PURDUE One Stamford Forum Stamford, CT 06901 -3431 Via Electronic Transmission: mcgs235@lni.wa.gov May 9, 2007 Gary Franklin, MD, MPH Chair, Agency Medical Directors Group Washington State Department of Labor Industries PO Box 44321 Olympia, WA 98504-4321 RE: Washington State Interagency Guideline on Opioid Dosing for Chronic Non- Cancer Pain Dear Dr. Franklin: This letter is being submitted in response to your recently published Interagency Guideline 0n Opioid Dosing for Chronic Non-Cancer Pain. Purdue Pharma L.P., a privately held pharmaceutical company founded by physicians, is focused on the needs of patients. We are known for our pioneering research on persistent pain, a principal cause of human suffering, and we have extensive experience with clinical issues concerning pain management due to our portfolio of pain medications. We appreciate your efforts to improve patient care and safety when using opioids to treat chronic pain and we share in this goal through extensive educational endeavors and publications. However, we are concerned that some of the restrictions you have placed on opioid prescribing are too stringent and may interfere with access to appropriate and effective pain care for persons suffering from chronic pain. While deaths involving prescription-opioid analgesics constitute a serious public health problem that needs to be prevented, limiting access to opioids for persons with chronic pain is not the answer. More often accidental deaths involving opioid analgesics are due to abuse or misuse of opioids and not due to the therapeutic use of opioids for chronic pain.1 Efforts to prevent drug abuse should not prevent patients from getting the treatment they need. According to your guideline, ?high-dose? opioid treatment is a total daily dose of opioid exceeding 120 mg of oral morphine equivalents. For OxyContin? (oxycodone controlled?release) Tablets, this would mean that doses above 40 mg every 12 hours Sabel J. Draft Washington State injury and violence prevention plan. Draft chapter on poisoning. Revised Jan 3, 2007. Department of Health website. Available at: Accessed March 14, 2007. Dedicated to Physician and Patient Purdue would be considered ?high dose? and should ?rarely? be prescribed, and then only after consultation with a pain specialist. The safety and ef?cacy of OxyContin doses greater than 40 mg every 12 hours in patients with chronic nonmalignant pain has been established in several randomized, controlled clinical trials.2?3?4 Additionally, a recently published study evaluated the use of OxyContin for up to 36 months in 219 patients with osteoarthritic pain, low back pain, and diabetic neuropathic pain. In this long?term study, the daily dose of OxyContin ranged from 10 mg to 293.5 mg (mean 52.5 mg/day). At entry into this study, 8% and 5% of the patients used daily doses of OxyContin in the range more, respectively.5 The clinical rationale for choosing this oral morphine equivalent cutoff dose in the guideline is, therefore, unclear to us. We are concerned that patients requiring more than 40 mg every 12 hours of OxyContin may be undertreated while they are waiting for consultations with pain specialists, as required by the guideline. On your website there is currently a list of 11 pain management specialists in Washington. While we realize this is not an all- inclusive list and that there are probably more pain specialists in Washington, there still may be a limited number of pain specialists available for patients to get the required consultations in a timely manner. Furthermore, the guideline states that in patients taking more than one opioid, the morphine equivalent dose calculation is based on the dose of all opioids prescribed. Patients on modi?ed-release opioids are often prescribed an immediate-release opioid for breakthrough pain on a p.r.n. basis. Patients may use one rescue dose on one day and maybe two rescue doses on another day and on other days may not require any supplemental analgesia. As such, the daily dose of the opioid for morphine equivalent dose calculation may vary from day to day. The stringent opioid dosing recommendations in the guideline may prevent clinicians from prescribing the recommended supplemental analgesia in order to avoid reaching the dose cutoff and, as a result, patients may suffer from undertreatment of incident or breakthrough pain. Additionally, patients may be considered as using morphine equivalents of greater than 120 mg/day based solely on maximum prescribed amount and not on actual use. One of the recommendations for assessing the effects of opioid treatment is the use of urine drug testing. The guideline states that a positive result should be interpreted with caution. We agree that urine drug testing may be useful in patients prescribed opioids to help monitor treatment adherence. However, we would like to emphasize that when using urine testing to assess adherence, negative results should also be interpreted with caution. It is well documented in the medical literature that false-negative immunoassay 2 Markenson JA, Croft J, Zhang PG, Richards P. Treatment of persistent pain associated with osteoarthritis with controlled-release oxycodone tablets in a randomized controlled clinical trial. Clin Pain. 524-535. 3 Gimbel JS, Richards P, Portenoy RK. Controlled?release oxycodone for pain in diabetic neuropathy A randomized controlled trial. Neurology. 4 Zautra Smith BW. Impact of controlled?release oxycodone on ef?cacy beliefs and coping efforts among osteoarthritis patients with moderate to severe pain. Clin Pain. 5 Portenoy RK, Farrar JT, Backonja MM, et al. Long-term use of controlled-release oxycodone for noncancer pain: results of a 3-year registry study. Clin Pain. Purdue screening results may occur in patients being treated with or opioids such as OxyContin.6?7?8?9 This may occur due to the standard cutoff values used in many immunoassays, which may be too high to detect levels of oxycodone in urine, due to minimal cross-reactivity of those immunoassays that are calibrated for morphine and codeine detection with or opioid analgesics. A negative immunoassay result means that at the time of specimen collection, concentrations for the substance tested were below the threshold limits required for a positive result, or substances in the urine are not being detected by the immunoassay due to speci?city of the test. The recommendation in the guideline to discontinue opioids if a patient ?fails? a drug test may result in discontinuation of opioids in adherent patients with legitimate medical need for taking opioid analgesics for chronic pain. The guideline goes further to state that before seeking pain management consultation for morphine equivalent doses above 120 mg/day, one of the conditions that should be met is that the prescriber must ensure that there is no evidence of drug-seeking behaviors. Pseudoaddiction is a term which has been used to describe patient behaviors that may occur when pain is undertreated. [0 It involves the misinterpretation of relief-seeking behaviors due to un- or under-treated pain as drug-seeking behaviors as might be encountered with an abuser. Misunderstanding of these signs may lead the clinician to inappropriately discontinue opioids. In the setting of unrelieved pain, the request for increases in drug dose requires careful assessment, renewed efforts to manage pain, and avoidance of stigmatizing labels. The possibility of pseudoaddiction as the reason for the drug-seeking behaviors is not addressed in the recommendations and instead you imply that these patients should be weaned off of opioids. Part 11 of your guidance mentions that opioid treatment may produce significant adverse effects and this is a reason to discontinue opioids. While we agree that an opioid should be discontinued if it causes signi?cant adverse effects that are not otherwise manageable, this does not preclude a trial of another opioid. Some patients appear to tolerate one opioid better than another and it is often useful to try a different opioid if the first is poorly tolerated. Also, some patients respond better to one opioid versus another. Genetic heterogeneity in the nociceptive pathways and in drug metabolism may contribute to the variability in patient responses to opioid analgesics.1 1?12?13?14 If a patient Elias M. Oxycodone in non-malignant pain: Drug diversion or laboratory error. Pain Clin. 163?164. 7 Von Seggem RL, Fitzgerald CP, Adelman LC, Adelman JU. Laboratory monitoring of OxyContin (oxycodone): Clinical pitfalls. Headache. 8 Fishman SM, Wilsey B, Yang J, Reis?eld GM, Bandman TB, Borsook D. Adherence monitoring and drug surveillance in chronic opioid therapy. Pain Manage. 9 Gourlay DL, Heit HA, Caplan YH. Urine drug testing in clinical practice: dispelling the and designing strategies. Available at: 171 UDT%202006.pdf. Accessed April 5, 2007. 1? American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine. De?nitions Related to the Use of Opioids for the Treatment of Pain, 2001. Galer BS, Coyle N, Pasternak GW, Portenoy RK. Individual variability in the response to different opioids: report of ?ve cases. Pain. ?2 Sinatra R. Opioid analgesics in primary care: Challenges and new advances in the management of noncancer pain. Am Board Fam Med. 2006; 19(2): 1 65-77. Purdue does not appear to obtain reasonable analgesia despite increasing doses of one opioid, many experts recommend that another should be tried.15 Highlighted above are some important clinical issues with chronic opioid therapy that we believe need more focus in the guidelines for opioid dosing. We realize that this is an educational pilot program and would appreciate your consideration of these issues as you assess the clinical effectiveness of this guideline. If you need any additional information or would like to discuss any of these concerns, please feel free to contact me. Sincerely, \w?gl; .. . 3/ Lally Samuel, MS J. David Haddox, Assoc. Director, Medical Services VP, Risk Management Health Policy (203) 588-8165 Enclosure: OxyContin [package insert]. Stamford, CT: Purdue Pharma LP. '3 Lotsch J, Starke C, Liefhold J, Geisslinger G. Genetic predictors of the clinical response to opioid analgesics: Clinical utility and future perspectives. Clin Pharmacokinet. '4 Jackson KC, Lipman AG. Opioid analgesics. In: Lipman AG, ed. Pain Management for Primary Care Clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004. '5 American Pain Society. Guideline for the Management of Pain in Osteoarthritis, Rheumatoid arthritis, and Juvenile Chronic Arthritis. Glenview, IL: American Pain Society; 2002:83,89. HCI TABLETS 10mg 20mg 40mg T?Orng? I'Mm'?ld OTOO3675-E DUPUT 7 WARNING: OxyContin is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine. Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when pre- scribing or dispensing OxyContin in situa- tions where the physician or pharmacist is concerned about an increased risk of mis- use, abuse, or diversion. OxyContin Tablets are a controlled-release oral formulation of oxycodone hydrochlo- ride indicated for the management of moderate to severe pain when a contin- uous, around-the-clock analgesic is need- ed for an extended period of time. OxyContin Tablets are NOT intended for use as a pro analgesic. OxyContin 80 mg and 160 mg Tablets ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. These tablet may cause fatal respiratory depression when administered to patients not previously exposed to opioids. OxyContin TABLETS ARE TO BE SWAL- LOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, OR CRUSHED. TAK- INC BROKEN, CHEWED, OR CRUSHED OxyConlin TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTEN- TIALLY FATAL DOSE OF OXYCODONE. DESCRIPTION Or-ryContin? (oxycodone hydrochloride controlled- release) Tablets are an opioid analgesic supplied tablet for oral administration. The tablet describe the amount of oxycodone pertablet as the hydrochloride salt The structural forrnulaforoxyoodorre hydrochloride is as foliows: MW 351.83 The chemical formula is 4, Sa-epoxy-14- hydroxy-3-methoxy-1 6-one hydrochloride. Oxycodone is a white, odorless powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dis- solves in water (1 in 6 to 7 mL). It is soluble in alcohol (octanol water partition coefficient 0.7). The tablets contain the following inactive ingredients: ammo- nio methacrylate copolymer, hypromellose, lactose, magnesium stearate, polyethylene glycol 400, povidone, sodium hydroxide, sorbic acid, stearyl alcohol, talc, titanium dioxide, and triacetin. The 10 mg tablets also contain: hydrox- ypropyl cellulose. The 20 mg tablets also contain: polysorbate 80 and red iron oxide. The 40 mg tablets also contain: polysorbate 80 and yellow iron oxide. The 80 mg tablets also contain: blue No. 2, hydroxypropyl cellulose, and yellow iron oxide. The 160 mg tablets also contain: FDBC blue No. 2 and polysorbate 80. CLINICAL PHARMACOLOGY Oxycodone is a pure agonist opioid whose principal therapeutic action is analgesia. Other members of the class known as opi- oid agonists include substances such as morphine, hydromorphone, fentanyl, codeine, and hydrocodone. Pharmacological effects of opioid agonists include anxiolysis, eupho- ria, feelings of relaxation, respiratory depres- sion, constipation, miosis, and cough sup- pression, as well as analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non?opi- oid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to anal- gesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depres- sron. Central Nervous System The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. Oxycodone produces respiratory depres- sion by direct action on brain stem respira- tory centers. The respiratory depression involves both a reduction in the responsive- ness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. Oxycodone depresses the cough re?ex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses Iowerthan those usually required for analgesia. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opi- oid overdose but are not pathognomonic pontine lesions of hemorrhagic or ischemic origin may produce similar find- ings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of OxyContin? overdose (See OVERDOSAGE). Gastrointestinal Tract And Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth mus- cle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contrac- tions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, bil- iary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Cardiovascular System Oxycodone may produce release of histamine with or without associated peripheral vasodi- lation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Concentration Efficacy Relationships Studies in normal volunteers and patients reveal predictable relationships between oxy- codone dosage and plasma oxycodone con- centrations, as well as between concentra- tion and certain expected opioid effects, such as pupillary constriction, sedation, overall ?drug effect?, analgesia and feelings of ?relaxation?. As with all opioids, the minimum effective plasma concentration for analgesia will vary 6) widely among patients, especially among patients who have been previously treated with potent agonist opioids. As a result, patients must be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of oxycodone for any individual patient may increase overtime due to an increase in pain, the development of a new pain and/or the development of analgesic toler- ance. Concentration Adverse Experience Relationships OxyContin" Tablets areassociated with typ- ical opioid-related adverse experiences. There is a general relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse experiences such as nausea, vom~ fling, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation is altered by the development of tolerance to opioid-related side effects, and the relation- ship is not clinically relevant. As with all opioids. the dose must be individ- ualized (see DOSAGE AND ADMINISTRA- TTON), because the effective analgesic dose for some patients will be too high to be toler? ated by other patients. PHARMACDKINETICS AND METABOLISM The activity of OxyContin Tablets is primarily due to the parent oxycodone. OxyContin Tablets are designed to provide controlled delivery of oxycodone over 12 hours. Breaking, chewing or OxyConIin Tablets eliminates the controlled delivery mechanism and results intherapid releaseandabsorption of a potentially fatal dose of oxycodone. . Oxycodone release from OxyConIin Tablets is pH independent. Oxycodone is well absorbed from OxyContin Tablets with an oral bioavailability of 60% to 87%. The relative oral bioavailability of OxyContin to immediate-release oral dosage forms is 100%. Upon repeated dosing in normal volunteers in phannacokinetic studies, steady- state levels were achieved within 24-36 hours. Dose proportionalin and/or bioavailability has been established forthe 10 mg, 20 mg, 40 mg, 80mg, and 160 plasma levels (Cmax) and extent of absorption (AUC). Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. The apparent elimination half-life of oxy- codone following the administration of OxyContin? was 4.5 hours compared to 3.2 hours for immediate-release oxycodone. Absorption About 60% to 87% of an oral dose of oxy- codone reaches the central compartment in comparison to a parenteral dose. This high oral bioavailability is due to low pro-sys- temic and/or ?rst-pass metabolism. In nor- mal volunteers, the of absorption is 0.4 hours for immediate-release oral oxycodone. In contrast, OxyContin Tablets exhibit a bipha- sic absorption pattern with two apparent absorption half?lives of 0.6 and 6.9 hours, which describes the initial release of oxy? codone from the tablet followed by a pro- longed release. PIasma Oxycodone by Time Dose proportionality has been established for the tablet for both peak plasma concentra- tions (Cmax) and extent of absorption (AUC) (see Table 1 below). Another study estab- lished that the 160 mg tablet is bioequivalent to 2 80 mg tablets as well as to 4 40 mg for both peak plasma concentrations (Cmax) and extent of absorption (AUG) (see Table 2 below). Given the short half-life of elimina- tion of oxycodone from 0xyContin?, steady- state plasma concentrations of oxycodone are achieved within 24?36 hours of initiation of dosing with OxyContin Tablets. In a study comparing 10 mg of OxyContin every 12 hours to 5 mg of immediate-release oxy- codone every 6 hours, the two treatments were found to be equivalent for AUC and Omar, and similar for 0min (trough) concentrations. There was less ?uctuation in plasma con- centrations for the OxyContin Tablets than for the immediate-release formulation. Plasma Oxycodone By Time Oxycode Concentration (nymL), Log Scale 0123456759101112 HoumFromDodng +10mg +20mg +40mg ?o?aomg?a-1aomgSIn9IoDose 10 mg q12h sroadv?mm TABLE1 Mean coefficient variation] noun Regimen.i AUC Cm Cone Dosage Form [nu-hr/mlif ML [Iris] [nu/ml] Single Dose 10mg0_x?ontin 106120.11 2.7[44.1] na 207.5[35.9] 21.4 [36.6] 3.2 [57.9] no. 40mgth 423.1 [33.3] 39.3 [34.0] 3.1 [77.4] no. 1085.5[32.3] 98.5 [32.1] n.a. MuitipleDose 10mg0xyConlin Tabletsq12tr 103.6[38.6] 15.1 [31.0] 3.2[695] 7.2[48.1] 5mgimmediato- release 95h 99.01362] 15.5[28.6] 1.6 [49.7] 7.4 [50.9] TABLE 2 Mean coefficient variation] from Regimen] Allow 6.- Tax Cone Dosage Form ing-Irr/mLH [rig/ml] [firs] [no/ml] SingIeDose 4x40 mg 0xyContIn* 1935.3 [34.7] 152.0 [28.9] 2.56 na 2x80 mg 1859.3 [30.1] 153.4 [25.1] 2.78 REL na 1x160 mg Moth" 1856.4 [30.5] 156.4 [24.8] 2.54 [36.4] as tfor single-dose for multi- ple-dose *data obtained while volunteers received naltrexone which can enhance absorption. 0xy00ntin? is NOT INDICATED FOB BECTAL ADMINISTRATTDN. Data from a study involv- ing 21 normal volunteers show that OxyConlin Tablets administered per rectum resulted in an AUG 39% greater and a Cmax 9% higher than tablets administered by mouth. Therefore, there is an increased risk of adverse events with rectal administration. Food Effects Food has no signi?cant effect on the extent of absorption of oxycodone from OxyContin. However, the peak plasma concentration of oxycodone increased by 25% when a OxyContin 160 mg Tablet was administered with a high-fat meal. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Oxycodone binding to plasma protein at and a pH of 7.4 was about 45%. Once absorbed, oxycodone is distrib- uted to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone has been found in breast milk (see PRECAU- TIONS). Metabolism Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides. The major circulat- ing metabolite is noroxycodone with an AUC Q9 ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a consid- erably weaker analgesic than oxycodone. Oxymorphone, although possessing anal? gesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. The fonnaiion of oxymorphone, but not norox- ycodone, is mediated by cytochrome P450 206 and, as such, its formation can, in theo- ry, be affected by other drugs (see Drug-Drug Interactions). Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts mea- sured in the urine have been reported as follows: free oxycodone up to 19%; conju- gated oxycodone up to 50%; free oxymor- phone conjugated oxymorphone 14%; both free and conjugated noroxycodone have been found in the urine but not quan- tified. The total plasma clearance was 0.8 L/min for adults. Special Populations Elderly The plasma concentrations of oxycodone are only nominally affected by age, being 15% greater in elderly as compared to young subjects. Gender Female subjects have, on average, plasma oxycodone concentrations up to 25% high- er than males on a body weight adjusted basis. The reason for this difference is unknown. Renal Impairment Data from a pharmacokinetic study involv- ing 13 patients with mild to severe renal dysfunction (creatinine clearance <60 mL/min) show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, and AUC values for oxy- codone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than normal subjects, respectively. This is accompanied by an increase in sedation but not by differ- ences in respiratory rate, pupillary constric- tion, or several other measures of drug effect. There was an increase in We of elim- ination for org/codone of only 1 hour (see PRECAUTIONS). Hepatic Impairment Data from a study involving 24 patients with mild to moderate hepatic dysfunction show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respec- tively, than normal subjects. AUC values are 95% and 65% higher, respectively. Oxymorphone peak plasma concentrations and AUC values are lower by 30% and 40%. These differences are accompanied by increases in some, but not other, drug effects. The t?/2 elimination for oxycodone increased by 2.3 hours (see PRECAUTIONS). Drug-Drug Interactions (see PRECAU- TIONS) Oxycodone is metabolized in part by cytochrome P450 206 to oxymorphone which represents less than 15% of the total administered dose. This route of elimination may be blocked by a variety of drugs certain cardiovascular drugs including amio- darone and quinidine as well as anti-depressants). However, in a study involv- ing 10 subjects using quinidine, a known inhibitor of cytochrome P450 206, the phar- macodynamic effects of oxycodone were unchanged. Pharmacodynamics A single-dose, double-blind, placebo? and dose-controlled study was conducted using OxyContin? (10anal- gesic pain model involving 182 patients with moderate to severe pain. Twenty and 30 mg of OxyContin were superior in reducing pain compared with placebo, and this difference was statistically significant. The onset of analgesic action with OxyContin occurred within 1 hour in most patients following oral administration. CLINICAL TRIALS A double-blind placebo-controlled, fixed- dose, parallel group, two-week study was conducted in 133 patients with chronic, mod- erate to severe pain, who were judged as hav- ing inadequate pain control with their current therapy. In this study, 20 mg OxyContin q12h but not 10 mg OxyContin q12h decreased pain compared with placebo, and this differ- ence was statistically significant. INDICATIONS AND USAGE OxyContin Tablets are a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around- the-clock analgesic is needed for an extend- ed period of time. OxyContin is NOT intended for use as a pm analgesic. Physicians should individualize treatment in every case, initiating therapy at the appro- priate point along a progression from non- opioid analgesics, such as non-steroidal anti-in?ammatory drugs and acetaminophen to opioids in a plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality (formedy known as the Agency for Health Care Policy and Research), the Federation of State Medical Boards Model Guidelines, or the American Pain Society. OxyContin is not indicated for pain in the immediate postoperative period (the first 12-24 hours following surgery), or if the pain is mild, or not expected to persist foran extended period of time. OxyContin is only indicated for postoperative use if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extend- ed period of time. Physicians should indi- vidualize treatment, moving from parenter- al to oral analgesics as appropriate. (See American Pain Society guidelines.) CONTRAINDICATIONS OxyContin? is contraindicated in patients with known hypersensitivity to oxycodone, or in any situation where opioids are contraindi- cated. This includes patients with significant respiratory depression (in unmonitored set- tings or the absence of resuscitative equip- ment), and patients with acute or severe bronchial asthma or hypercarbia. OxyContin is contraindicated in any patient who has or is suspected of having paralytic ileus. WARNINGS OXYCONTIN ARE TO BE SWAL- LOWED WHOLE, AND ARE NOT TO BE BRO- KEN, CHEWED OR CRUSHED. TAKING BRO- KEN, CHEWED OR CRUSHED OXYCONTIN TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXYCODONE. OxyContin 80 mg and 160 mg Tablets ARE FOR USE IN PATIENTS C9 ONLY. These tablet may cause fatal respiratory depression when admin- istered to patients not previously exposed to opioids. OxyContin BO mg and 160 mg Tablets are for use only in opioid-tolerant patients requiring daily oxycodone equivalent dosages of 160 mg or more for the 80 mg tablet and 320 mg or more for the 160 tablet. Care should be taken in the pre- scribing of these tablet Patients should be instructed against use by indi- viduals other than the patient for whom it was prescribed, as such inappropriate use may have severe medical conse- quences, including death. Misuse, Abuse and Diversion of Opioids Oxycodone is an opioid agonist of the mor- phine-type. Such drugs are sought by drug abusers and people with addiction disor- ders and are subject to criminal diversion. Oxycodone can be abused in a manner sim? ilarto other opioid agonists, legal or illicit This shodld be considered when prescribing or dispensing OxyContin in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. OxyConttn has been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. These prac- tices will result in the uncontrolled delivery of the opioid and pose a signi?cant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION). Concerns about abuse, addiction, and diver- sion should not prevent the proper man- agement of pain. Heatthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for informa- tion on how to prevent and detect abuse or diversion of this product. Interactions with Alcohol and Drugs of Abuse Oxycodone may be expected to have addi- tive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. DRUG ABUSE AND ADDICTION OxyContin1D is a mu-agonist opioid with an abuse liability similar to morphine and is a Schedule II controlled substance. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is sub- ject to criminal diversion. Drug addiction is characterized by comput- sive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. "Drug-seeking? behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of of?ce hours, refusal to under- go appropriate examination, testing or refer- ral, repeated ?loss? of prescriptions, tam- pering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). ?Doctor shopping? to obtain additional pre- scriptions is common among drug abusers and people suffering from untreated addic- tion. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tol- erance and of physical depen- dence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combina- tion with other substances. OxyContin, like other opioids, has been divert- ed for non-medical use. Careful record-keep- ing of prescribing information, including quan- tity, frequency, and renewal requests is strong- ly advised. Proper assessment of the patient, proper pre- scribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. OxyContin consists of a dual-polymer matrix, intended for oral use only. Abuse of the crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients, especially talc, can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvu- lar heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Respiratory Depression Respiratory depression is the chief hazard from oxycodone, the active ingredient in OxyContin? as with all opioid agonists. Respiratory depression is a particular problem in elderly or debilitated patients, usually fol- lowing large initial doses in non-tolerant patients, or when opioids are given in con- junction widr other agents that depress respi- ration. Oxycodone should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pul- monate, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pro-existing respiratory depression. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opi- oid analgesics should be considered, and opioids should be employed only under care- ful medical supervision at the lowest effec- tive dose. Head Injury The respiratory depressant effects of opioids include carbon dioxide retention and sec- ondary elevation of cerebrospinal fluid pres- sure, and may be markedly exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure.0xycodone produces effects on pupitlary response and consciousness which may obscure neuro- logic signs of further increases in intracra- nial pressure in patients with head injuries. Hypotensive Effect OxyContin may cause severe hypotension. There is an added riskto individuals whose abil- ityto maintain blood pressure has been com- promised by a depleted blood volume, orafter concurrent administration with drugs such as phenothiazines or other agents which com- promise vasomotor tone. Oxycodone may produce orthostatic hypotension in ambulato- ry patients. Oxycodone, like all opioid anal- gesics ofthe morphine-type, should be admin- istered with caution to patients in circulatory shock since vasodilation produced by the drug may further reduce cardiac output and blood pressure. PRECAUTIONS General Opioid analgesics have a narrow therapeu- tic index in certain patient populations, espe- cially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia out- weigh the known risks of respiratory depres? sion, altered mental state, and postural hypotension. Use of OxyContin? is associated with increased potential risks and should be used only with caution in the following conditions: acute alcoholism; adrenocortical insuf?ciency Addison?s disease); CNS depression or coma; delirium tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic The administration of oxycodone may obscure the diagnosis or clinical course In patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Interactions with other CNS Depressants OxyContin should be used with caution and started in a reduced dosage (1/3 to 1/2 of the usual dosage) in patients who are concur- rently receiving other central nervous system depressants including sedatives or hyp- notics, general anesthetics, phenothiazines, other tranquilizers, and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in com- bination with the usual doses of OxyContin. Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics penta- zocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal in these patients. Ambulatory Surgery and Postoperative Use OxyContin is not indicated for pre-emptive analgesia (administration pre-operatively for the managemem of postoperative pain). OxyContin is not indicated for pain in the immediate postoperative period (the first 12 to 24 hours following surgery) for patients not previously taking the drug, because its safety in this setting has not been established. OxyContin is not indicated for pain in the postoperative period if the pain is mild or not expected to persist for an extended period of lime. OxyContin is only indicated for postoper- ative use if the patient is already receiving the drug prior to surgery or if the postop- erative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate (See American Pain Society guidelines). Patients who are already receiving OxyContinP Tablets as part of ongoing analgesic therapy may be safely continued on the drug if appropriate dosage adjust- ments are made considering the proce- dure, other drugs given, and the temporary changes in physiology caused by the sur- gical intervention (see DOSAGE AND ADMINISTRATION). OxyContin and other morphine-like opioids have been shown to decrease bowel motil- ity. Ileus is a common postoperative com- plication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postOperative patients receiving opioids. Standard supportive therapy should be implemented. Use in Pancreatic/Biliary Tract Disease Oxycodone may cause spasm of the sphinc- ter of Oddi and should be used with caution In patients with biliary tract disease, includ- ing acute pancreatitis. Opioids like oxy- codone may cause increases in the serum amylase level. Tolerance and Physical Dependence Tolerance Is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease pro- gression or other external factors). Physical dependence is manifested by withdrawal after abrupt discontinuation of a drug or upon administration of an antagonist Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syn- drome is characterized by some or all of the following: restlessness, Iacrimation, rhi- norrhea, yawning, perspiration, chills, myal- gia, and mydriasis. Other also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, Insomnia, nausea, anorexia, vom- iting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly dis- continued (see DOSAGE AND ADMINIS- TRATION: Cessation of Therapy). Information for Patients/Caregivers If clinically advisable, patients receiving OxyContin Tablets ortheir caregivers should be given the following information by the physician, nurse, pharmacist, or caregiver: 1. Patients should be aware that OxyContin Tablets contain oxycodone, which is a mor- phine-like substance. 2. Patients should be advised that OxyContin Tablets were designed to work property only if swallowed whole. OxyContin Tablets will release all their contents at once if broken, chewed, or crushed, resulting in a risk of fatal overdose. 3. Patients should be advised to report episodes of breakthrough pain and adverse experi- ences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. 4. Patients should be advised not to adjust the dose of OxyContin? without consulting the pre- scribing professional. 5. Patients should be advised that OxyContin may impair mental and/or physical ability required forthe performance of potentially haz- ardous tasks driving, operating heavy machinery). 6. Patients should not combine OxyContin with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death. 7. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regard- ing the effects of analgesics and other drug use during pregnancy on themselves and their unborn child. 8. Patients should be advised that OxyContin is a potential drug of abuse. They should pro- tect it from theft, and it should never be given to anyone otherthan the individual for whom it was prescribed. 9. Patients should be advised that they may pass empty matrix ?ghosts? (tablets) via colostomy or in the stool, and that this is of no concern since the active medication has already been absorbed. 10. Patients should be advised that if they have been receiving treatment with OxyContin for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the OxyContin dose, ratherthan abrupt- ly discontinue it, due to the risk of precipitat- ing withdrawal Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication. 11. Patients should be instructed to keep OxyContin in a secure place out of the reach of children. When OxyContin is no longer needed, the unused tablets should be destroyed by ?ushing down the toilet. Use in Drug and Alcohol Addiction OxyContin is an opioid with no approved use in the management of addictive disorders. its proper usage in individuals with drug or alco- hol dependence, either active or in remission, is for the management of pain requiring opi- oid analgesia. Drug-Drug Interactions Opioid analgesics, including OxyContin?, may enhance the neuromuscular blocking action of skeletal muscle relaxants and pro- duce an increased degree of respiratory depression. Oxycodone is metabolized in part to oxy- morphone via cytochrome P450 206. While this pathway maybe blocked by a variety of drugs certain cardiovascular drugs including amiodarone and quinidine as well as antidepressants), such block- ade has not yet been shown to be of clini- cal significance with this agent. Clinicians should be aware of this possible interac- tion, however. Use with CNS Depressants OxyContin, like all Opioid analgesics, should be started at ?la to V2 of the usual dosage in patients who are concurrently receiving other central nervous system depressants includ- ing sedatives or hypnotics, general anes- thetics, phenothiazines, centrally acting anti- emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or come may result. No specific interaction between oxycodone and monoamine oxidase inhibitors has been observed, but caution in the use of any opi? oid in patients taking this class of drugs is appropriate. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of oxycodone to evaluate its car- cinogenic potential have not been conduct- ed. Oxycodone was not mutagenic in the fol- lowing assays: Ames Salmonella and E. coli test with and without metabolic acti? vation at doses of up to 5000 pg, chro- mosomal aberration test in human lym- phocytes in the absence of metabolic acti- vation at doses of up to 1500 pg/mL and with activation 48 hours after exposure at doses of up to 5000 ,ug/mL, and in the in vivo bone marrow micronucleus test in mice (at plasma levels of up to 48 ,ug/mL). Oxycodone was clastogenic in the human chromosomal assay in the pres- ence of metabolic activation in the human chromosomal abenation test (at greaterthan or equal to 1250 pg/mL) at 24 but not 48 hours of exposure and in the mouse lym- phoma assay at doses of 50 pg/mL or greater with metabolic activation and at 400 jug/mL or greater without metabolic activation. Pregnancy Teratogenic Effects Category B: Reproduction studies have been performed in rats and rabbits by oral administration at doses up to 8 mg/kg and 125 mg/kg, respec- tively. These doses are 3 and 46 times a human dose of 160 mg/day, based on mg/kg basis. The results did not reveal evidence of harm to the fetus due to oxycodone. There are, however, no adequate and well-con- trolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearty needed. Labor and Delivery OxyContinm is not recommended for use in women during and immediately priorto labor and delivery because oral opioids may cause respiratory depression in the newborn. Neonates whose mothers have been taking oxycodone chronically may exhibit respira- tory depression and/or withdrawal symp- toms, either at birth and/or in the nursery. Nursing Mothers Low concentrations of oxycodone have been detected in breast milk. Withdrawal symp? toms can occur in breast-feeding infants when maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving OxyContin because of the possibility of sedation and/or respiratory depression in the infant. Pediatric Use Safety and effectiveness of OxyContin have not been established in pediatric patients below the age of 18. It must be remembered that Oxycontin Tablets cannot be crushed or divided for administration. Geriatric Use In controlled pharmacokinetic?studies'i?n elderly subjects (greater than 65 years) the clearance of oxycodone appeared to be slightiy reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% (see PHARMACOKINETTCS AND METABOLISM). Of the total number of subjects (445) in clinical studies of OxyContin, 148 were age 65 and older (including those age 75 and older) while 40 were age 75 and older In clinical trials with appropriate ini- tiation of therapy and dose titration, no unto- ward or unexpected side effects were seen in the elderly patients who received OxyContin. Thus, the usual doses and dos- ing intervals are appropriate for these patients. As with all opioids, the starting dose should be reduced to 1/s to 1/2 of the usual dosage in debilitated, non?tolerant patients. Respiratory depression is the chief hazard in elderty or debilitated patients, usu- ally following large initial doses in non-tolerant patients, or when opioids are given in con- junction with other agents that depress res~ piration. Laboratory Monitoring Due to the broad range of plasma concen- trations seen in clinical populations, the vary- ing degrees of pain, and the development of tolerance, plasma oxycodone measurements are usually not helpful in clinical manage- ment. Plasma concentrations of the active drug substance may be of value in selected, unusual or complex cases. Hepatic Impairment A study of OxyContin in patients with hepat- ic impairment indicates greater plasma con- centrations than those with normal func- tion. The initiation of therapy at 1/3 to 1/2 the usual doses and careful dose titration is warranted. Renal impairment In patients with renal impairment, as evi- denced by decreased creatinine clearance (<60 mL/min), the concentrations of oxy- codone in the plasma are approximately 50% higher than in subjects with normal renal function. Dose initiation should follow a conservative approach. Dosages should be adjusted according to the clinical situation. Gender Differences In pharmacokinetic studies, opioid-naive females demonstrate up to 25% higher aver- age plasma concentrations and greater fre- quency of typical opioid adverse events than males, even after adjustment for body weight. The clinical relevance of a difference of this magnitude is low fora drug intended for chronic usage at individualized dosages, and there was no male/female difference detected for ef?cacy or adverse events in clin- ical trials. ADVERSE REACTIONS The safety of OxyContin? was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received OxyContin in total daily doses ranging from 20 mg to 640 mg per day. The average total daily dose was approximately 105 mg per day. Serious adverse reactions which may be associated with OxyContin Tablet therapy in clinical use are those observed with other opi- oid analgesics, including respiratory depres- sion, apnea, respiratory arrest, and (to an even lesser degree) circulatory depression, hypotension, or shock (see OVERDOSAGE). The non-serious adverse events seen on initiation of therapy with OxyContin are typ- ical opioid side effects. These events are dose-dependent, and their frequency depends upon the dose, the clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent include: constipation, nausea, som- nolence, dizziness, vomiting, pruritus, headache, dry mouth, sweating, and asthe- nra. In many cases the frequency of these events during initiation of therapy may be mini- mized by careful individualization of starting dosage, slow titration, and the avoidance of large swings in the plasma concentrations of the opioid. Many of these adverse events will cease or decrease in intensity as OxyContin therapy is continued and some degree of tolerance is developed. Clinical trials comparing OxyContin with immediate-release oxycodone and placebo revealed a similar adverse event profile between OxyContin and immediate-release oxycodone. The most common adverse events reported by patients at least once during therapy were: TABLE 3 Immediate- OxyContin Release Placebo (n=227) (n=225) (n=45) (96) Constipation (23) (26) (7) Nausea (23) (27) (11) Somnolence (23) (24) (4) Dizziness (13) (16) (9) Pmr?ttus (13) (12) (2) Vomiting (12) (14) (7) Headache (7) (B) (7) Div Mouth (6) (7 (2i Aslhenia (6) (7) Sweating (5) (6) (2) The following adverse experiences were reported in OxyContin?-treated patients with an incidence between 1% and In descending order of frequency they were anorexia, nervousness, insomnia, fever, con- fusion, diarrhea, abdominal pain, dyspep- sia, rash, anxiety, euphoria, postural hypotension, chills, twitching, gastritis, abnor- mal dreams, thought abnormalities, and hic- cups. The following adverse reactions occurred in less than 1% of patients involved in clin- ical trials or were reported in postmarketing experience. General: accidental injury, chest pain, facial edema, malaise, neck pain, pain, and symp- toms associated with either an anaphy? lactic or anaphylactoid reaction Cardiovascular: migraine, syncope, vasodi? Iation, ST depression Digestive: eructation, flatulence, gastrointestinal disorder, increased appetite, nausea and vomiting, stomatitis, ileus Hemic and Metabolic and Nutritional: dehydration, edema, hyponauemia, peripheral edema, syn- drome of inappropriate antidiuretic hormone secretion, thirst Nervous: abnormal gait, agitation, amne- sia, depersonalizaticn, depression, emo- tional lability, hallucination, hyperkinesia, hypesthesia, hypotonia, malaise, paresthe- sia, seizures, speech disorder, stupor, tinni- tus, tremor, vertigo, withdrawal with or without seizures Respiratory: cough increased, pharyngitis, voice alteration Skin: dry skin, exfoliative dermatitis, urticaria Special Senses: abnormal vision, taste per- version Urogenital: amenorrhea, decreased libido, dysuria, hematuria, impotence, polyuria, uri- nary retention, urination impaired DVERDOSAGE Acute overdosage with oxycodone can be manifested by respiratory depression, som- nolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death. Deaths due to overdose have been report- ed with abuse and misuse of OxyContin?, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicat- ed that the risk of fatal overdose is further increased when OxyContin is abused con- currently with alcohol or other CNS depres- sants, including other opioids. In the treatment of oxycodone overdosage, primary attention should be given to the re- establishment of a patent airway and insti- tution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pul- monary edema accompanying overdose as indicated. Cardiac arrest or may require cardiac massage or defibrillation. The pure opioid antagonists such as nalox- one or nalmefene are specific antidotes against respiratory depression from opioid overdose. Opioid antagonists should not be administered in the absence of clinically sig- nificant respiratory or circulatory depres- sion secondary to oxycodone overdose. In patients who are physically dependent on any opioid agonist including OxyContin, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence The severity of the withdrawal produced will depend on the degree of phys- ical dependence and the dose of the antag- onist administered. Please see the prescribing information for the speci?c opioid antagonist for details of their proper use. DOSAGE AND ADMINISTRATION General Principles OXYCONTIN IS AN OPIOID AGONIST AND A SCHEDULE Il CONTROLLED SUB- STANCE WITH AN ABUSE LIABILITY SIM- ILAR TO MORPHINE. OXYCODONE, LIKE MORPHINE AND OTHER OPIOIDS USED IN ANALGESIA, CAN BE ABUSED AND IS SUBJECT TO CRIMINAL DIVERSION. OXYOONTIN TABLETS ARE TO BE SWAL- LOWED WHOLE AND ARE NOT TO BE BROKEN, OHEWED, OR ORUSHED. TAK- ING BROKEN, OHEWED, OR ORUSHED TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXY- OODONE. One OxyContin 160 mg tablet is com- parable Io two 80 mg tablets when taken on an empty stomach. With a high-fat meal, however, there is a 25% greater peak plasma concentration fol- lowing one 150 mg tablet. Dietary cau- tion should be taken when patients are initially titrated to 160 mg tablets (see DOSAGE AND ADMINISTRATION). Patients who are not currently taking opioid analgesics should generally be started on the lowest appropriate dose (see DOSAGE AND ADMINISTRATION: Initiation of Therapy). in treating pain it is vital to assess the patient regularly and systematically. Therapy should also be regularly reviewed and adjusted based upon the patient?s own reports of pain and side effects and the health profes- sional?s clinical judgment. OxyContin Tablets are a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around- the?clock analgesic is needed for an extend- ed period oi time. The controlled-release nature of the formulation allows OxyContin to be effectively administered every 12 hours (see CLINICAL PHAR- AND METABOLISM). While symmetric (same dose AM and PM), around-the-clock, q12h dosing is appropri- ate for the majority of patients, some patients may benefit from asymmetric (different dose given in AM than in PM) dosing, tailored to their pain pattern. It is usually appropriate to treat a patient with only one opioid for around- the-clock therapy. Physicians should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the American Pain Society and the Federation of State Medical Boards Model Guidelines. Healthcare professionals should follow appropriate pain management princi- ples of careful assessment and ongoing monitoring (see BOXED WARNING). Initiation of Therapy It is critical to initiate the dosing regimen for each patient individually, taking into account the patients prior opioid and non-opioid analgesic treatment. Attention should be given to: 7 (1 the general condition and medical status otihe patient; (2) the patients opioid exposure and opioid tol? erance (ii any); . (3) the daily dose, potency, and kind of the anal- gesic(s) the patient has been taking; (4) the reliability of the conversion estimate used to calculate the dose of oxycodone; (5) special safety issues associated with con- version to OxyContin? doses at or exceeding 160 mg q12h (see Special Instructions for OxyContin 80 mg and 160 mg Tablets); and (6) the balance between pain control and adverse expenences. Care should be taken to use low initial doses of OxyContin in patients who are not already opioid-tolerant, especially those who are receiving concurrent treatment with mus- cle relaxants, sedatives, or other CNS active medications (see PRECAUTIONS: Drug- Drug Interactions). Experience indicates a reasonable starting dose of OxyContin for patients who are tak? ing non-opioid analgesics and require continuous around-the-clock therapy for an extended period of time is 10 mg q12h. If a non-opioid analgesic is being provided, it may be continued. OxyContin should be individually titrated to a dose that provides adequate analgesia and minimizes side effects. For initiation of OxyContin therapy for patients previously taking opioids, the conversion ratios from Foley, KM. 1985; 313284- 95], found below, are a reasonable starting point, although not veri?ed in well-controlled, multiple-dose trials. 1. Using standard conversion ratio estimates (see Table 4 below), multiply the mg/day of the pre- vious opioids by the appropriate multiplication factors to obtain the equivalent total daily dose of oral oxycodone. 2. When converting from oxycodone, divide the 24-hour oxycodone dose in half to obtain the twice a day (q12h) dose of OxyContin. 3. Round down to a dose which is appropriate for the tablet available. 4. Discontinue all other around?the-clock opioid drugs when OxyContin therapy is initiated. 5. No ?xed conversion ratio is likelyto be satisfactory in all patients especially patients receiving 18198001- old doses. The recommended doses shown in Tabie 4 are only a starting point, and close obser- vation and frequent titration are indicated until patients are stable on the new therapy. TABLE 4 Multiplication Factors for Converting the Daily Dose of Prior Opioids to the Daily Dose of Oral Oxycodone" (Mg/Day Prior Opioid Factor: Mg/Day Oral Oxycodone) Oral Prior Parenteral Prior Opioid Opioid Oxycodone 1 Codeine 0.15 Hydrocodone 0.9 Hydromorphone 4 20 Levorphanol 7.5 15 Meperidine 0.1 0.4 Methadone 1.5 3 Morphine 0.5 3 *To be used only for conversion to oral oxy- codone. For patients receiving high-dose parenteral opioids, a more conservative conversion is warranted. For example, for high-dose parenteral morphine, use 1.5 instead of 3 as a multiplication factor. In all cases, supplemental analgesia should be made available in the form of a suitable short-acting analgesic. OxyContina can be safely used concomitantly with usual doses of non-opioid analgesics and analgesic adjuvants, provided care is taken to select a proper initial dose (see PRECAUTIONS). Conversion from Transdermal Fenianyl to OxyContin Eighteen hours following the removal of the transdermal fentanyl patch, OxyContin treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative oxy- codone dose, approximately 10 mg q12h of OxyContin, should be initially substitut- ed for each 25 [Jg/hl' fentanyl transdermal patch. The patient should be followed closely for early titration, as there is very limited clinical experience with this con- version. Managing Expected Opioid Adverse Experiences Most patients receiving opioids, especially those who are opioid-naive, will experience side effects. Frequently the side effects from OxyContin are transient, but may require evaluation and management. Adverse events such as constipation should be anticipated and treated aggressively and prophylacti- cally with a stimulant laxative and/or stool softener. Patients do not usually become tolerant to the constipating effects of opioids. Other opioid-related side effects such as sedation and nausea are usually self-limited and often do not persist beyond the first few days. If nausea persists and is unaccept- able to the patient, treatment with antiemet- ics or other modalites may relieve these and should be considered. Patients receiving OxyContin? may pass an intact matrix ?ghost? in the stool or via colostomy. These ghosts contain little or no residual oxycodone and are of no clinical consequence. Individualization of Dosage Once therapy is initiated, pain relief and other opioid effects should be frequently assessed. Patients should be titrated to adequate effect (generally mild or no pain with the regular use of no more than two doses of supplemen- tal analgesia per 24 hours). Patients who experience breakthrough pain may require dosage adjustment or rescue medication. Because steady-state plasma concentra- tions are approximated within 24 to 36 hours, dosage adjustment may be carried out every 1 to 2 days. ltis most appropriate to increase the q12h dose, not the dosing frequency. There is no clinical information on dosing intervals shorterthan q12h. As a guideline, except for the increase from 10 mg to 20 mg qt 2h, the total daily oxycodone dose usually can be increased by 25% to 50% of the cur- rent dose at each increase. if signs of excessive opioid-related adverse experiences are observed, the next dose may be reduced. If this adjustment leads to inadequate analgesia, a supplemental dose of immediate-release oxycodone may be given. Alternatively, non-opioid analgesic adjuvants may be employed. Dose adjust- ments should be made to obtain an appro- priate balance between pain relief and opi- oid-related adverse experiences. If significant adverse events occur before the therapeutic goal of mild or no pain is achieved, the events should be treated aggressively. Once adverse events are under control, upward titration should con- tinue to an acceptable level of pain control. During periods of changing analgesic require- ments, including initial titration, frequent con- tact is recommended between physician, other members of the healthcare team, the patient and the caregiver/family. Special Instructions for OxyContin 80 mg and 160 mg Tablets (For use in opioid- tolerant patients only.) OxyContin 80 mg and 160 mg Tablets are for use only in opioid-tolerant patients requiring daily oxycodone equivalent dosages of 160 mg or more for the 80 mg tablet and 320 mg or more for the 160 mg tablet. Care should be taken in the prescribing of these tablet Patients should be instructed against use by individuals other than the patient for whom it was prescribed, as such inap- propriate use may have severe medical consequences, including death. One OxyContin? 160 mg tablet is com- parable to two 80 mg tablets when taken on an empty stomach. With a high-fat meal, however, there is a 25% greater peak plasma concentration following one 160 mg tablet. Dietary caution should be taken when patients are initially titrat- ed to 150 mg tablets. Supplemental Analgesia Most patients given around-the-clock ther- apy with controlled-release opioids may need to have immediate-release medication available for exacerbations of pain orto pre- vent pain that occurs predictably during cer- tain patient activities (incident pain). Maintenance of Therapy The intent of the titration period is to estab- lish a patient-specific q12h dose that will maintain adequate analgesia with accept- able side effects for as long as pain relief is necessary. Should pain recurthen the dose can be incrementally increased to re-estab- lish pain control. The method of therapy adjustment outlined above should be employed to re-establish pain control. During chronic therapy, especially for non- cancer pain the continued need for around-the-clock opioid therapy should be reassessed periodically every 6 to 12 months) as appropriate. Cessation of Therapy When the patient no longer requires therapy with OxyContin Tablets, doses should be tapered gradually to prevent signs and symp- toms of withdrawal in the physically depen- dent patient. Conversion trom OxyContin to Parenteral Opioids To avoid overdose, conservative dose con version ratios should be followed. SAFETY AND HANDLING OxyContin Tablets are solid dosage forms that contain oxycodone which is a controlled sub- stance. Like morphine, oxycodone is controlled under Schedule II of the Controlied Substances Act. OxyContin has been targeted fortheft and diversion by criminals. Heatthcare professionals should con- tact lheir State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. HOW SUPPLIED OxyContin? (oxycodone hydrochloride con- trolled?release) Tablets 10 mg are round, unscored, white-colored, convex tablets imprinted with 00 on one side and 10 on the other. They are supplied as follows: NDC 59011-100?10: child-resistant closure, opaque plastic bottles of 100 NDC 59011-100-20: unit dose packaging with to individually numbered tablets per card; two cards per glue end carton OxyContin? (oxycodone hydrochloride con- trolled-release) Tablets 20 mg are round, unscored, pink-colored, convex tablets imprinted with DC on one side and 20 on the other. They are supplied as follows: NDC 59011 -103-10: child-resistant closure, opaque plastic bottles of 100 NDC 59011-103-20: unit dose packaging with to individually numbered tablets per card; two cards per glue end carton OxyContin? (oxycodone hydrochloride con- trolled-release) Tablets 40 mg are round, unscored, yellow-colored. convex tablets imprinted with 00 on one side and 40 on the other. They are supplied as follows: NDC 59011-105-10: child-resistant closure, opaque plastic bottles of 100 NDC 59011-105-20: unit dose packaging with to individually numbered tablets per card; two cards per glue end carton OxyContin? (oxycodone hydrochloride con- trolled-release) Tablets 80 mg are round, unscored, green-colored. convex tablets imprinted with 00 on one side and 80 on the other. They are supplied as follows: NDC 59011-107-10: child-resistant closure, opaque plastic bottles of 100 N00 59011?107-20: unit dose packaging with 10 individually numbered tablets per card; two cards per glue end carton 0xyContin? (oxycodone hydrochloride con- trolled-release) Tablets 160 mg are caplet- shaped. unscored, blue-colored. convex tablets imprinted with 00 on one side and 160 on the other. They are supplied as fol- lows: NDC 59011-109?10: child-resistant closure, opaque plastic bottles of 100 N08 59011-109-20: unit dose packaging with 10 individually numbered tablets per card; two cards per glue end carton Store at excursions permitted between Dispense in tight. light-resistant container. Healthcare professionals can telephone Purdue Pharma?s Medical Services Department (1-888-726-7535) for infor- mation on this product. CAUTION DEA Order Form Required. ?2002. 2004. 2005. 2007. Purdue Pharma LR Purdue Pharma LE. Stamlord. CT 06901-3431 U.S. Patent Numbers 5.266.331; 5.508.042; 5.549.912; and 5.656.295 January 15. 2007 0T00367J-E 00P017