama Society of Health-System Pharmacists American Association for Higher Education American Association of Colleges of Pharmacy American Pharmaceutical Association American College of Clinical Pharmacy American Society of Hospital Pharmacists College of Psychiatric & Neurologic Pharmacists Rho Chi Pharmacy Honor Society Phi Lambda Sigma Teaching: Complete teaching record available upon request. Teaching (Other): Team Mentor, Pharmacy Practice Experience, Auburn, University, 1997- present. Instructor, Psychiatric Pharmacotherapy Module. Auburn University, 1996-98. Post Graduate Resident/Fellows: Janet Kinney Parker, Pharm.D. Pharmacy Program Director 3 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSUU Memberships in Professional and Scholarly Organizations: Western State Hospital W-27-19 Fort Steilacoom, Washington (1980-82) Johnnie Lienemann, Pharm.D. Clinical Coordinator St. Vincent Stress Center 8401 Harcourt Road Indianapolis, Indiana (1982-84) Merlin V. Nelson, Pharm.D. Assistant Professor of Pharmacy Practice Wayne State University Detroit, Michigan (1983-85) Frank Lobeck, Pharm.D. Assistant Professor of Pharmacy Practice University of Oklahoma Oklahoma City, Oklahoma (1984-86) Carl Hemstrom, Pharm.D. (Deceased) Assistant Professor of Pharmacy Practice Veterans Administration Medical Center (119) 500 West Fort Street Boise, Idaho (1985-87) Keith Anderson, Pharm.D. Psychopharmacy Specialist Veterans Administration Medical Center 4800 Linwood Boulevard Kansas City, Missouri (1987-89) Sylvia LaCombe, Pharm.D. 3491 Edinburghist V3C-452 Port Coquitlan, British Columbia Canada V3B-4K4 (1988-90) Steve Stanislav, Pharm.D. Assistant Professor School of Pharmacy University of Texas at Austin Austin, Texas (1989-91) 4 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSUV LaGenia Bailey, Pharm.D Assistant Professor of Pharmacy Practice College of Pharmacy Department of Pharmacy Practice 833 S. Wood Chicago, Illinois (1986-88) Juan Avila, Pharm.D. Assistant Professor School of Pharmacy Duquesne University Pittsburgh, Pennsylvania (1990-92) Kay McCrary, Pharm.D. Marion Merrell-Dow Kansas City, Missouri (1991-93) Mark Schneiderhan, Pharm.D. Clinical Assistant Professor University of Illinois Chicago, Illinois (1992-94) Michelle Kendall, Pharm.D. Veterans Administration Oklahoma City, Oklahoma (1993-95) Amy Gross, Pharm.D. Express Scripts Minneapolis, Minnesota (1993-95) Administrative Activities (Other): Preceptor, Psychopharmacy Residents and Fellows (American Society of HospitalPharmacists Accredited Specialty Residency), Western Missouri Mental HealthCenter, 1981-94. Coordinator, Affective Disorders Clinic, Western Missouri Mental Health Center, 1980-90. Administrative Activities (Service to Standing Committees): Chairman, Executive Committee, Auburn University Harrison School of Pharmacy, 1994 to present. Member, Provost's Council, Auburn University, 1994 to present. Member, Dean’s Forum, Auburn University, 1995 to present. 5 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVM Director, Psychopharmacy Education and Research Programs, Western Missouri Mental Health Center, 1981-94. Member, University Senate, Auburn University, 1994 to 2001, 2003-4, 2004-5, 2008-9, 2010-13. Member, Budget Advisory Council, Auburn University, 1995-96, 2001-2, 2008-2012 Chair, Strategic Planning Committee, Auburn University Harrison School of Pharmacy, 1994 to present. Member, Budget Committee, University of Missouri-Kansas City School of Pharmacy, 1987-90, 1992-94. Member, Executive Committee, University of Missouri-Kansas City School of Pharmacy, 1981-84; 1987-94. Member, University of Missouri-Kansas City Faculty Senate, 1986-88. Member, Graduate Affairs Committee, University of Missouri-Kansas City School of Pharmacy, 1987-88. Member, Promotion and Tenure Committee, University of Missouri-Kansas City School of Pharmacy, 1985-86. Member, Curriculum Committee, University of Missouri-Kansas City School of Pharmacy, 1979-80, 1984-85, 1985-86, 1987-88 (Ex officio). Member, Medical Education Committee, Department of Psychiatry, University of Missouri-Kansas City School of Medicine, 1979-84. Administrative Activities (Committees, Other): Chair, College of Veterinary Medicine Dean Search Committee, 2012-13. Chair, Auburn University, Health Sciences Initiative Planning Group, 2008-9. Member, Auburn University, Advisory Board of Deans, Research Initiative for the Study of Diversity, 2008-09. Member, Alabama Department of Public Health Pandemic Influenza Healthcare Committee 2007-present Member, Security Task Force, Auburn University, 2007-08 Ad Hoc Committee on Implementation of Auburn University Harrison School of Pharmacy Mobile Satellite, 2006-07. Member, Auburn University Black Belt Initiative, 2003. 6 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVN Member, Admissions and Academic Requirements Committee, University of MissouriKansas City School of Pharmacy, 1981-1983 Member, Auburn University Medical Clinic Planning and Building Committee, 2000-03 Member, AU I 85 Corridor Task Force, 2003 Chairman, Auburn University Environmental Institute, 2003-2004 Chair-elect, Auburn University Environmental Institute, 2002-2003 Member, Campaign Needs Assessment Committee, Auburn University, 2000, 2003. Member, Faculty Senate Workload Policy Committee, Auburn University, 1997-98. Co-Chair, As Hoc Committee on Workload Policy, Auburn University, 1995-97. Member, Auburn University Committee for Outsourcing Student Health Services, 199496. Chairman, Auburn University Student Health Center, Continuous Quality Improvement/Personal Assessment and Counseling Service, Auburn University, 199495. Member, Student Health RFP Committee, Auburn University, 1994-95. Member, Committee for Criteria for Advancement of a School to a College, Auburn University, 1996. Chairman, Clinical Pharmacy Practice Department Head Search, Auburn University School of Pharmacy, 1994-96. Member, UMKC School of Pharmacy Non-traditional Doctor of Pharmacy Degree Task Force, 1993-94. Member, UM/LU/UWC USAID Proposal Working Group, 1992-93. Member, Ad Hoc Committee for University of Missouri-Kansas City and the University of Western Cape, South Africa, Community Partnership for Promotion of Community and Individual Health, 1992-93. Chairman, University of Missouri-Kansas City, Council on Planning and Evaluation, Ad Hoc Committee Site Visit Team for School of Nursing, April 30 1992. Chairman, Pharmacy Practice Faculty Search Committee, University of Missouri-Kansas City School of Pharmacy, 1991-92, 1993-94. 7 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVO Chairman, Associate Dean for Academic and Student Affairs Search, Auburn University School of Pharmacy, 1995-97. Member, Pharmacology Chairman Search Committee, University of Missouri-Kansas City School of Pharmacy, 1992-94. Member, Pharmaceutical Science Chairman Search Committee, University of MissouriKansas City School of Pharmacy, 1991-94. Member, UMKC Regional PET SCAN Committee, University of Missouri-Kansas City School of Medicine, 1991-92. Chairman, Ad Hoc Honor Council Committee, University of Missouri-Kansas City School of Pharmacy, 1989-90. Chairman, Ad Hoc Committee on Track-in Curriculum Modifications, University of Missouri-Kansas City School of Pharmacy, 1988. Member, University of Missouri-Kansas City, Image Research Study Committee, 198788. Chairman, Search Committee for Psychopharmacy Faculty, University of MissouriKansas City School of Pharmacy, 1986-87. Chairman, Search Committee for Clinical Faculty for Veterans Administration Medical Center and Western Missouri Mental Health Center, University of Missouri-Kansas City School of Pharmacy, 1985-86. Member, Search Committee for Dean, University of Missouri-Kansas City School of Pharmacy, 1984-1986. Chairman, Ad Hoc Committee on Promotion and Tenure for Clinical Faculty, University of Missouri-Kansas City School of Pharmacy, 1985-86. Member, Search Committee, Assistant Dean of Professional Practice, University of Missouri-Kansas City School of Pharmacy, 1984-85. Member, Ad Hoc Committee on Promotion and Tenure, University of Missouri-Kansas City School of Pharmacy, 1984-85, 1985-86. Member, Ad Hoc Planning Committee for Establishing Pharm.D. Curriculum, University of Missouri-Kansas City School of Pharmacy, 1984-85. Member, Ad Hoc Planning Committee on Research Development at University of Missouri-Kansas City School of Pharmacy, 1984-85. Chairman, Drug Utilization Review Committee, Western Missouri Mental Health Center, 1983-84. 8 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVP Member, Search Committee for Drug Information Faculty, University of MissouriKansas City School of Pharmacy, 1985-86. Member, Pharm.D. Task Force (Ad Hoc Committee to evaluate B.S. and Pharm.D. Programs), University of Missouri-Kansas City School of Pharmacy, 1980-82. Professional Activities (Invited Lectures, Workshops, Professional Presentations): 2012 Evans, RL. Agent of Change: People. Implementing Progress in an Ever Changing Environment. Fall Architects Invitational Conference, Atlanta, Georgia, October 19, 2012. Invited. 2009 Evans, RL. Leadership: Musings and Ramblings of a Dean. Phi Lamba Sigma Society, Pharmacy Leadership Conference. Auburn, Alabama, March 28, 2009 2008 Evans, RL. Implementing Breakthroughs for the Next Generation of Practitioners, National Association of Boards of Pharmacy/American Association of Colleges of Pharmacy, District III Annual Meeting, San Destin, Florida, August 19, 2008. Evans, RL. I am professional? So What is it Going to Take?. University of Tennesse at Memphis. Rho Chi Banquet. Memphis, Tennessee, Februrary 9, 2008. Invited 2007 Evans RL. Effective Modalities for Enhancing Entry-level Pharmacy Programs. Nova Southeastern University. NSU College of Pharmacy Faculty Development Session. Ft. Lauderdale, Florida, May 9, 2007. Invited. 2004 Evans RL. Tales From The Front: Consequences Of Failing A Student. American College Of Clinical Pharmacists. Annual Meeting. Dallas, Texas, October 26, 2004. Invited. 2002 Beck, DE, Evans RL, Monaghan M, Stohs S, Boyce E, Downs G. Outcomes Assessment: Moving from Innovation to Integration, AACP Special Session, AACP Meeting, Kansas City, MO. Contributed. 1999 Evans RL. So you want to be a Dean, Huh? Career Development Workshop. American Association of Colleges of Pharmacy. Interim Meeting, Washington, DC, March 1, 1999. Invited. Beck DE, Evans RL, Stadler HA, Jungnickel PW. “Implementation of a Pharmacy School Continous Quality Improvement Program; Phases I and II.” Poster. OneHundredth Annual Meeting of the American Association of Colleges of Pharmacy, Boston, Massachusetts, July 1999. Contributed. 1998 Evans RL. Pharmacy Education in the 21st Century: A Continuing Evolution. The University of Georgia 50th Annual Postgraduate Pharmacy Seminar, Pharmacy 2048: The Next Fifty Years, Athens, Georgia, May 17, 1998. Invited. 9 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVQ Evans RL. Psychiatric Pharmacy in Context: Perspectives of a Clinical Paper Pusher. College of Psychiatric and Neurologic Pharmacists Annual Meeting, Chicago, May 2004. Invited. Lee S, Cates M, Drake R, Evans RL. Clinical Assessment of Depression Patients. Alabama Pharmacy Association Mid-Winter Conference. Tuscaloosa, Alabama, February 13, 1998. Invited 1995 Evans RL. Moving Pharmacy into the Future. The Alabama Pharmacy Association District Meetings. District 12, Evergreen, Alabama, October 30, 1995; District 5, Tuscaloosa, Alabama, November 6, 1995; District 4, Montgomery, Alabama, November 7, 1995; District 11, Auburn, Alabama, November 13, 1995. Invited. Evans RL. Cocaine Induced Aggression. The 30th Annual ASHP Midyear Clinical Meeting and Exhibits, Las Vegas, Nevada, December 5, 1995. Invited. 1994 Evans RL. Group Dynamics: How to Get Your Patients to Talk to Each Other. The 29th Annual ASHP Midyear Clinical Meeting and Exhibits, Miami Beach, Florida, December 7, 1994. Invited. Evans RL. Risperidone: A Review. The Las Vegas Medical Center, August 4, 1994. Invited. Evans RL. Using Medications Properly to Improve Health and Reduce Health Care Costs. The Self-Care Conference, Mid-America coalition on Healthcare meeting, Kansas City, Missouri, June 8, 1994. Invited. Evans RL, McDade SA, Rutledge CO, Tong TG. Workshop Facilitator. The Case Method in Pharmaceutical Education. Academic Management Symposium, American Association of Colleges of Pharmacy, Interim Meeting, Hilton Head, South Carolina, February 24-26, 1994. Invited. Evans RL. Psychotropic medications in the long term care setting. Presented at the Kansas Pharmacy Association, Consultant Pharmacists Workshop, Lawrence, Kansas, February 6, 1994. 1993 Evans RL. "Don't Be Afraid of Psychotherapeutics." Presented at Clinical Pearls session, American Society of Hospital Pharmacist, Midyear Clinical Meeting, Atlanta, Georgia, December 7, 1993. Invited. Evans RL (Chairman). "Treatment Options for Obsessive Compulsive Disorder". Presented at Recent Advances in Treatment of Obsessive Compulsive Disorders Seminar, American Society of Hospital Pharmacist, Midyear Clinical Meeting, Atlanta, Georgia, December 6, 1993. Invited. Evans RL (Chairman). Rationale Pharmacotherapy of Obsessive Compulsive Disorder. Presented at Psychiatric Disorders and Treatment Outcomes in Managed Care: A Focus on Patients with OCD Symposium. Phoenix, Arizona, November 13, 1993. Invited 10 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVR Dean JO, Evans RL Lewis H, Vanderveen RP. Panel discussion. Continuous Quality Improvement in Pharmaceutical Education, American Association of Colleges of Pharmacy, Hilton Head, South Carolina, February 27, 1994. Invited. Individual Faculty Interviews, Procedure and Development of Interview Skills, American Council on Pharmaceutical Education Accreditation Forum, American Association of Colleges of Pharmacy Annual Meeting, San Diego, California, July10, 1993. Invited. Sommi RW, Evans RL, Klutman N, Henry D. "Experiential Performance Assessment: Changes, Methods, and Meaning." Mid America College of Clinical Pharmacy Education Forum. Kansas City, Missouri, January 12, 1993. Invited. 1992 Evans RL. Alprazolam-XR Pharmacokinetics: A Review." Presented at Alprazolam-XR in the Management of Anxiety Symposium, Rosemont, Ill., September 4, 1992. Invited. Evans, RL. "Redefinition of Scholarship: A Chairman's Perspective." Presented at the Section of Teachers of Pharmacy Practice, American Association of Colleges of Pharmacy Annual Meeting, Washington, D.C., July 12, 1992. Invited. 1991 Evans RL (Chairman), Marken PA, Sommi RW. “Solving the Comorbidity Puzzle.” Symposium at the 26th Annual ASHP Midyear Clinical Meetings and Exhibits, New Orleans, Louisiana, December 10, 1991. Invited. Evans RL (Workshop Facilitator). "Greater Kansas City Society of Hospital Pharmacists Communications Seminar." Kansas City, Missouri, October 24, 1991. Invited. Coleman M, Evans RL, Reidhead V. "Managing Diversity in the Work Place: Interpersonal Relationships. Workshop conducted at the Biannual Conference for Department Chairpersons and Directors, University of Missouri, Lake Ozark, Missouri, October 12-13, 1991. Invited. Evans, RL. "Cost of Uncontrolled Anxiety." Workshop presented at Ohio Society of Hospital Pharmacists, Hudson, Ohio, October 10-11, 1991. Invited. Evans RL. "Recognition and Treatment of Panic Disorder." Presented at West Central Missouri Pharmacists Association Meeting, Booneville, Missouri, April 18, 1991. Invited. Evans RL. "The Pharmacist's Role in Anxiety Management." Teleconference presented at the "Greater Minnesota Pharmacy Gathering" of the Minnesota Pharmacists Association, Minneapolis, Minnesota, April 7, 1991. Invited. Evans, RL (Chairman and faculty). "Psychiatric Comorbidity with Medical Illness: Impact, Recognition and Treatment." A symposium presented at the Winter Practice and Research Forum of the American College of Clinical Pharmacy, Ft. Lauderdale, Florida, February 10, 1991. Invited. 1990 Evans, RL (Chairman and faculty). Anxiety Disorders: Treatment and Management Issues for the Pharmacist." A symposium presented at the Midyear Clinical Meeting of 11 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVS Evans, RL. "Treatment and Diagnosis of Anxiety and Depression in the Elderly." Ohio Society of Hospital Pharmacists, Hudson, Ohio, October 10-11, 1991. Invited. the American Society of Hospital Pharmacists, Las Vegas, Nevada, December 3, 1990. Invited. Evans RL. "Anxiety Disorders in Primary Care: A New Approach to Diagnosis and Management." Presented to: the Greater Omaha Pharmacy Society, Omaha, Nebraska, November 19, 1990; Mid Missouri Society of Hospital Pharmacist, Columbia, Missouri, November 28, 1990. Invited. Evans RL. "A New Look at Anxiety, Depression, and Panic Disorders." Presented at the National Association of Retail Druggists Annual Meeting, Nashville, Tennessee, October 24, 1990. Invited. Coleman M, Evans RL, Reidhead V. "Pharmacy Supervisor: How Can You Help Your Staff Learn to Counsel Anxiety Patients" Evans RL. Presented at the University of Kansas and Veterans Administration Medical Center Hospital Pharmacies Administrator's Conference, Kansas City, Missouri, August 30, 1990. Invited. Evans RL, Guthrie S. "National Anxiety Awareness Program" Symposium presented at the Michigan Pharmacists Association's Annual Convention, Grand Traverse, Michigan, August 13, 1990. Invited. Evans RL. "Treatment of Anxiety Disorders: A Case History." Presented at Anxiety Disorders: Treatment and Management Issues For the Pharmacists' Symposium, Scottsdale, Arizona, June 16, 1990. Evans, RL (Co-Chairman and faculty). Invited. Evans RL. "Evaluation of Mental Health Outcomes: Is it Possible?" Presented at the Mental Health Benefits for the 1990's: Paying for What Works, A Senior Management Invitational Symposium, The Institute for Behavioral Healthcare, Dallas, Texas, May 11, 1990. Invited. Evans RL. "Issues in the Treatment of Anxiety: Therapeutic Use of Antianxiety Agents and Abuse. Presented at the Hall County Pharmacists Association Meeting, Grand Island, Nebraska, March 21, 1990. Invited. 1989 Evans RL. "Appropriate Use of Medications in the Treatment of Panic Disorder." Presented for Comprehensive Mental Health Services, Independence, Missouri, December 14, 1989. Invited. Evans RL. "Establishing Expectations for Staff Pharmacists' Patient Counseling Activities." University of Kansas and Veterans Administration Medical Center Hospital Pharmacies Administrator's Conference, Kansas City, Missouri, November 30, 1989. Invited. Evans RL. "The Process of Patient Consultation" Presented at the Patient Consultation: An Important Aspect of Professional Pharmacy Services Conference, University of 12 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVT Evans RL, Demmer D, Crook D. “Greater Kansas City Counseling Skills Clinic for Pharmacists." Sponsored by the Greater Kansas City Society of Hospital Pharmacists, April 6, May 4, June 8, July 13, 1990. (Co-facilitator). Invited. Missouri-Kansas City, School of Pharmacy, Kansas City, Missouri, November 12, 1989. Invited. Evans RL. "Preceptor Skills." Presented at the Clinical Communication Skills for the 1990's Program, Missouri Society of Hospital Pharmacists Fall Meeting, Osage Beach, Missouri, November 4, 1989. Invited. Evans RL. "Tweaking Neurons in the Treatment of Unresponsive Schizophrenic Patient: Results of an Ongoing Study." Presented to Western Missouri Mental Health Center Medical Staff, Kansas City, Missouri, October 25, 1989. Invited. Evans RL. "Where Are We and Where Are We Going?" Presented at the Symposium for Mental Health/Mental Retardation/Substance Abuse Pharmacists, University of Georgia, Athens, Georgia, October 9, 1989. (Keynote Speaker). Invited. Evans RL. "Pharmacokinetic and Pharmacodynamics of Benzodiazepines and Buspirone. Presented to the Ozark Society of American Psychiatric Association, Springfield, Missouri, May 12, 1989. Invited. Evans RL. "Overview of Hypnotic and Benzodiazepine Use." Presented at the South Dakota Pharmaceutical Association, Black Hills Winter Seminar, Rapid City, South Dakota, February 18- l 9, 1989. Invited. Evans RL. "Antidepressant Agents: Old and New," Presented at Recent Drug Development Conference, University of Montana, School of Pharmacy, Missoula, Montana, November 6, 1988. Evans RL. Greater Kansas City Clinical Conference. Workshop leader. Kansas City, Missouri, October 5, 1988. Evans RL, "Anxiety: Diagnosis and Current Treatment Perspectives." Evans RL. Presented to the Research Medical Center Staff Conference, Kansas City, Missouri, June 29, 1988. Evans RL, "The Use and Misuse of Benzodiazepines." Evans RL. Presented at University Hospital Staff Conference, Seattle, and Western State Hospital, Fort Steilacoom, Washington, June 23, 1988. Evans RL. "Overview of Antipsychotics." Presented at the Las Vegas Medical Center, First Annual Psychopharmacology Conference, Las Vegas, New Mexico, April 23-24, 1988. Evans RL. "Treatment of Affective Disorders with Tegretol." Presented at the Comprehensive Mental Health Center, Independence, Missouri, April 14, 1988. Evans RL. "Pharmacokinetics and Pharmacodynamics of Benzodiazepines and Buspirone." Presented at the Anxiety Disorders: Biological Basis and Pharmacotherapeutic Approaches to Treatment Conference, The University of Illinois at Chicago, Chicago, Illinois, March 25, 1988. 13 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVU 1988 Evans RL. "A Pharmacist's Perspective on Psychiatric Rating Scales." Presented at the American Society of Hospital Pharmacists Midyear Clinical Meeting, Psychopharmacy SIG meeting, Atlanta Georgia, December 10, 1987. Evans RL. "Rational Approach to the Treatment of Sleep Disorders." Presented for the Salt Lake Area Society of Hospital Pharmacists, Salt Lake City, Utah, November 1987. Evans RL. "Central Nervous System Stimulants." Presented to the University of Missouri-Kansas City Athletic Department, Kansas City, Missouri, October 13, 1987. Evans RL. "Neuroleptic Malignant Syndrome." Presented to Nursing Staff, Western Missouri Mental Health Center, Kansas City, Missouri, July 23, 1987. Evans RL. "Clinical Pharmacist Use of Multicenter Trial Concepts in Completing Phase IV Research." Presented to the Faculty of University of Idaho College of Pharmacy, Pocatello, Idaho, March 1987. 1986 Evans RL. "Neuroleptic Malignant Syndrome: Clinical Presentation and Treatment." Presented at the Neurology/Neurosurgery Conference, Menorah Medical Center, Kansas City, Missouri, August 13, 1986. Also presented for the Medical Staff at Western Missouri Mental Health Center, Kansas City, Missouri, October 10, 1986. Evans RL (Faculty). "Communications Skills Workshop." Conducted at the Annual Meeting of the American Association of Colleges of Pharmacy, Toronto, Ontario, July 15, 1986. Evans RL (Panelist). "Teaching and Research in the Pharmaceutical Sciences in Pharmacy Schools." Conducted at the Federation of the American Society of Experimental Biology, St. Louis, Missouri, April 14, 1986. Evans RL. "Pharmacology for Community Residential Facility Aides." Presented at New Horizons Assistance Corporation, Kansas City, Missouri, February 11 & 12, 1986. Evans RL. "Antipsychotic Medication for Elderly Patients." Presented at the Annual Seminar of the Missouri Society of the American College of General Practitioners, Kansas City, Missouri, January 26, 1986. 1985 Evans RL. "Critical Review of the Use of Carbamazepine in the Treatment of Affective Disorders." Presented at Grand Rounds Presentation, Department of Psychiatry, University of Kansas Medical School, Kansas City, Kansas, March 8, 1985. Evans RL. "Patient Communications Workshop for Hypertensive and Diabetic Counseling Clinic Members." Presented at Truman Medical Center, Kansas City Missouri, February 12, 1985. 14 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSSVV Evans RL (Faculty). "Neurological Complications of Psychotropic Agents." Evans RL. Presented at the Neurology/Neurosurgery Conference, Menorah Medical Center, Kansas City, Missouri, May 21, 1986. Evans RL. "The Clinical Presentation and Drug Treatment of Panic Disorders." Presented at Truman Medical Center Family Practice Noon Conference, Lee's Summit, Missouri, January 16, 1985. Evans RL. "Overview of Psychopharmacology for Family Practitioners." Presented to the Department of Family Practice, University of Kansas Medical Center, Kansas City, Kansas, November 6, 1985. Evans RL. "Psychotropic Drug Use in the Elderly." Presented for the Wichita Pharmaceutical Association, Wichita, Kansas, November 3, 1985. Evans RL. "Calcium Channel Blockers in the Treatment of Affective and Schizophrenic Disorders." Presented to Western Missouri Mental Health Center Medical Staff, Kansas City, Missouri, October 30, 1985. Evans RL. "Generic Psychotropic Agents: Are They Different?" Presented at the St. Louis State Hospital, St. Louis, Missouri, July 26, 1985. Evans RL. "Perspectives on Psychiatric Social Work: Medication Overview." Presented at the Western Missouri Mental Health Center, Kansas City, Missouri, June 13, 1985. Evans RL (Faculty). "How to Prepare Your Pharmacy For Medicare Survey." Workshop conducted at the Annual Meeting of American Society of Hospital Pharmacists, Reno, Nevada, June 6, 1985. Evans RL. "Psychiatric Medications." In-service for Emergency Shelter Coalition of Kansas City, Western Missouri Mental Health Center, Kansas City, Missouri, May 6, 1985. Evans RL. "Consideration of Generic Neuroleptics for Pharmacists." Presented at the Linn County Pharmacy Association Meeting, Cedar Rapids, Iowa, April 24, 1985. Evans RL. "Legal Drugs of Abuse." Presented at the Drug Use and Drug Abuse Seminar: Teleconference, University of Missouri-Kansas City, School of Pharmacy, Kansas City, Missouri, April 16, 1985. 1984 Evans RL. "Practical Approaches to Treating the Depressed Elderly." Presented at The Silent Dilemma: Afflictions of the Elderly Symposium, Creighton University Omaha, Nebraska, October 28, 1984. Evans RL. "Clinical Presentation and Treatment of Organic Brain Syndrome." Presented at the Silent Dilemma: Afflictions of the Elderly Symposium, Creighton University, Omaha, Nebraska, October 28, 1984. 15 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMM Evans RL (Moderator). "Workshops for the Psychopharmacy Practitioner." Conducted for the Psychopharmacy Special Interest Group Meeting, Annual Meeting of the American Society of Hospital Pharmacists, Reno, Nevada, June 6, 1985. Evans RL. "Panic Disorders: A Review of Pharmacological Approaches." Presented to Western Missouri Mental Health Center Medical Staff, Kansas City, Missouri, October 10, 1984. Evans RL. "The Drug Treatment of Panic Disorders." Presented at the Panic Disorder Conference, Missouri Institute of Psychiatry, Springfield, Missouri, October 5, 1984. Evans RL. "Introduction to Counseling Skills in Pharmacy Practice." Presented at the Annual Meeting of the Kansas Pharmacists Association, Lawrence, Kansas, September 22, 1984. Evans RL. "Nursing Orientation: Psychopharmacology." Presented at the Western Missouri Mental Health Center, Kansas City, Missouri, August 15, 1984. Evans RL. "Legal Drugs of Abuse." Presented at the Drug Use and Drug Abuse Seminar, University of Missouri-Kansas City, School of Pharmacy, Kansas City, Missouri, September 18, 1984. Evans RL (Chairman and Faculty). "Current Clinical Perspectives on Depression, Anxiety and Insomnia." Regional Psychopharmacy Symposia. Sponsored by an Educational Grant from the Upjohn Company. Southern Region, Atlanta, Georgia, March 26-27, 1984; Eastern Region, New York, New York, May 16-17, 1984; Central Region, Arlington Heights, Illinois, June 13-14, 1984. Evans RL. "Psychotropic Drug Use in the Elderly." Presented to the Department of Family Practice, University of Kansas Medical Center, Kansas City, Missouri, March 1984. Evans RL (Faculty), Demmer D. "If I Could Walk in That Guy's Shoes, Would I Be a Better Practitioner?" A Communication Skills Workshop for Pharmacists. University of Montana, Continuing Education Program, Bozeman, Montana, February 17-19, 1984. 1983 Evans RL (Moderator and Faculty), Erman M and Juhl R. "Recognition of Sleep Disorders and Treatment." Upjohn Seminar. Presented at the 1983 Midyear Clinical Meeting, American Society of Hospital Pharmacists, Atlanta, Georgia, December 7, 1983. Evans RL. "Carbamazepine Use in the Treatment of Affective Disorders." Presented to Western Missouri Mental Health Center Medical Staff, Kansas City, Missouri, October 12, 1983. Evans RL (Faculty), Demmer D. "Did I Say That? What I Really Wanted to Say Was..." A Communication Skills Workshop for Pharmacists. University of Missouri-Kansas City School of Pharmacy Long Weekend, Lake of the Ozarks, Missouri, April 29, 1983. 16 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMN Evans RL. "Psychopharmacology." Presented at the 2nd Annual Springfield Family Practice Symposium, Springfield Academy of Family Physicians, St. John's Regional Medical Center, Springfield, Missouri, April 14, 1984. Evans RL. "Psychotropic Potpourri." Presented to Greater Kansas City Psychological Association, Kansas City, Missouri, April 26, 1983. Evans RL. "Geriatric Psychopharmacology for the Social Worker." Presented at St. Luke's Hospital, Kansas City, Missouri, April 12, 1983. Evans RL. Lecturer on Psychotropic Agents. Presented at Webster Nursing College, St. Luke's Hospital, Kansas City, Missouri, April 12, 1983. Evans RL. "Drugs with a Therapeutic Window." Presented at the Western Missouri Mental Health Center General Staff Presentation, Kansas City, Missouri, February 3, 1983. 1982 Evans RL (Moderator and Faculty), Kushi R, Bitar A, Gutchman D. "Therapeutic Dilemma: Tardive Dyskinesia." Panel Discussion presented at the 1982 Midyear Clinical Meeting, American Society of Hospital Pharmacists, Los Angeles, California, December, 1982. Ereshefsky L, Crabtree B, Evans RL (Panelist), Stimmel G, Votolato N. "Biochemical Strategies in the Treatment of Refractory Depression." Mead Johnson Symposium. Presented at the 1982 Midyear Clinical Meeting, American Society of Hospital Pharmacists, Los Angeles, California, December, 1982. Evans RL. "Lithium Clinic: A Retrospective Analysis." Presented at the Western Missouri Mental Health Center General Staff Presentation, Kansas City, Missouri, September 30, 1982. 1981 Evans RL (Faculty). "Communicating with the Psychiatric Patient in Your Mental Health Practice." A workshop conducted at the Symposium for Mental Health Pharmacists, Athens, Georgia, October 25-27, 1981. Evans RL. "How to Get the Most Out of Medication Without Letting It Get You." Presented for the "Life-Altering Illnesses and Cancer Information Series," The Mental Health Association of Johnson County, Prairie Village, Kansas, September 1, 1981. Evans RL, Panelist. "Life-Altering Illness and Cancer Information Series." Televised on "Around Town with Ann Debus," Channel 19, Kansas City, Missouri, August 28, 1981. Evans RL (Faculty). "What You Are Is What You Were When." Communications Workshop conducted for the Kansas Pharmacists' Association Annual Meeting, Topeka, Kansas, May 29, 1981. 17 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMO Evans RL. "Antidepressant and Antianxiety Agents." Presented for the Pharmacology for Health Professionals Seminar and Teleconference New Drugs and New Drug Therapy, Continuing Education, University of Missouri-Kansas City School of Pharmacy, Kansas City, Missouri, November 9, 10, 23, 1982. Evans RL. "Endorphins in Psychiatry." Presented to the Western Missouri Mental Health Center Medical Staff, Kansas City, Missouri, March 25, 1981. Evans RL. "Drug Therapy of Human Behavior." Presented for the Continuing Education Lecture Series for Nursing, Baptist Memorial Hospital, Kansas City, Missouri, March 16, 23, 30, 1981. 1980 Evans RL. "Drug Utilization Review: Overview." Presented during "Dialogue on Contemporary Issues in Psychopharmacology, A Panel Presentation." American Society of Hospital Pharmacists Midyear Clinical Meeting, San Francisco, California, December, 1980. Evans RL. "Communications - The Health Care Delivery Team." Presented during "A Symposium on Consulting with Your Patients," at the Virginia Pharmaceutical Association, the District of Columbia Pharmaceutical Association and the Maryland Pharmacy Continuing Education Coordinating Council, Arlington, Virginia, September 7, 1980. Evans RL. "Counseling the Cancer Patient." Presented at the Symposium on Current Concepts of Cancer Chemotherapy and Pain Control, New Mexico Pharmaceutical Association Annual Meeting, Albuquerque, New Mexico, May 24, 1980. Evans RL, Faculty. "Interpersonal Aspects of Interviewing and Counseling Techniques in Health Care Communications." Presented at the Association of Faculties of Pharmacy of Canada (AFPC) Teachers' Conference, Calgary, Alberta, Canada, May 19, 1980. 1979 Evans RL, Platek T. "DSM-III: Implications for Pharmacists in Mental Health." Presented at the Midyear Clinical Meeting, American Society of Hospital Pharmacists, Las Vegas, Nevada, December 5, 1979. Evans RL. "Over-the-Counter Drugs: A Rational Approach to Their Selection." Presented for the Holistic Health Care Program, The Mental Health Association of Johnson County, Baptist Memorial Hospital, Kansas City, Missouri, October 19, 1979. Evans RL. Seminar Series on Psychopharmacology and Therapeutics, Presented at the Rainbow Mental Health Center, Kansas City, Kansas, July 5, 10, 12, 17, 1979. Evans RL. "Mental Health Pharmacy in the State System." Presented at the Missouri Mental Health Pharmacy Workshop, St. Louis State Hospital, St. Louis, Missouri, May 21, 1979. Evans RL. "Clinical Clerkships." Presented at the University of Missouri-Kansas City School of Pharmacy, Pharmacy Long Weekend, Kansas City, Missouri, April 27, 1979. 18 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMP Evans RL (Faculty). American Association of Colleges of Pharmacy Lilly Canada Pharmacy Education Communications Skills Workshop, Calgary, Alberta, Canada, May 15-17, 1980. 1978 Evans RL (Faculty). American Association of Colleges of Pharmacy Lilly Pharmacy Education Communications Skills Workshops, Boulder, Colorado, March 12-14, 1978; Lincoln, Nebraska, April 30-May 2, 1978; Athens, Georgia, October 25-31, 1978. Evans RL. "Community Care: A Component of an Ambulatory Care Teaching Program." Presented at the University of Oklahoma College of Pharmacy Annual Faculty Retreat, Roman Nose, Oklahoma, October 21, 1978. Evans RL. "Community Clerkships, The Kansas City Experience." Presented at the FiftyThird Annual Meeting, Sixth District, National Association of Boards of Pharmacy, American Association of Colleges of Pharmacy, St. Louis, Missouri, October 16, 1978. Evans RL (Moderator). "Special Session on Achieving Better Communications, A Must for Pharmacy Students." Annual Meeting of the American Association of Colleges of Pharmacy, Seattle, Washington, August 8, 1978. Evans RL. "Evaluate the Home Pharmacy." Presented at Medical Self-Help Series, Missouri Western State College, St. Joseph, Missouri, July 20, 1978. Evans RL. "Experiences in Clinical Community Pharmacy Practice." Presented at University of Kansas Student American Pharmaceutical Association Lecture Series, Lawrence, Kansas, February 7, 1978. Evans RL. Changing Professional Image." Presented at the University of Missouri-Kansas City Medical School, Kansas City, Missouri, December 9, 1977. Evans RL, Wright B, Williams S. Written patient instruction: improving readability can enhance effectiveness. Presented at the 1977 Midyear Clinical Meeting, American Society of Hospital Pharmacists, Atlanta, GA, December 8, 1977. Invited. Evans RL. "Developing Innovative Pharmacy Services in the Community Setting." Presented at the Annual Meeting of the American College of Apothecaries, Las Vegas, Nevada, October 16, 1977. Evans RL. "Development of Student Communication Skills: A Current Happening." Presented at the Fifty-Second Annual Meeting, Sixth District, National Association of Boards of Pharmacy ÄÄ American Association of Colleges of Pharmacy, Kansas City, Missouri, October 10, 1977. Evans RL. "Developing a Patient Profile and Patient Consultation Step by Step." Presented at the University of Missouri School of Pharmacy Long Weekend, Four Seasons Lodge, Lake of the Ozarks, Missouri, April 23, 1977. Evans RL. "Community Clinical Practice." Presented at the Annual Convocation of the St. Louis College of Pharmacy, St. Louis, Missouri, March 28, 1977. Evans RL. "Pharmacist/Patient Consultation and the Art of Acquiring a Medication History." Presented at the University of Missouri-Kansas City Annual Alumni Ski Trip, Keystone, Colorado, January, 1977. 19 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMQ 1977 1976 "Clinical Community Pharmacy." Evans RL. Presented at the Region 6 Meeting, Student American Pharmaceutical Association, Kansas City, Missouri, October 8, 1976. Evans RL, Gumbhir AK, Brown WM. "Clinical Practice, A Community Setting." Presented before the Section of Teachers of Clinical Instruction of the American Association of Colleges of Pharmacy, Minneapolis, Minnesota, July 22, 1976. 1974 Evans RL. Medication maintenance interviews by pharmacists in mental health. An audiovisual presentation presented at the Second Annual National Conference for Mental Health Pharmacists, Memphis, TN, June 6-7, 1974. Invited. 1975 Evans RL. "How Pharmacy Interfaces with Mental Health." Presented at the Third Annual National Conference for Mental Health Pharmacists, Gainesville, Florida, June 25, 1975. 1973 Evans RL. "Clinical Pharmacy Service Applications in Mental Health Facilities University of Tennessee." Presented at the National Conference of Mental Health Pharmacists, Georgia Center for Continuing Education, Athens, Georgia, September 5-7, 1973. Evans RL. "Student as a Learner." Presented at The Effective Learning and Instruction Seminar, American Association of Colleges of Pharmacy, The University of Georgia Center for Continuing Education, Athens, Georgia, July 10-13, 1973. 2013 Stevenson, T., Schuessler, J., Sanderson, B., Westrick, S., American Association of Colleges of Pharmacy, Chicago, IL, "Integration of interprofessional education activities within existing pharmacy and nursing courses", Academic, International, PeerReviewed/Refereed, Published in Proceedings, Accepted. (July 2013). 2012 Evans, R, Kelley, Kristi, McDonough, Sharon, American Association of Colleges of Pharmacy Annual Meeting, "Mapping the Future of IPE in Schools Located on Nonmedical campuses," American Association of Colleges of Pharmacy, Orlando, FL. (July 2012). 2011 Liles, Anne, Hester, Elizabeth, Kelley, Kristi, Chung, Allison, Jungnickel, Paul, American Association of Colleges of Pharmacy Annual Meeting, "Development and incorporation of a professionalism assessment into a doctor of pharmacy program," American Association of Colleges of Pharmacy, San Antonio, TX. (July 2011). 2010 Kleppinger, Erika, Donaldson, Amy, Lorenz, Raymond, Parsons, Daniel, American Association of Colleges of Pharmacy Annual Meeting and Seminars, "Development of an Integrated Pharmacy Skills Laboratory Course Sequence [poster presentation]," AACP, Seattle, WA. (July 2010). 20 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMR Professional Activities (Contributed Papers, Abstracts Published): 2009 T. Lynn Stevenson, Lea S. Eiland, Dana G. Carroll, Allison M. Chung, Kristi W. Kelley, Lori B. Hornsby, April Staton, R. Lee Evans. Professional and Personal Development Activities for Fourth Year Student Pharmacists. Annual Meeting of the American Association of Colleges of Pharmacy, Boston, Massachusetts, July 18, 2009. 2008 Lea Eiland, Lee Evans, Erika Kleppinger, Emily Mann, Karen Marlowe, Lynn Stevenson. Auburn University Harrison School Of Pharmacy: A Health Care Provider Helping the Citizens of Alabama Meet the Healthcare Goals of 2015, Annual Meeting of the American Association of Colleges of Pharmacy, Chicago, Illinois, July 22, 2008. Evans RL, Mummert C, Sowers S. A New Facility Enables Transformation in Pedagogy, Society of College and University Planners Southern Regional Conference. New Orleans, Louisiana, November 6, 2008 2003 Krueger JL, Beck DE, Evans RL. Instilling a Patient Care Culture: Engaging All Students and Faculty in the Continuous Care of Community-based Patients, Annual Meeting of the American Association of Colleges of Pharmacy, Minneapolis, MN, July 2003. Evans RL. Pharmacy - ACES Alliance in Alabama, Extension Pharmacy Alliance for Community Health. Annual Meeting of the American Association of Colleges of Pharmacy, Minneapolis, MN, July 2003. 2000 Evans RL, Ramsay KC. Planning for Bricks and Mortar in Support of 21st Century Pharmacy Education, Annual Meeting of the American Association of Colleges of Pharmacy, San Diego, California, July 2000. 1999 Beck DE, Evans RL, Stadler HA, Jungnickel PW. Implementation of a Pharmacy School Continuous Quality Improvement Program: Phases I and II. One Hundredth Annual Meeting of the American Association of Colleges of Pharmacy, Boston, Massachusetts, July 1999. Outcomes Assessment Committee. Implementation of a Pharmacy School Continuous Quality Improvement Program: Phases III: Curricula Outcomes Assessment Using Milestone Exams, One Hundredth Annual Meeting of the American Association of Colleges of Pharmacy, Boston, Massachusetts, July 1999. 1997 Beck DE, Evans RL, Anderson-Harper H, Smith R. Curriculum Work Group. The Auburn Pharm.D. curriculum. Year 1 Implementation, and Vision. American Journal of Pharmaceutical Education. 1996:60:103S. 1996 Faculty Mentor Group. The Auburn University School of Pharmacy Orientation Program: An Authentic Experience. American Journal of Pharmaceutical Education. 1996:60:101S. 21 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMS Evans RL. Achieving Excellence in Experiential Learning In these Dynamic Times: Are We Waiting Until Experiential Learning is Broken to Fix It? (Panelist) Annual Meeting of the American Association of Colleges of Pharmacy, Minneapolis, MN, July 2003. Faculty Mentor Group. Reflections on a pilot faculty-peer mentor team experience. American Journal of Pharmaceutical Education. 1996:60:91S. Evans RL, Stoner SC, Bailey L, Sommi RW, Marken PA. Clinical Response of Refractory Schizophrenic Patients Exposed to Optimal Antipsychotic Serum Concentrations. The 31st Annual ASHP Midyear Clinical Meeting and Exhibits, New Orleans, Louisiana, December 11, 1996. Sommi RW, Evans RL, Stoner SC, Bailey L, Marken PA, Bunker MT. Clinical Response of Refractory Schizophrenic Patients Exposed to Optimal Antipsychotic Serum Concentrations. The 1996 MSHP/KSHP Spring Meeting, Kansas City, Missouri, April 12, 1996. Contributed. 1993 Sommi RW, Marken PA, Evans RL. Therapeutics group discussions: balancing resources and outcome. Presented at the American Association of Colleges of Pharmacy Annual Meeting, San Diego, CA, July, 1993. Contributed. 1992 Sommi RW, Avila J, Pierce CA, Evans RL. Outcome assessment of antipyschotic versus nonantipyschotic treatment of dually diagnosed cocaine users with a psychiatric diagnosis: interim analysis. Presented at 1992 KSHP-MSHP Spring Meeting, Kansas City, MO, May 1992. 1991 Evans RL. Evaluation of alprazolam's effect on panic symptoms and arrhythmias in patients with coexisting mitral valve prolapse and panic disorders. Presented at the Midyear Clinical Meeting of the American Society of Hospital Pharmacists, New Orleans, LA, December 12, 1991. Contributed. Sommi RW, Avila J, Pierce CA, Evans RL. Outcome assessment of antipsychotic versus nonantipsychotic treatment of dually diagnosed cocaine users with a psychiatric diagnosis: interim analysis. Presented at Midyear Clinical Meeting of American Society of Hospital Pharmacists, December 12, 1991. Contributed. Evans RL, Bell HH, Sommi RW, Stanislav SW, Pierce C. Evaluation of alprazolam's effect on panic symptoms and arrhythmias in patients with coexisting mitral valve prolapse and panic disorder. Presented at the Missouri Society of Hospital Pharmacists Spring Meeting, St. Louis, MO, May, 9, 1991. Contributed. 1987 Evans RL, Smith RB, Wells BG, Ereshefsky L, Antal EJ. Use of multicenter trial concepts in completing clinical pharmacy research. Presented at the Federation International Pharmaceutique Meeting in Amsterdam, The Netherlands, September 4, 1987. Contributed. 22 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMT Evans RL, Anderson-Harper H, Banga A, Beck D, et al. The Auburn University School of Pharmacy Orientation Program: An AUthentic Experience. 1996 AACP Meeting, Reno, Nevada, July 17, 1996. Contributed. 1986 Lobeck F, Nelson MV, Evans RL. A comparison of four methods of dosing lithium. Presented at the American Society of Hospital Pharmacists Midyear Clinical Meeting Research Forum, Las Vegas, NV, December 1986. Contributed. Evans RL, Nelson MV, Melethil SK, Hornstra RK, Townsend R, Smith RB. Evaluation of the potential pharmacokinetic interaction of lithium and alprazolam. Presented at the American College of Clinical Pharmacy Annual Meeting, Chicago, IL, July 31, 1986. Contributed. Wells BG, Evans RL, Ereshefsky L, et al. Clinical interactions of alprazolam and imipramine. Presented at the American Psychiatric Association Annual Meeting, New Research Poster Presentations, Washington, D.C., May 12, 1986. Contributed. 1985 Lobeck F, Jethanandani V, Evans RL. Haloperidol Concentrations in a Patient with Mild Chronic Renal Failure. Presented at the 1985 Midyear Clinical Meeting, American Society of Hospital Pharmacists, New Orleans, LA, December 10, 1985. Contributed. 1982 Evans RL, Kinney J. Retrospective analysis of the influence on patient care variables of a lithium clinic coordinated by a clinical pharmacist. Presented at the 1982 Midyear Clinical Meeting, American Society of Hospital Pharmacists, Los Angeles, CA, December 9, 1982. Contributed. 1979 Evans RL, Grundeman B. Selective use of a psychiatric facility for undergraduate clerkships. Presented at the Annual Meeting of the American Association of Colleges of Pharmacy, Denver, CO, July, 1979. Contributed. 1978 Evans RL, Brown WM, Gumbhir AK, Williams S. Development of clinical pharmacy practice models in community pharmacies. Presented at the 1978 American Pharmaceutical Association Annual Convention, Montreal, Quebec, Canada, May 16, 1978. Contributed. Gumbhir AK, Brown WM, Evans RL, Williams S. Evaluation of clinical practice in community pharmacies. Presented at the 1978 American Pharmaceutical Association Annual Convention, Montreal, Quebec, Canada, May 16, 1978. Contributed. 1977 Evans RL. Developing innovative pharmacy services in the community setting. Presented at the Annual Meeting of the American College of Apothecaries, Las Vegas, NV, October 16, 1977. Contributed. Evans RL. Development of student communication skills: a current happening. Presented at the Fifty-Second Annual Meeting, Sixth District, National Association of Boards of Pharmacy--American Association of Colleges of Pharmacy, Kansas City, MO, October 10, 1977. Contributed. 23 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMU Antal EJ, Ereshefsky L, Wells B, Evans RL, Richards RL, Townsend RJ, Smith RB. Multicenter evaluation of the kinetic and clinical interaction of alprazolam and imipramine. Presented at the American Society for Clinical Pharmacology and Therapeutics Annual Meeting, Washington, D.C., March 20, 1986. Contributed. 1976 Gumbhir AK, Brown WM, Evans RL. Methodology for evaluating clinical pharmacy services in community pharmacies. Presented before the Economic and Administrative Science Section of the Academy of Pharmaceutical Sciences, American Pharmaceutical Association Annual Meeting, New Orleans, LA, April 5, 1976. Contributed. Evans RL. Clinical Community Pharmacy. Presented at the Region 6 Meeting, Student American Pharmaceutical Association, Kansas City, MO, October 8, 1976. Contributed. Evans RL, Gumbhir AK, Brown WM. Clinical practice--a community setting. Presented before the Section of Teachers of Clinical Instruction of the American Association of Colleges of Pharmacy, Minneapolis, MN, July 22, 1976. Contributed. 1973 Coleman JH, Evans RL, Rosenbluth SA. Extended clinical roles for the pharmacist in psychiatric care. Presented at the Annual Meeting of the American Society of Hospital Pharmacists, Boston, MA, July 28, 1973. Contributed. Evans RL. University of Tennessee, College of Pharmacy, Doctor of Pharmacy psychiatric rotation. An audiovisual production presented at the American Association of Colleges of Pharmacy Effective Learning and Instruction Seminar. The University of Georgia Center for Continuing Education, Athens, GA, July 10-13, 1973. Contributed. Evans RL. A community pharmacy in psychiatric care: a pilot project. Presented at the 1973 Southeastern Regional Conference for Hospital Pharmacy Teachers and Residents. The University of Georgia Center for Continuing Education, Athens, GA, January 29, 1973. Contributed. Evans RL. Student as a learner. Presented at The Effective Learning and Instruction Seminar, American Association of Colleges of Pharmacy, The University of Georgia Center for Continuing Education, Athens, GA, July 10-13, 1973. Contributed. 1972 Evans RL. Experience with a decentralized pharmacy communication report. Presented at the 1972 Regional Conference of Hospital Pharmacy Teachers and Residents. The University of Georgia Center for Continuing Education, Athens, GA, February 5, 1972. Contributed. Evans RL. Patient prescription records and drug utilization review. Presented for the U.S. Public Health-Supported Short-Term Training Course in Institutional Pharmacy Practice at the Medical University of South Carolina, College of Pharmacy, Charleston, SC, January 9, 1972. Contributed. Professional Activities (Editorial and Reviewer Service): Reviewer and Judge: Best Student Poster, ACCP Annual Meeting, 2013. 24 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTMV Evans RL. Clinical pharmacy service applications in mental health facilities --University of Tennessee. Presented at the National Conference of Mental Health Pharmacists, Georgia Center for Continuing Education, Athens, GA, September 5-7, 1973. Contributed. Reviewer: American College of Clinical Pharmacy Virtual Poster Symposium, 2012-14. Reviewer: American Journal of Pharmaceutical Education, 1981 (2), 1983 (2), 2004 (1), 2006 (1), 2007 (1), 2008 (1), 2013 (2) Member: Editorial Board: Advances in Pharmacy, 2004. Reviewer: The Journal of Pharmacy Technology, 2002. Reviewer: AstraZeneca “Psychiatric Pharmacy Practice” Award 2001, 2003. Reviewer: Journal of the American Pharmaceutical Association, 2000, 2003. Reviewer: American College of Clinical Pharmacy, 1995 (4), 1996 (5), 1997 (7), 1998 (10), 2000 (6), 2006 (Annual and Spring meeting abstracts). Reviewer: American Journal of Health-System Pharmacy, 1998, 2001 (1), 2003 (1) Member: Scanning Team, Auburn Horizon, 1995-1996. Reviewer: American Journal of Hospital Pharmacy, 1982 (1), 1985 (1), 1992 (1), 1993 (1), Member: Astra Clinical Pharmacy Research Award Grant Selection Committee, 1989. Reviewer: Clinical Pharmacy, 1982 (1), 1983 (1), 1985 (1), 1986 (1). Reviewer: Drug Intelligence and Clinical Pharmacy, 1985 (1), 1986 (1), 1987 (1), 1988 (2), 1989 (1), 1990 (1). Reviewer: Pharmacotherapy, 1989 (1), 1999 (1), 2000 (1), 2006 (1), 2007 (1). Reviewer: The Consultant Pharmacist, 1986 (1). Reviewer: ADIS (American Drug Information Services) Press, 1982 (1). Member: Editorial Committee: Psychopharmacy Newsletter, 1982-1987. Reviewer: Hospital Formulary Service Monographs, American Society of Hospital Pharmacists, 1975-77, 1982 (1). Advisor: Smith DL: Medication Guide for Patient Counseling Second Edition. Philadelphia: Lea & Febiger, 1981. Reviewer: Grussing, PG: The Internship Experience: A Manual for Pharmacy Preceptors and Interns. Chicago, 1980. 25 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNM Reviewer: Hospital Formulary, 1987 (1). Reviewer: Applied Therapeutics for Clinical Pharmacists, Third Edition. Chapter 30, Psychosis, Applied Therapeutics. San Francisco, 1980. Reviewer: Patient Care (Journal of Practical Continuing Education for Primary Care Physicians), 1976-77 (1). Reviewer: The Annals of Pharmacotherapy, 1999 (1). Professional Activities (Service to Professional Societies): Alabama Pharmaceutical Association Member: Coalition of Alabama Pharmacy Practitioners, 2007 Member: Board of Trustees, 1994-present. Member: Alabama Commission on Pharmacy, 1994-1998. American Society of Health-System Pharmacists Co-Chair: Ad Hoc Committee on Student Recruitment for Psychopharmacy Residencies and Fellowships, Psychopharmacy Specialty Practice Group, American Society of Hospital Pharmacists, 1990-91. Member: Selection Panel for the Fellowship in Psychiatric Pharmacotherapy. Research and Education Foundation, Inc., American Society of Hospital Pharmacists, 1983-84, 1987, 1989, 1990, 1991, 1992, 1993. Chairman: Ad Hoc Committee on Demand, Psychopharmacy Special Interest Group, Petition for Specialty Recognition to Board of Pharmaceutical Specialties, American Society of Hospital Pharmacists, 1986-89. Member: Task Force on Special Interest Group Program Assessment, American Society of Hospital Pharmacists, 1985-86. Consultant: Psychopharmacy Residency Program Accreditation Application, American Society of Hospital Pharmacists, 1985. Chairman: Nominations Committee, Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1984-85. Immediate Past Chairman: Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1984-85. 26 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNN Faculty Representative: Appointed to the American Society of Hospital Pharmacists Information Network for Students, 1986-90. Member Ex Officio: Advisory Working Group (AWG) on Contemporary Practice, Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1984-85. Member Ex Officio: Advisory Working Group on Education, Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1984-85. Chair: Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1983-84. Chair: Ad Hoc Committee of American Society of Hospital Pharmacists Psychopharmacy Special Interest Group for Drafting Practice Standards for Clinical Pharmacy Specialists in Psychiatry, 1982-84. Chair Designate: Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1982-83. Reviewer: Pharmacy Services in Long-Term Care Facilities. A project of the Council on Education and Manpower, American Society of Hospital Pharmacists, 1981. Chairman: Contemporary Practice Working Group, Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1980-83. Review Panelist: Contributed Papers and Case Proposals, Midyear Clinical Meeting, American Society of Hospital Pharmacists, 1979 (6), 1982 (6). Member: Committee for the Accreditation of Specialty Residencies in Psychiatry. American Society of Hospital Pharmacists, 1979-80, 1980-81. Member: Panel on Class Labeling System being developed for the Food and Drug Administration by the American Society of Hospital Pharmacists (Served as reviewer on Tricyclic Antidepressant monograph), 1976-77. Member: Ad Hoc Steering Committee for the Formation of a Psychiatry Special Interest Group, American Society of Hospital Pharmacists, 1974-75. Member: Counter Task Force on Clinical Residencies, Mental Health Section, American Society of Hospital Pharmacists, 1974-75. American Association of Colleges of Pharmacy Member, Consulting Services Board, 2014 - present. Chair Elect, Chair and Immediate Past Chair, Council of Deans, 2010-13. Chair, Nominations Committee, Council of Deans, 2012-13. 27 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNO Member: Communications Committee, Psychopharmacy Special Interest Group, American Society of Hospital Pharmacists, 1976-78. Member, Membership Model Task Force, 2012. Chair, Executive Vice President and CEO Evaluation Committee. 2011-12. Member, AACP Investment Committee – 2012-13 Dean Facilitator, AACP Academic Leadership Fellows Program, 2007, 2013. Mentor, AACP Academic Leadership Fellows Program, 2005-13. Delegate, AACP House of Delegates, 1995 – present. Member, AACP Strategic Planning Committee – 2011-13 Member, AACP Academic Affairs Committee, 2006-07. Member, AACP/ACPE Joint Task Force on Assessment and Accreditation, 2002-02. Member: AACP Institutional Research Advisory Committee, 2001-03. Chair: Council of Faculties Business Session, American Association of Colleges of Pharmacy, Interim Meeting, Hilton Head, South Carolina, March 3, 1994. Chair: Workshop on Outcomes Assessment in Pharmaceutical Education, Joint Council of Deans/Council of Faculties Session, American Association of Colleges of Pharmacy, Interim Meeting, Hilton Head, South Carolina, February 27, 1994. Chair: Nominations Committee for AACP member of American Council of Pharmaceutical Education, 1993-94. Chair: Section of Teachers of Pharmacy Practice, Planning Commission, American Association of Colleges of Pharmacy, 1991-94. Member: AACP/IAC Subcommittee for the Development of a Pharmaceutical Industry Teaching Module. 1992-present. Chair-elect: Council of Faculties, American Association of Colleges of Pharmacy, 199293. Chair: Quorum Committee, Council of Faculties, American Association of Colleges of Pharmacy, 1992-93. Member: Annual Meeting Program Planning Committee, American Association of Colleges of Pharmacy, 1992-94. 28 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNP Chair: Council of Faculties, American Association of Colleges of Pharmacy, 1993-94. Member: Interim Meeting Program Planning Committee, American Association of Colleges of Pharmacy, 1992-94. Chair: Planning Committee for Training Conference for Clinical Researchers in the Pharmaceutical Sciences. Sponsored by the National Institute of Drug Abuse/American Association of Colleges of Pharmacy / American College of Clinical Pharmacy. Supported by NIDA's Initiative for Underrepresented Scholars in Drug Abuse Research Training Program. Program held March 25-26 and October 19-20, 1992. Member: Section of Teachers of Pharmacy Practice, Planning Commission, American Association of Colleges of Pharmacy, 1991-93. Member: Task Force on Faculty Models, Section of Teachers of Pharmacy Practice, American Association of Colleges of Pharmacy, 1990-91. Chair: Orientation of New and Aspiring Faculty Committee, Council of Faculties, American Association of Colleges of Pharmacy, 1988-89. Member: Nominations Committee for the American Association of Colleges of Pharmacy Section of Teachers of Pharmacy, 1988-89. Panelist: Young Investigator Program Competition, Pharmacy Practice Section, American Association of Colleges of Pharmacy, August 1988. Reviewer: Extramural Course in Pharmacotherapeutics for American Association of Colleges of Pharmacy's Curriculum Resources Consortium, October 28, 1987. Liaison: University of Missouri-Kansas City Section of Teachers of Clinical Instruction, American Association of Colleges of Pharmacy, 1984-88. Chair: Standing Rules Committee of the Council of Faculties, American Association of College of Pharmacy, 1982-83. Faculty Delegate: Annual Meeting, American Association of Colleges of Pharmacy, Kansas City, Missouri, June 27-July 2, 1982. Alternate Faculty Delegate: Annual Meeting, American Association of Colleges of Pharmacy, Scottsdale, Arizona, June 1981. Participant: American Association of Colleges of Pharmacy, Lilly Invitational Conference on Communication Skills Competencies, Kansas City, Missouri, November 6, 1980. Member: Committee on Resources for Teaching Communications Skills in Pharmacy Schools, a Joint Effort of the American Association of Colleges of Pharmacy and Eli Lilly and Company, 1978-80. 29 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNQ Secretary: Council of Faculties, American Association of Colleges of Pharmacy, 198588. Member: Joint National Association of Boards of Pharmacy, American Association of Colleges of Pharmacy Committee to Develop The Internship Experience: A Manual for Pharmacy Preceptors and Interns, 1978-80, 1980-81. Member: Subcommittee for Clerkship/Externship, Academic Affairs Committee, American Association of Colleges of Pharmacy, 1978-79, 1979-80, 1980-81. American Colleges of Clinical Pharmacy Reveiwer: Incidence and Onset of Clozapine-Induced Agranulocytosis, Leukipenia and Neutropenia in Singapore, ACCP Annual Meeting, 2012. Reveiwer: Second Generation Antipsychotic Prescribing Patterns For Veterans With Posttraumatic Stress Disorder Over a Ten-Year-Period, 2012 ACCP Annual Meeting, 2012. Reveiwer: Effects of Pharmacist Drug Regiment Reviews on Physicians’ Compliance with Recommended Laboratory Monitoring Criteria for Psychotropic Medications at a State Supported Living Center, 2012 ACCP Virtual Poster Symposium and 2012 ACCP Annual Meeting, 2012. Reviewer: Factors Associated with Para-Suicidal Behavior Among Depressed Patients in Penang, Malaysia, 2012 ACCP Virtual Poster Symposium, 2012. Reviewer: American College of Clinical Pharmacy, Winter Practice and Research Forum Abstracts, 1991-00. Member: Long Range Planning Committee, American College of Clinical Pharmacy, 1990-92. Reviewer: American College of Clinical Pharmacy Research Institute, Mead Johnson Research Award in CNS Pharmacotherapy, 1989. Reviewer: American College of Clinical Pharmacy Annual Meeting Abstracts, 1987-04. Member: Industrial Relations Committee, American College of Clinical Pharmacy, 1986-87. College of Psychiatric and Neurologic Pharmacists Alabama Liaison for the College of Psychiatric and Neurologic Pharmacists, 2007-2010. Strategic Planning Committee, 2008. Founding Member, 1998. 30 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNR Reviewer: American College of Clinical Pharmacy Focus on New Drugs. 1991. Member, Nominations and Awards Committee, 1998-03. Professional Activities (Other): Member: Alabama Statewide Area Health Education Centers Advisory Council, 2012 – present. Chair: Alabama Project: Implementation of Statewide Diabetic Management Program. 2007-09. Member: Board of Directors for the Institute for Healthcare Leadership. Columbus, Georgia. 2001 – 2003. Pharmacy Think Tank Regarding Rural Health Access, Montgomery, Alabama, 2000. Participant: State of Alabama Department of Public Health Asthma Prevention and Treatment Coalition, Montgomery, Alabama, 2000. State of Alabama Department of Public Health Arthritis Prevention and Treatment Coalition, Montgomery, Alabama, 2000. Rural Alabama and Mississippi Health Professional Training Consortium (The RAM Interdisciplinary Program) Advisory Council, Birmingham, Alabama, 1999-2000. Chair: Subcommittee to Develop Arthritis Training Module for Health Care Practitioners, Alabama Department of Public Health Arthritis Control Program. 2001 Member, Alabama Department of Pubic Health Healthy Alabama 2010, 1999-present. Member, American Council on Pharmaceutical Education Accreditation Site Visit Evaluation Team. 1994, 1996, 1998, 2001, 2003. Co-hosted, Southeastern Schools of Pharmacy Dean’s Symposium, Montgomery, Alabama, June 4-6, 1996. Member, Missouri-Pew Health Professions Partnership, 1993-94. Member, Fellowship Advisory Committee, Marion Merrell Dow Inc., Pharmacoepidemiology and Health Economics Fellowships, 1992-93. Member, Robert Woods Johnson Foundation Practice Sites: State Primary Care Development Strategies Grant Application Steering Committee and Work Group, State of Missouri, Department of Public Health, 1992-93. Member: Drug Utilization Steering Committee, State of Missouri, Department of Social Services, 1988. 31 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNS Governor's Appointee: Alabama Health Care Reform Task Force, 2001 Judge for Resident presentations: Midwest Residents Conference, Hyatt Regency Hotel, Kansas City, MO, April 29-30, 1988. Workshop Leader: Missouri Society of Hospital Pharmacists Conference on Clinical Pharmacy. Osage Beach, MO, November 6-7, 1987. Member, Investigational Review Board, Western Missouri Mental Health Center, 1984-91. Member, Professional Review Committee, Department of Mental Health, State of Missouri. 1983-94 Member, Pharmacy and Therapeutics Committee, Western Missouri Mental Health Center, 1982-88. Chair: Task Force Report on Pharmacy Policy and Procedures in the State of Tennessee Mental Health Facilities, Department of Mental Health Resources, 1974. Member: Committee on Arrangements, Second Annual National Conference of Mental Health Pharmacists, Memphis, TN, June 6-7, 1974. Professional Activities (Consulting): Member, Murty Pharmaceuticals Advisory Board. Lexington, KY, 1996. Member, Janssen CNS Regional Advisory Forum. Chicago, IL, November 11, 1993. Member: National Advisory Committee: Strategies for Applying Drug Use Review (DUR) in a Medicaid Population. Center On Drugs & Public Policy, University of Maryland, Baltimore, MD, 1992-93. Member: The Economic Costs of Anxiety Disorders Committee. Institute for Behavior and Health, Inc., Rockville, MD, 1992-93. Panel Member: Development, Applicability and Consensus Approval of Drug Use Criteria for Alprazolam. Office of Professional Programs, Philadelphia College of Pharmacy and Science. Philadelphia, PN, October 8-9, 1991. Member: The Committee For Responsible Use of Psychiatric Medication. September, 1990-92. Member: Continental Healthcare Systems, Inc. Advisory Board. Kansas City, MO, 1989-date. Consultant: Comprehensive Mental Health Services. Independence, MO, 1989-to date. 32 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNT Member: CME National Advisory Board. Pragmaton. Chicago, IL, 1993. Thesis Committee Consultant: Cheryl A. Burlett, M.S. Candidate, Department of Pharmacy Practice, University of Kansas, Medication Non-Compliance Among Psychiatric Patients--An Inability or Unwillingness to Comply, 1988-90. Consultant: Haldol® Patent Expiration Task Force. McNeil Laboratories, Spring House, Pennsylvania, April 7, 1986. Consultant: Preparation of GAPS grant entitled, Development of Effective Tools to Increase Minority Awareness of Pharmacy as a Career Choice. University of MissouriKansas City School of Pharmacy. Grant funded 1986. Pharmacy Consultant in Mock Medicare Certification Survey for Western Missouri Mental Health Center. Consultant: Pharmacokinetic Principles of Generic Substitution for Psychotropic Agents. Sandoz Pharmaceuticals. Topeka, Kansas, May 8, 1985; Jefferson City, MO, December 1984; Little Rock, AK, June 22, 1984; Denver, CO, January 23, 1986. Member: Professional Advisory Council, Home Health Care of St. Luke's, Inc., Kansas City, MO, 1985-1987. Consultant: Region VII Clinical Advisory Network, Region VII, U.S. Public Health Service, Department of Health & Human Services. 1983-1984. Clinical Pharmacy Consultant to St. Joseph State Hospital, St. Joseph, MO. Clinical Pharmacy Consultant to Prairie View Mental Health Center, Newton, KS. Evaluation of need to establish clinical pharmacy programs, 1981. Consultant: Medicare Surveyor, Public Health Service, ADAMHA, NIMH, Division Branch of Mental Health Service. Member: State of Tennessee Drug Contracts Awards Board. List of medico-legal consultations and expert witness services is available on request. Publications: Cain J, Campbell T, Brennan Congdon H, Hancock K, Kaun M, Lockman P, Evans RL. Pharmacy Student Debt and Return on Investment of a Pharmacy Education. Am J Pharm Educ. 2014: Volume 78, Issue 1, Article 5. Braxton-Lloyd, K, Evans, RL. Reimbursement model for pharmacist-directed medication therapy management. J Am Pharm Assoc. 2012;52:161-169. doi: 10.1331/JAPhA.2012.11228 33 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNU University of Minnesota College of Pharmacy, Evaluation of Proposed Community Pharmacy Clerkship Program. February 1980. Duncan-Hewitt W, Jungnickel P, Evans RL. Development of an office of teaching, learning and assessment in a pharmacy school. Am J Pharm Educ. 2007;71(2):Article 35. Lloyd KB. Thrower RM, Walters NB, Krueger KP, Stamm PL, Evans RL. Implementation of a weight management pharmaceutical care service. Ann Pharmacother 2007 Feb ;41(2):185-192. Epub 2007 Feb 6. (DOI 10.1345/aph.1E466) Evans RL. Patient-Centered Therapy Can Improve Health Care, Reduce Cost. Birmingham News, June 27, 2004. Evans RL. Health care costs can be contained through patient-centered therapy. Published in: AU Report, Auburn University, 2004 May 37(18):2. Stadler H., Evans RL., Beck D, Krueger J. et al. Innovative strategies for communitybased learning at Auburn University. Published in: Learner-Centered Universities for the New Millenium, Rand Afrikans University, Johannesburg, South Africa, July 2001. Beck DE and other members of Outcomes Assessment Committee. Implementation of a pharmacy school continuous quality improvement program: Phase III_Curricula Outcomes Assessment Using Milestone Exams, American Journal of Pharmaceutical Education, 63 (Winter Suppl), 82S (1999). Beck, DE, Evans RL, Anderson-Harper H, Smith R. Curriculum work groupl the Auburn Pharm.D. curriculum; year one implementation and vision. American Journal of Pharmacy Education 1997;61:103S. Evans RL. Will Mentoring Undergraduates Inhibit Society Abandonment? Auburn Horizon, the Newsletter for Higher Education Issues, Auburn University, March/April 1996. Marken PA, McCrary K, Lacombe S, Sommi RW, Evans RL. et al. Preliminary comparison of the predictive and empiric lithium dosing: impact on patient outcome. The Annals of Pharmacotherapy. 1994 Nov;28:1148-1152. Evans RL. Counseling the anxiety patient: aspects in providing pharmaceutical care. Drug Store News. Evans RL. Yellow brick road to pharmacy education’s success. American Journal of Pharmaceutical Education. 1994;58(3):352. Evans RL. Redefining Scholarship: Is it a Faculty Responsibility. American Journal of Pharmacuetical Education 1994;58:238-241. 34 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTNV Evans RL, Stoner SC, Bailey L, Sommi RW, Marken PA. Clinical response or refractory schizophrenic patients exposed to optimal antipsychotic serum concentrations. International Pharmaceutical Abstracts 1996 Nov; 33(21):2314. Evans RL. Achieving the master performance: pharmacy education becoming symphonic. Accepted American Journal of Pharmaceutical Education, Spring 1994. Evans RL. Academe defrosting: reflections of the chair. American Journal of Pharmaceutical Education 1993;57:443-444. Marken PA, Evans RL. A survey of psychopharmacy curriculum and faculty at schools of pharmacy. American Journal of Pharmaceutical Education 1993;57:330-332. Evans RL. Alprazolam-SR: A pharmacokinetic review. Psychiatric Annals, 1993; Oct Supl:8-13. Rice CD, Pierce C, Evans RL. Awareness of precautions to dental treatment in patients with mitral valve prolapse. General Dentistry 1994;42: 77-78. Evans RL, Magarian EO, Meyer SM, Smith GH, Zanowiak P. Academic life: a guide for prospective faculty. American Association of Colleges of Pharmacy. 1990. Antal EJ, Grasela TH, Ereshefsky L, Wells BG, Evans RL, Smith RB. A multi-center study to evaluate the pharmacokinetic and clinical interactions between alprazolam and imipramine. Journal of Pharmacokinetics and Biopharmaceutics 1991;19:93S-100S. Sommi RW, Evans RL, Stanislav SW. The growth of psychopharmacy. Journal of the American Society of Hospital Pharmacists 1991;48:(6):1185-1189. Evans RL, Sommi RW, Marken TA. Social issues surrounding benzodiazepine use. Healthways Communications, Inc., Elizabeth, New Jersey, 1991. Evans RL. Book Review: Appleton WS. Practical Clinical Psychopharmacology, Baltimore, Williams and Williams, 1988. Clinical Pharmacy 1989;8:455-56. Hemstrom CA, Evans RL, Lobeck FG. Haloperidol decanoate: a depot antipsychotic. Drug Intell Clin Pharm 1988;22:290-5. Bailey L, Evans RL. Antipsychotic Agents. Pharmat Inc., Lawrence, KS. 1988. Nelson MV, Tutag-Lehr V, Evans RL. Elevations in thyroid-stimulating hormone in normal subjects after receiving short-term lithium carbonate. Drug Intell Clin Pharm March 1988;22:202-4. Evans RL. A pharmacokinetic profile of hypnotics. In Ermam MK. Insomnia: issues and insights in the 80's. Hospital Practice 1988;23:15-19. Wells BG, Evans RL, Ereshefsky L, et al. Clinical outcome and adverse effect profile associated with concurrent administration of alprazolam and imipramine. Journal of Clinical Psychiatry 1988;49:394-399. 35 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOM Evans RL, Nelson MV, Melethil SK. Evaluation of the potential pharmacokinetic interaction of lithium and alprazolam. J. Clin. Psychopharmacology 1990;10:355-359. Evans RL. Minutes of the council of faculties business meeting: July 13, 1987, Charleston, SC. American Journal of Pharmaceutical Education 1987;51:473. Lobeck F, Nelson MV, Evans RL, Hornstra RK. A comparison of four methods of dosing lithium. Clinical Pharmacy 1987;6:230-233. Grasela TH, Antal EJ, Ereshefsky L, Evans RL, Wells BG, Smith RB. An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug-drug interaction. Clinical Pharmacology and Therapeutics 1987;42:433-41. Evans RL. Selecting a benzodiazepine hypnotic. Hospital Therapy Mar 1986;67-75. Lobeck F, Evans RL. Haloperidol concentrations in an elderly patient with moderate chronic renal failure. Journal of Geriatric Drug Therapy 1986; 1(2):91-97. Evans RL. The psychiatric patient: factors that influence compliance with outpatient therapy. Patient Counseling in Community Pharmacy 1985;4:3-8. Evans RL, Richart N. Psychiatric disorders. In: Wiener MB et al. (eds.), Clinical Pharmacology and Therapeutics in Nursing, 2nd ed. New York: McGraw-Hill, 1985. Erman MK, Evans RL, Kroboth PD. A pharmacokinetic profile of hypnotics: clinical perspectives for hospital pharmacists. Monograph developed from a Symposium conducted by Pragmaton Publication, Arlington Heights, IL. The Upjohn Company, 1984. Evans RL, Khalid S, Kinney JL. Antimalarial psychosis revisited. Archives of Dermatology June 1984;120:765-767. Evans RL, Kinney JL. Toxicities of amoxapine (letter to the editor). Clinical Pharmacy 1983;2:108. Kinney JL, Evans RL. Evaluation of amoxapine--a new tricyclic antidepressant. Clinical Pharmacy 1982;1:417-424. Evans RL. Alprazolam. Drug intelligence and clinical pharmacy 1981;15:633-638. Evans RL. Case studies in psychiatry. Statewide Pharmacy Seminars. Department of Continuing Education, School of Pharmacy, University of Missouri-Kansas City, 1980. Evans RL. Book Review: Johnson FN, Handbook of lithium therapy. Baltimore: University Park Press, 1980. American Journal of Pharmaceutical Education 1980;44:446-447. 36 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTON Erman MK, Kroboth PD, Evans RL. Insomnia in hospitalized patients: clinical perspectives for nurses. Monograph developed from Drug Therapy for Insomnia in Hospitalized Patients Symposium conducted by Pragmaton Publications, Arlington Heights, IL. The Upjohn Company, June 1984. Evans RL, Richart N. Psychiatric disorders. In: Wiener MB et al. (eds.), Clinical pharmacology and therapeutics in nursing. New York: McGraw-Hill 1980. Evans RL. Community care clerkships: the Kansas City experience. In: Proceedings of the 53rd Annual Joint Meeting of the National Association of Boards of Pharmacy and the American Association of Colleges of Pharmacy, St. Louis, MO, October 1978. Evans RL. Development of student communication skills: a current happening. In: Proceedings of the 52nd Annual Meeting of the American Association of Colleges of Pharmacy and the National Association of Boards of Pharmacy, District Six Meeting, Kansas City, MO, October 9, 1977. Evans RL. Tools for monitoring psychotropic drug therapy. Voices-77, Journal of the American Society of Hospital Pharmacists 1977;7(10). Brown WM, Gumbhir AK, Evans RL, Williams S, Jamison ML. A manual for the development of clinical pharmacy practice models in community pharmacies. School of Pharmacy, University of Missouri-Kansas City, January 1977. Evans RL, Kirk RF, Walker PW, Rosenbluth SA, McDonald J. Medication maintenance of mentally ill patients by a pharmacist in a community setting. American Journal of Hospital Pharmacy 1976;33:635-38. Evans RL. Patient monitoring and consultation workbook for self-study learning package. School of Pharmacy, University of Missouri-Kansas City, and School of Pharmacy Component, Western Missouri Area Health Education Center, June 1976. Evans RL. Community pharmacy-based medication maintenance. Proceedings of the National Conference for Mental Health Pharmacists, University of Georgia, Division of Pharmaceutical Services, Athens, GA, 1974. Coleman JH, Evans RL, Rosenbluth SA. Extended clinical roles for the pharmacist in psychiatric care. American Journal of Hospital Pharmacy 1973;30:1143-1146. Grants and Contracts: Braxton-Lloyd, Kimberly (Principal), Evans, R (Supporting), "Development and Implementation of the Alabama State Wellness Center," Sponsored by State Employee Insurance Board (SEIB), Alabama State Funding (only agencies from the State of Alabama such as ADECA or ALDOT), $815,140.00. (June 2010 - Present). Braxton-Lloyd, Kimberly (Supporting), Evans, R (Supporting), Veal, Don (Principal), Agrawal, Prathima (Supporting), Cook, Royrickers (Co-Principal), "Auburn University 37 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOO Evans RL. How pharmacy interfaces with mental health. Proceedings of the Third Annual National Conference for Mental Health Pharmacists, Gainesville, FL, June, 1975. Rural Broadband Initiative," Sponsored by U.S. Department of Commerce, Federal, $4,600,000.00. (July 2010 - December 2012). Alabama Department of Public Health and Centers for Disease Control and Prevention CHEMPACK Grant, 2004, $3,000. Development of a Comprehensive Ability-Based Outcomes Curriculum Using a Consortium Model. FIPSE, U.S. Department of Education, 1998. $179,360. (not funded.) Southwest Alabama Area Health Education Center, Bureau of Health Manpower, Division of Medicine of the United States Public Health Services. (Participant). 19951998. Preparing Pharmacy Graduates to Change Agents as the Profession Transitions to new Professional Business Environments. (Co-investigator) Evans RL. The Procter & Gamble. 1998, $455,272. (not funded.) Auburn Center for Rural Development: Building a Sustainable Economy through Integration, Application, and Connection. (Investigator), Evans RL, USDA. 1997. (not funded.) Development of the office of pharmaceutical care. (Co-Investigator), Evans RL, Brown W, Euler M, Fritsch M, Guy MB, Marken PA, Smith D. Glaxo Pharmaceuticals, 1994, $419,591. A multicenter, double-blind, placebo-controlled parallel group dose ranging study to evaluate the efficacy, safety and tolerability of a new antipsychotic in the treatment of acute schizophrenia. (Co-Investigator) Sommi RW, Anya I, Munro S, Marken PA, Switzer J, Schneiderhan ME, and Evans RL. Boots Pharmaceuticals, 1993, $145,215. An optional, multicenter, open label, long-term study to evaluate the efficacy and safety of an investigational antipsychotic in fixed doses in the treatment of schizophrenia. (CoInvestigator), Sommi RW, Anya I, Munro S, Marken PA, Switzer J, Schneiderhan ME, and Evans RL., Boots Pharmaceuticals, 1993, $166,320. Curricular quality management: developing a strategy for assessing educational outcomes to drive curricular reform. (Co-Investigator), Sommi RW, Marken PA, Evans RL. American Association of Colleges of Pharmacy Grant Award for Pharmacy Schools, 1993, $32,661. (Approved not funded.) Pharmaceutical care practice model for senior adults. John W. and Effie E. Speas Memorial Trust. (Co-Investigator), 1993, $23,000. 38 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOP Pharmaceutical care practice model for senior adults. John W. and Effie E. Speas Memorial Trust. (Co-Investigator) Evans RL, Euler, Marken PA, Fritsch M, Brown W, Sommi RW , 1993, $23,000. Haldol® concentrations and ADRs in black vs. white schizophrenics. Research Institute of the American College of Clinical Pharmacy. (Co-Investigator) 1993 (not funded.) Increasing senior citizen awareness of pharmaceutical care. University Associates, University of Missouri-Kansas City. (Co-Investigator and Coordinator), 1992-93, $20,000. Provisions for a drug information pharmacist. Veterans Administration Medical CenterKansas City. (Co-Principle Investigator), 1991- 94, $25,430. Evaluation of national DUE criteria for alprazolam. Office of Professional Programs, Philadelphia College of Pharmacy and Science. (Co-Principal Investigator), 1992, $2,000. Evaluation of a new antianxiety medication in the elderly. Sandoz Pharmaceuticals. (Co-Investigator), 1992, $113,000, (Contract Study). A prospective, multicenter, open-label study of the long-term safety of an investigational antianxiety agent in outpatients with generalized anxiety disorder. International Clinical Research Consortium. (Co-Investigator), 1992, $80,000, (Contract Study). A double-blind randomized comparison of buspirone, propranolol and placebo in the management of chronic aggression. American Society of Hospital Pharmacists Research and Education Foundation. (Co-Investigator) 1991 (not funded.) Guidebook on the management of dysfunctional behaviors in the nursing home elderly: focus on pharmacological and nonpharmacological methods. Department of Mental Health, State of Missouri. (Co-Investigator), 1992, $7895. University of Missouri-Kansas City community partnerships with health professions education. W.K. Kellogg Foundation. $7.2 million. (Co-Principle Investigator) (not funded.) A multidisciplinary approach to teaching. Public Health Service Model Education Grant Program. $143,000.00 (Yr 1), $126,000.00 (Yr 2). (Co-Principal investigator) (not funded.) Drug information services contract. Truman Medical Center, (Co-Investigator) 1990-ongoing, $18,500. Contract to provide Clinical Coordinator for Department of Pharmacy at Western Missouri Mental Health Center. (Co-Investigator) 1989-93, $14,400. 39 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOQ Awareness of precautions to dental treatment in patients with mitral valve prolapse. University of Missouri-Kansas City, School of Dentistry. Co-principal investigator, 1991. A single blind comparison of pharmacokinetic and empiric lithium dosing methods: effects on clinical course of acute mania. Faculty Research Grant Award, University of Missouri-Kansas City. (Investigator) 1989, $3,990. A placebo controlled dose response study of ci-943 in hospitalized chronic schizophrenic patients in acute exacerbation. Parke Davis Pharmaceutical Company. (Co-principal investigator) 1989, $114,313 (Contract Study). An open-label study of ci-943 in chronic schizophrenic patients. Parke Davis Pharmaceutical Company. (Co-Principal investigator) 1989, $117,767 (Contract Study). Evaluation of the effect of alprazolam on mitral valve prolapse patients exhibiting arrhythmias and panic disorder symptoms. Mid-America Cardiology Associates Foundation. (Co-Principle Investigator) 1987, $15,000 (Protocol designed and written by Co-Principle Investigators). Assessment of clinical response of the recalcitrant schizophrenic patients exposed to optimal antipsychotic serum levels. Weldon Spring Grant. (Principal Investigator) 1986, $18,780. Empiric dosing versus a mathematical dosing method for lithium: examination of dosing accuracy and patient outcome. Faculty Research Grant Award, (Principal investigator) 1985, $3,000. Assessment of pharmaceutical services in Missouri's mental health facilities. State of Missouri Department of Health. Study Completed. (Co-principal Investigator) 1984, $30,000. Evaluation of the potential pharmacokinetic interaction of lithium and alprazolam. The Upjohn Company. Study Completed. (Principal Investigator) 1983-84, $20,000 (Protocol written by principal investigator). A multicenter study to evaluate the pharmacokinetic and clinical interaction between alprazolam and imipramine. The Upjohn Company. Study completed. (Principal Investigator) 1983-84, $10,000 (Multicenter concept initiated by PI; protocol written by PI). Double-blind placebo-controlled comparison of the antidepressant effects of indalpine and imipramine in depressed outpatients. Kendle Research Associates. Drug withdrawn from trial, June 1984. (Principal Investigator) 1983-1985, $59,000 (Contract study). Double-blind comparison of the long-term safety and efficacy of WHR-2520 (indalpine) and imipramine in depressed outpatients. Kendle Research Associates. (Drug withdrawn from trial, June 1984.) (Principal Investigator) 19831985, $29,000 (Contract study). 40 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOR Grant in support of Western Missouri Mental Health Center/University of MissouriKansas City psychopharmacy residency/fellowship research and education programs, The Upjohn Company, 1984, $5,000. Community pharmacy - clinical pharmacy practice models project. U.S. Department of Health, Education, and Welfare. (Assistant Project Director) 1975-78. Public health service grant MH-13694. National Institute of Mental Health. Extended Pharmacy Roles in Psychiatric Care, University of Tennessee, College of Pharmacy, Memphis, Tennessee. (Investigator). 1972-74. Public health service grant MH-12306. National Institute of Mental Health. A multidisciplinary role for a health professional, University of Tennessee, College of Pharmacy. (Investigator) 1971-74. Honors: Saklad Memorial Lecture Award awarded by the College of Psychiatric and Neurologic Pharmacists, May 2002. Pharmacy Leadership Society, Phi Lamda Sigma, University of Missouri-Kansas City, March 1994. Fellow of American Society of Hospital Pharmacists, March 1993. Thomas Garrison Award for Outstanding Contribution to Hospital Pharmacy. Awarded by the Missouri Society of Hospital Pharmacists, Research and Education Foundation, Kansas City, Missouri, May 7, 1992. Recipient of Missouri Society of Hospital Pharmacists Research and Education Foundation Upjohn Poster Award. Missouri Society of Hospital Pharmacists Spring Meeting, St. Louis, Missouri, May 9, 1991. Named as a member of American Council on Pharmaceutical Education Evaluation Team, March 1990. Recommend by APhA as member of JCAHO's clinical indicator panel. April 19, 1988. Selected as member of Mead Johnson's Visiting Faculty Program, 1987-89. Awarded Certificate of Recognition for Conducting Training and Sharing Professional Expertise. Western Missouri Mental Health Center August 28, 1986. University of Kansas City Faculty Fellow, 1985-86. Recommended as possible Candidate for Office of President of American Society of Hospital Pharmacists, 1985, 1986. 41 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOS Invited Participant: Conference on the Social and Economic Costs of Anxiety Disorders in the United States. Hosted by the Institute for Behavior & Health, Inc., Rockville, Maryland, June 11-12, 1992. Outstanding Young Men of America, 1983. Recipient, Innovative Teaching Award, University of Missouri-Kansas City, School of Pharmacy Foundation, 1977-78. Programs Undertaken to Improve Competency: Facilitator: American Association of Colleges of Pharmacy, Academic Leadership Fellowship Program, 2007-08, 2012-13. Attended: Accreditation Council for Pharmacy Education Site visit training. Chicago, IL, April 7-8, 2008. Evans RL. Sexual Harassment in Higher Education, The Current Sate of the Law Workshop. Auburn University Hotel & Conference Center, Auburn, AL, April 8, 1999. Evans RL. Legal Trends in High Education Workshop. Auburn University Hotel and Conference Center, Auburn, AL, March 17, 1999. Auburn University Training and Development Courses: Interpersonal Communication; How to Meet the Media; Listening, Seven Habits; and Thinking Outside the Lines.19992000. Attended: Alabama Pharmacy Association Annual Meeting, 1994-2013. Attended: National Supermarket Pharmacy Conference, Phoenix, Arizona, April 2000. Attended: Technology Bootcamp I, Auburn University School of Pharmacy, September 1999. Attended: Annual International Meeting of the College of Psychiatric & Neurological Pharmacists, 1999, 2003-2008, 2009, 2014. Attended: American Association of Colleges of Pharmacy Interim Meetings, 1990, and 1992-2014. Attended: American Pharmacists Association Annual Meeting, 1997-2005, 2007, 2008, 2009, 2013. Attended: American Association of Colleges of Pharmacy Annual Meetings, 1973-1979 and 1981-2013 Attended: NACDS Annual Meeting, 1998, 2000-2014 Membership: Organizational Systems: A Conference on Authority, Role, and Task. Sponsored by the Central States Center of the A.K. Rice Institute and the University of 42 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOT Attended: APA Mid-Winter Conference, Auburn, Alabama, February 2000-2014. Missouri, March 1-3, 1985; March 7-9, 1986; February 27-28, March 1, 1987; February 12-14, 1988; March 12-14, 1993, March, 1998. Attended: NABP/AACP District III Meeting, 1994-2013. Attended: Academic Leadership Institute. AACP/Glaxo Wellcome. Durham, NC, February 22-26, 1998. Attended: Responsibility Centered Management: Indiana University Experience. Auburn University Hotel and Conference Center, Auburn, AL, January 16, 1998. Attended: AACP/Glaxo New Dean's Leadership Institute, R. David Thomas Center, Duke University Conference, Durham, NC, January 31-February 4, 1993, 1997. American Society of Hospital Pharmacists Midyear Clinical Meeting, 1971-1987 and 1989-2002, 2004, 2007-2009, 2011, 2013. Attended: CASE Conference: Major Gift Fund Raising for Deans, Washington, DC, January 23-24, 1996. Attended: Stephen Covey Workshop: Putting First Things First. Kansas City, MO, March 8, 1994. Attended: Academic Management Symposium, The Case Method in Pharmaceutical Education, American Association of Colleges of Pharmacy, Hilton Head, SC, February 24-26, 1994. Attended: Facilitators’ Meeting for the PHARMACISTS-PATIENT CONSULTATION PROGRAM-UNIT 2: How to Counsel Patients in Challenging Situations. Chantilly, VA, September 29-October 1, 1993. Attended: Academic Management Symposium, The 7 Habits of Highly Effective People. AACP Interim Meeting, Washington, D.C., March 3-5. 1993. Attended: New Clinical Drug Evaluation Unit (NCDEU) Annual Meeting. Sponsored by the National Institute of Mental Health, Pharmacologic and Somatic Treatments Research Consortium, 1984, 1986, 1988, 1989, 1992. Attended: Effective Business Writing, University of Missouri-Kansas City, Kansas City, MO, October 22, 1992. Attended: Kansas/Missouri Society of Hospital Pharmacists Joint Meeting, Kansas City, MO, 1988, 1989, 1991, 1992. Attended: A. K. Rice Institute, Scientific Meeting. St. Louis, MO, May 31-June 3, 1991. 43 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOU Attended: University of Missouri-Kansas City School of Pharmacy Alumni Conference, Kansas City, MO, 1987, 1989, 1991, 1992, 1993. Attended: Biannual Conference for Department Chairpersons and Directors, University of Missouri, Lake Ozark, MO, October 12-13, 1991. Attended: Meeting of Pharmacy Practice Chairs, sponsored by the American Association of Colleges of Pharmacy and held at the American Society of Hospital Pharmacists Midyear Clinical Meeting, Las Vegas, NV, December 2, 1990. Attended: ICI/AACP The Changing Face of Pharmaceutical Education. Carlsbad CA, June 21-24, 1990. Attended: Enhancing Executive Leadership in Schools of Pharmacy, Part III, sponsored by American Association of Colleges of Pharmacy, Monterey, California, February 1517, 1990. Trainee in Psychotherapy, 1985-1989. Attended: Midwestern Conference of Residents, 1986, 1988, 1989. Participated on Advanced Training Staff: Organizational Systems; A Conference on Authority, Role and Task. Sponsored by A.K. Rice Institute and the University of Missouri, Columbia, MO, March 31, April 1-2, 1989. Attended: Enhancing Executive Leadership in Schools of Pharmacy, Part II, sponsored by American Association of Colleges of Pharmacy, Danna Point, CA, March 2-5, 1989. Attended: Visiting Faculty Program in Psychiatry sponsored by Mead Johnson Pharmaceuticals, Scottsdale, AZ, March 9-12, 1989, March 3-6, 1988. Attended: KRCE Workshop: Creativity and Teaching, Rockhurst College, March 2, 1988. Attended: Enhancing Executive Leadership in Schools of Pharmacy, Part I, sponsored by American Association of Colleges of Pharmacy, San Diego, CA, February 18-20, 1988. Organized and participated in: A Preconference A.K. Rice Institute Workshop for University of Missouri-Kansas City School of Pharmacy Faculty. Kansas City, MO, January 30, 1988. Attended: Missouri Society of Hospital Pharmacists Conference on Clinical Pharmacy, Osage Beach, MO, November 6-7, 1987. Attended: University of Missouri Leadership Conference for Academic Administrators. Gravois Mills, MO, October 4-6, 1987. 44 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTOV Attended: National Science Foundation Presentation, University of Missouri-Kansas City, April 7, 1988. Participated: Pharmacy Faculty Visitation Program, Sandoz Pharmaceuticals, East Hanover, NJ, June 22-July 3, 1986. Sponsored by the Pharmaceutical Manufacturers Association. Attended: American Psychiatric Association Annual Meeting, Washington, D.C. May 12, 1986. Attended: Patient Education in the Primary Care Setting Fifth Annual Conference, Kansas City, MO, September 1982. Service to the Community (Selected): Member: Auburn Rotary Club, Auburn, Alabama, 1995- present. Evans, RL. Drug Related Problems: A U.S. Crisis. Auburn Rotary Club, April 13, 2001. Invited. Speaker: Cherokee County Auburn Club, Centre, Alabama, May 16, 2000. Speaker: McIntosh Area Auburn Club Griffin, Georgia Spring BBQ, 1998. Speaker: Montgomery Rotary, April 1, 1998. Speaker: Auburn Club Meeting, Oxford, Alabama. June 17, 1996. Academic Representative, Calhoun-Cleburne Counties Auburn Club Spring Banquet, 1996. Interview with-TV K.C. Spotlight, Responsible Use of Psychiatric Medications, Kansas City, MO, May 15, 1991. Interview with KUSA-TV4, Colorado Today, Responsible Use of Psychiatric Medications, Denver, CO, April 16, 1991. Interview with KMBC-TV 9 on Light Therapy, February 2, 1988. Interview with Bob Werley for KMBC-TV 9. Discussion concerning ongoing research, Assessment of Clinical Response of the Recalcitrant Schizophrenic Patients Exposed to Optimal Antipsychotic Serum Level, February 5, 1987. Interview with Maria Antonio for KMBC-TV 9. Dangers of 'Crack' Use, June 1986. Interview with Bob Werley for KMBC-TV 9. Pharmacy Ethics, Drug Profiles and Choosing a Pharmacist, October 18, 1985. Interview with Bob Werley for KMBC-TV 9. Kiddie Drugs and Their Hazards, 1984. 45 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTPM Interview with WDAF-TV (NBC) Midday, Responsible Use of Psychiatric Medications, June 13, 1991. 46 Expert Report/6731 Revised April 2014 2010-2014 Legal case participation by Roswell Lee Evans 2014 – Juan Carlos Chavez v. John Palmer, Case No. 3:14-cv-110-J-39JBT 2014 – State of Florida v. Paul Augustus Howell, Case No. 1992-22-CFC 2014 – State of Missouri v. Candace D. Richardson, Case No. 13LA-CR00041-01 2014 – State of Florida v. Robert L. Henry, Case No. 87-18628 CF10A 2014 – In RE: Ohio execution protocol, protocol litigation, Case No. 2:11-CV-1016 2014 – Eddie Wayne Davis v. State of Florida, Case No. SC14-1178 2013 – State of Florida v. Thomas Knight, Case No. 04-1980-CF-341-A 2012 – State of Georgia v. Daniel Greene, Indictment No. 91-CR-165 t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSTPO 2010 – Olivia Bury v. Jeffery Weaver, M.D., and Jackson County Orthopedics, State of Missouri