THE UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION } Petition to Require Purdue Pharma L.P. to } } Revise the Labeling of OxyContin® Tablets to Strengthen Warnings of the Greater Potential for } } Developing Side Effects and Adverse Drug Reactions Due to Prescribing Dosing } Frequencies in Excess of the Recommended } Guidelines } ~~~~~~~~~~~~~~~~~~ } Submitted by: Richard Blumenthal Attorney General State of Connecticut January 23, 2004 Docket No. CITIZEN PETITION Richard Blumenthal, the Attorney General for the State of Connecticut ("Petitioner"), submits this Petition to request action by the Food and Drug Administration ("FDA") regarding the narcotic analgesic OxyContin® Tablets ("OxyContin"). Specifically, the undersigned requests that the Commissioner of the FDA require Purdue Pharma L.P. ("PPLP") to take various actions to expressly warn prescribers of the increased occurrence of side effects or potentially serious adverse reactions resulting from prescribing OxyContin at dosing intervals less than the manufacturer's recommended every 12 hours. The action proposed includes: strengthening the drug's ''black box" warning statement, supplementing the labeling with additional bolder warnings, and initiating a "Dear Healthcare Professional" letter. In the alternative, the Petitioner asks this agency to disseminate these warnings through a Safety Alert, Public Health Advisory, Talk Paper, or Urgent Notice. Information obtained by the Petitioner and included herein from PPLP and its internal documents, as well as from independent sources and medical experts, establishes that (1) the incidence of prescribing OxyContin at dosing intervals more frequent than the recommended every 12 hours ("ql2h") has risen, on average, to approximately 20% of all prescriptions written, a practice due, at least in part, to a fundamental misunderstanding by healthcare providers of OxyContin's unique drug delivery system, which differs from the delivery systems of other opioids; (2) certain patients receiving OxyContin at intervals more frequent than q12h are more at risk of developing side effects and potentially serious adverse reactions due to the phannacologic action of the drug; and (3) the increase in the number of doses beyond the recommended two per day increases the potential for diversion of the drug for illicit use. 2 This Petition is submitted pursuant to § 4 (d) of the Administrative Procedure Act, 5 U.S.C. § 553 (e), 21 C.F.R. §§ 10.20, 10.30, and pursuant to§§ 331(a) and 352(a) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. §§ 301, et seq. I. INTRODUCTION Millions of Americans suffer from pain related to disease or injury, and chronic pain is a significant health issue in American society, affecting an estimated 50 million people. In fact, pain is a primary reason people seek medical care, with some experts estimating that almost 80% of all visits to healthcare providers are related to pain. Among ~e myriad of treatment options available in the United States to treat patients in pain, and the one that has grown the most in medical acceptance and popularity, is the use of opioid analgesics. Prior to the mid- l 990s the long-term use of opioids was primarily limited to the treatment of cancer patients. In the mid-1990s, due, in part, to educational and research initiatives financed by the American Pain Society, American Geriatric Society, and drug manufacturers, including PPLP, the critical importance of pain management and treatment was recognized and the use of opioids was determined to be acceptable and appropriate for the treatment of nonmalignant chronic pain, i.e., back pain, osteoarthritis, migraines, and postoperative pain. Now, pain is recognized as the "Fifth Vital Sign," and pain management has become a required part of all treatment plans at accredited healthcare facilities. This positive development is largely due to the implementation of new standards by the Joint Commission on Accreditation of Healthcare Organizations, an independent, not-for-profit organization that evaluates and accredits nearly 17,000 healthcare organizations and programs in the United States. 3 The recognition of pain as a reason for medical treatment, and the acceptance of new fonns of pain treatment, have improved and enhanced the lives of countless Americans. They have given new physical and emotional comfo1t and opportunity to people whose quality of life is diminished by severe chronic pain. With the growth in the healthcare community's awareness of the importance of pain management and the significant role that opioids play in treating both malignant and nonmalignant pain, the number of prescriptions for opioid analgesics predictably and dramatically increased. For example, from 1996 to 2000 the number of prescriptions ilispensed for all common opioid analgesics (such as codeine, hydrocodone, morphine and hydromorphone) 1 increased by approximately 23% and the sales of all opioid analgesics in the United States increased from approximately $2.9 bilJion to $4.2 billion, an increase of almost 45%. In 2003, sales of opioid analgesics in the United States are estimated to be slightly more than $5 billion. PPLP is a mid-sized pharmaceutical manufacturer engaged in research, development, production, marketing and licensing of both prescription and over-the-counter medicines and hospital products. PPLP is part of a privately held international consortia of companies operating in 18 countries, which includes Mundipharma (operating in Europe, Asia, Australia and South America), Napp Pharmaceutical Group in the U.K., and Purdue Phanna of Canada. PPLP is recognized for its proprietary controlled-release technologies and other innovative drug delivery systems, and markets the leading oral formulation of oxycodone, OxyContin. P~LP also markets MS-Con tin, a leading controlled-release version of morphine, and i's expected, sometime in 2004, to launch Palladone™ Capsules, the first once-a-day oral hydrornorphone preparation. 1 Drug Enforcement Administration, Office of Diversion Control," Working to Prevent the Diversion and Abuse of OxyContin," June 12, 2001. 4 OxyContin was approved for distribution by the FDA in 1995 and first marketed in 1996. The drug is a controlled-release formulation of oxycodone derived from the opium alkaloid, thebaine, and, at the time of its launch, was indicated for the management of "moderate to severe pain where use of an opioid analgesic is appropriate for more than a few days." Unlike Percocet or Percodan, which are short-acting opioid combination analgesics usually administered every 4 to 6 hours, OxyContin was developed and approved as a controlled-release formulation intended to deliver a consistent level of pain relief over a 12 hour period. It is the opinion of many healthcare practitioners in the pain management area that controlled-release analgesics provide stable pain relief for the patient and avoid the peaks and troughs in the relief and pain cycle often associated with the shorter acting drugs. OxyContin is currently approved in I Omg, 20mg, 40mg, 80mg and 160mg tablet strengths.2 When prescribed and used correctly in accordance with approved manufacturer and FDA guidelines, OxyContin is widely regarded as an effective tool in managing moderate to severe chronic pain around-the-clock for an extended period of time. As OxyContin sales increased dramatically3, so did the abuse and diversion of the drug. The illicit market for OxyContin stems, in large part, from the ability of addicts or abusers to circumvent the drug's controlled-release formulation by crushing and chewing the tablet, or by 2 PPLP has voluntarily withdrawn the l 60mg strength tablet from the market due to concerns of overdose resulting from illicit use. While OxyContin is presently the only controlled-release oxycodone painkiller available for use in the United States, there are other controlled-release opioid analgesics containing different opioids that are available for pain management and which compete with OxyContin. Among the other controlled-release opioid analgesics that compete with OxyContin are: MS-Contin (Purdue Pharma), Oramorpb SR (Elan), Avinza (Ligand), Duragesic (Janssen), and at least one generic controlled-release morphine product (Endo). In light of a recent federal court decision, it is likely that a generic version ofOxyContin will be introduced at some point in 2004. See Purdue Pharma L.P., et al. v. Endo Pharmaceuticals, Inc., Ruling, (S.D.N.Y., Jan. 5, 2004) (Stein, USDJ). 3 According to the Drug Enforcement Administration, prescriptions for OxyContin during the years 1996 through 2000 increased by 1,800%. Drug Enforcement Administration, Office of Diversion Control, "Working to Prevent the Diversion and Abuse of OxyContin," June 12, 2001. 5 dissolving it in water and injecting it, thereby releasing all the oxycodone in the tablet into the bloodstream at once, causing what is commonly described as a "heroin-like high." In April 2001, in response to escalating reports of abuse, diversion and potential misuse of OxyContin, and in an effort to stem these concerns, the FDA met with PPLP executives to address these developments, as well as the agency's belief that "doctors did not have the right perception about the use of OxyContin ... that prescribing behavior is too casual," the consequence of this trend being that "prescribing of OxyContin is creeping into a whole population of people where it doesn't belong."4 During the meeting, an FDA official suggested that PPLP needed a new educational and marketing message that "discloses the risks" and "does not promote off-label use ... " since the "danger is not conveyed very strongly" in the promotional materials.5 As a result, in July 2001 the dmg's indication was revised to "the management of moderate to severe pain when a continuous around-the-clock opioid is needed for an extended period of time." Additional revisions and strengthened warnings to the OxyContin labeling included a "black box" warning advising patients and prescribers, among other things: (i) that the drug should not be crushed, chewed or broken due to the potential for a rapid release and absorption of a "fatal dose" of oxycodone, (ii) that it is not intended for PRN use, (iii) that it has an abuse liability similar to morphine and (iv) that prescribers and pharmacists should be cautious in prescribing or dispensing the drug where there is "an increased risk of misuse, abuse or diversion." These efforts, as the FDA stated on its internet website at the time of the revisions, were "intended to change prescription practices as well as increase the 4 5 PPLP Minutes ofFDA/PPLP Meeting, April 23, 2001. FDA Meeting Minutes ofFDAIPPLP Meeting, April 23, 2001. 6 physicians' focus on the potential for abuse, misuse, and diversion ... and lessen the chance that OxyContin will be prescribed inappropriately ...." (emphasis added). 6 On January 17, 2003, the FDA issued a Warning Letter to PPLP citing the company for disseminating misleading OxyContin advertisements in the October and November 2002 issues of the Journal ofthe American Medical Association. Among the FDA's stated reasons for its letter was PPLP's failure to present and disclose "critical" safety information in its OxyContin promotions. Following this Warning Letter, the Petitioner initiated an investigation into PPLP's marketing practices and requested that the company produce documents responsive to specific document requests. PPLP voluntarily complied with this request and cooperated with Petitioner's investigation, producing more than forty-thousand documents over a three month time period. In addition to reviewing documents produced by PPLP, the Petitioner also conducted interviews of fonner PPLP sales representatives, interviewed healthcare professionals and reviewed other publicly available information. On September 8, 2003, the Petitioner met with senior PPLP executives to discuss concerns arising out of the investigation. Petitioner met again with PPLP executives on November 17, 2003. In conjunction with both of these meetings PPLP voluntarily provided the Petitioner with additional documents and infonnation relevant to the issues discussed. 7 6 FDA Talk Paper, July 25, 2001. PPLP appears to have a completely different interpretation of the purpose of the drug's 2001 revised indication. The FDA believed the old indication was "too broad" and the drug was "not appropriate for ambulatory and post-operative use ...." PPLP Minutes ofFDAIPPLP Meeting, April 23, 2001. As a result, the FDA and PPLP negotiated changes to the labeling in July 2001 which were intended to "change prescription practices." FDA Talk Paper, July 25, 2001. Although the FDA may have believed the revisions narrowed the indication, PPLP, in its 2002 OxyContin budget plan clearly felt the labeling changes "expanded the indication .... This broad labeling is likely to never again be available for an opioid seeking FDA approval. This may give OxyContin Tablets a competitive advantage." 2002 OxyContin Budget Plan. Further, PPLP reiterated in its plan that one of its primary "communication objectives" for 2002, was to "[b]roaden Oxycontin Tablets usage in the management of pain" and "stressed" one area to focus was "post-operative pain.... " 2002 OxyContin Budget Plan. 7 See discussion infra, Section V. 7 As will be discussed in the Statement of Factual Grounds, the Petitioner's investigation has determined that a relatively large percentage of prescriptions for OxyContin are being written off-label at dosing intervals not recommended in the manufacturer's guidelines or in the FDA approval, a practice which may adversely affect the health of certain patients who are prescribed the drug in this malUler. fu addition, Petitioner's investigation revealed that such offlabel prescribing may not only affect patient health, but may also contribute to increased availability of the drug for illicit purposes. Evidence developed through Petitioner's investigation revealed that many prescribers are prescribing the drug at dosing intervals that are shorter than the manufacturer's ql2h recommended guideline, apparently unaware that in doing so, they may be placing their patients at risk of incurring increased incidence of side effects and possibly serious adverse reactions due to the pharmacologic action of this controlled-release drug when prescribed in this manner. For example, increasing a patient's total daily dose of oxycodone by prescribing an additional dose of OxyContin, once every eight hours ("q8h"), rather than increasing the q 12h dose, will cause a more rapid accumulation of oxycodone, thereby possibly raising oxycodone plasma concentrations above the level deemed safe in clinical tests. This prescribing practice is not within the manufacturer's OxyContin dosing guidelines approved by the FDA. The evidence also demonstrates that the trend of prescribers writing OxyContin scripts for dosing intervals shorter than q12h has been increasing; and that PPLP has become quite concerned that prescribing in this manner could, and for certain at-risk patients - - probably did - - lead to increased patient side effects and adverse reactions, a consequence that is not explicitly stated in the drug's labeling. PPLP has also become concerned that increasing the number of OxyContin 8 doses beyond the recommended two daily doses increases the potential that the additional doses may be diverted for illicit use. For the reasons that follow, Petitioner believes that practitioners and the public have not been fully informed of the potential risks associated with these practices. The purpose of this Petition, therefore, is to bring this evidence to the Commissioner and request that the FDA fully consider the information and, if deemed appropriate, take the action proposed below by the Petitioner or such other steps as are necessary to ensure that prescribers receive complete, adequate warnings of the health ramifications of this potentially problematic prescribing practice, so that they can factor the increased risks into their prescription decisions and provide more fully informed treatment to their patients who need effective and appropriate pain relief. 8 II. ACTION REQUESTED 21 C.F.R. § 201.57 requires drug manufacturers to include certain information in their labeling, including warnings, precautions and the identification of adverse reactions associated with the use of the drug. 9 The Federal Food, Drug and Cosmetic Act provides that a drug shall be deemed to be "misbranded" if its labeling is "false or misleading in any particular." 21 U.S.C. § 352 (a). Pursuant to 21 C.F.R. § 201 .57 and 21 U.S.C. § 352 (a), the Petitioner requests that the Commissioner act immediately to require PPLP to inform all prescribers of the potential risks associated with prescribing OxyContin at dosing intervals less than q 12h. Such immediate action, as requested below, must include the dissemination of specific warning information to 8 Full and clear disclosure of the potential for adverse reactions takes on even greater urgency following a recent court decision invalidating certain of PPLP's patents related to OxyContin due to inequitable conduct before the Patent and Trademark Office, leading to the potential for generic versions of the drug to be made available for sale in the near future. See n.2, supra. 9 A prescription drug's " labeling" includes "all written, printed or graphic matter accompanying an article at any time while such article is in interstate commerce or held for sale after shipment or delivery in interstate commerce." 21 C.F.R. § 1.3. 9 healthcare professionals related to appropriate prescribing of OxyContin and the revision of the current safety labeling of OxyContin, including: A. Revising the Black Box Label The following warning should be required to be added to the labeling of OxyContin: WARNING: (The following is in addition to the warnings currently contained in the labeling) The recommended dosing guideline for OxyContin is ql2h. The side effect profiles and other clinical documentation only support this dosing schedule. Increasing the patient's total daily oxycodone dose by adding one or more doses is not within the recommended dosing gui4elines. Dosing OxyContin at intervals of q8h or shorter may cause an increase in oxycodone plasma concentrations and thereby increase the risks of side effects such as euphoria and sedation. Proper dosing further minimizes the potential for abuse and diversion. B. Strengthened Warning and Safety Labeling Increasing the patient's total daily dose of oxycodone by prescribing OxyContin at intervals shorter than q 12h will increase oxycodone concentration in the plasma to levels that may exceed the levels depicted in the OxyContin labeling (Plasma Oxycodone by Time). 10 Titrating the patient in this manner by increasing the dosing frequency to q8h or more frequently will cause acute successive increases in plasma concentrations of oxycodone and is not within the recommended dosing guidelines. The increased plasma concentrations will be most acute in the time period it takes for the patient to achieve steady-state. Further, increasing the daily dose of oxycodone by increasing the dosing frequency will alter the side effect and adverse reaction profiles contained in the OxyContin package insert. Titrating the patient's total daily dose of oxycodone by shortening the interval between 10 See infra Table 2, Section IIl.C.2. 10 administration to less than q l 2h for the 80mg and 160mg doses of OxyContin further increases the already heightened risks attendant with prescribing these dosage strengths. This information should be added to relevant sections of the labeling, including but not limited to, the following sections: Warnings, Special Populations, Precautions, Adverse Reactions, Dosage and Administration - General Principles, Individualization of Dosage and Special Instrnctions for OxyContin 80mg and 160mg Tablets. In addition, adverse drug reactions associated with this dosing schedule identified and reported during post-approval use of OxyContin should be included in a Post-Marketing Experience section added to the drug's labeling. C. The Issuance of a " Dear Healthcare Professional" Letter PPLP should be required immediately to inform all prescribers of controlled substances in the United States about the potential risks of prescribing OxyContin at dosing intervals shorter than q1 2h. D. FDA Notice to Healthcare Practitioners and the Public. In addition, or as an alternative, to action by PPLP, the FDA should disseminate these warnings through a Safety Alert, Public Health Advisory, Talk Paper or Urgent Notice. ill. A. STATEMENT OF FACTUAL GROUNDS The Pharmacokinetics of OxyContin and the Science of q12h OxyContin is a controlled-release opioid that was designed to deliver a consistent level of oxycodone for 12 hours. The drug's patented delivery system - - the "AcroContin™" system 11 - - is constructed scientifically for q 12h or biphasic absorption. Biphasic absorption describes a 11 PPLP's internal documents stress that it is essential for prescribers to understand the difference between OxyContin's "AcroContin™ delivery system," which is intended for q12h administration, and MS-Contin's "Contin" delivery system, where the "duration of action is 8-12 hours." OxyContin q 12'1 Workshop, (July 25, 2001) (hereinafter "OxyContin qi 2h Workshop"). 11 two-stage process by which the oxycodone in the OxyContin tablet is dissolved and absorbed. The two stages comprise an initial rapid release stage, where oxycodone from the tablet's surface is absorbed and onset of analgesia occurs within 42 minutes to one hour, followed by a prolonged stage where the oxycodone is slowly diffused through the tablet's matrix and absorbed. According to PPLP, this means that within the first two hours oftalcing the.drug, 38% of the available oxycodone in each tablet is absorbed into the bloodstream, with the remaining 62% delivered slowly over the next 10 hours. OxyContin's labeling specifically provides that the elimination half-life of OxyContin - the time it talces to decrease the plasma concentration of the oxycodone found in each tablet to half its value - - is 4.5 hours. The expected elimination half-life of a drug is a central component of the time it will take a patient to reach equilibrium, which is essentially the point at which the amount of the drug entering the body equals the amount being eliminated or excreted. This process is generally referred to as "steady-state." When the amount of a patient's total daily dose of a drug is increased, the concentration of that drug in the plasma will continually climb until steady state is reached, at which point the drug concentration level will again flatten out or plateau. Generally, it takes five half-lives to reach steady state; hence, the longer the elimination half-life of a drug, the longer it takes to reach steady-state and, accordingly, the greater the concentration of the drug in the plasma will increase before it plateaus. Similarly, if the total daily dose of a drug is increased at the same time that the dosing interval is decreased, there will be even greater accumulation of the drug in the plasma because more drug is being absorbed and metabolized than is being excreted. This will result in higher drug concentrations in a compressed period of time. This process will continue until equilibrium or steady-state is again reached. If, however, drug concentrations exceed the therapeutic 12 threshold (the point at which maximum tolerated side effects occur), then the patient runs the risk of experiencing potentially significant adverse events. The goal of any long-term drug administration regimen - - such as an OxyContin regimen - - is to achieve a steady state plateau that results in a relatively consistent and stable level of oxycodone concentration, and thus, pain relief. According to PPLP, clinical testing of OxyContin demonstrated that steady state levels were reached within 24-36 hours of the initiation of dosing. The OxyContin package insert contains cautionary language in two primary areas that are particularly relevant to this Petition. First, prescribers are advised to be especially vigilant when prescribing the 80mg and 160mg doses to patients not previously exposed to opioids, as these strengths could cause fatal respiratory depression. Second, prescribers are advised that plasma concentrations of oxycodone may be even greater for patients in certain populations whose ability to eliminate the drug from their systems might be compromised to some degree. This is particularly relevant to the elderly (over 65 years), and patients with renal (kidney) or hepatic (liver) impairment who may, as a result, have higher oxycodone plasma concentrations than other patient populations. As long as initiation of therapy and dosing are "appropriate," however, the insert continues, no ''untoward or unexpected side effects" were seen in these populations. 12 There are 29 references in the current OxyContin package insert that support q12h dosing. All of the existing absorption data and blood level information contained therein is based on q l 2h dosing principles and side effect profiles, which indicate that "sedation" often does not persist beyond a few days and that the occurrence of "euphoria" was reported in less than 5% of patients participating in the clinical trials that supported the FDA's approval of 12 OxyContin™ package insert. ©2001 Puxdue Phanna L.P. Stamford, CT 06901. 13 OxyContin. 13 Equally important, PPLP's internal documents indicate that "100% of patients in clinical trials were dosed at q l 2h" and the package insert states "[t ]here is no clinical information on dosing intervals shorter than q12h." In short, all of the PPLP recommended prescribing guidelines for OxyContin, safety information and the FDA approval for marketing are based on q 12h dosing. As the Director of the FDA' s Controlled Substance Staff stated when discussing the drug's 12 hour controlled-release formulation, "the safety of the drug is based on taking the drug exactly as intended." B. 14 PPLP's Ability to Track OxyContin Prescriptions Drug manufacturers use increasingly sophisticated data collection techniques and resources to track prescription generation. Through these sources, a company such as PPLP can determine which drugs are being dispensed from pharmacies in a given locale or even which drugs a specific physician prescribes. The data and other information gleaned from the prescriptions are then used by the manufacturer to formulate the marketing plan for its products. PPLP purchases several such data products from IMS Health. 15 One service, the ''National Prescription Audit Plus," is a national sample of about 22,000 retail pharmacies, which tracks prescriptions from these pham1acies and extrapolates the data to the national level. This information allows PPLP to see specific data, including new and refill prescriptions filled by the pharmacy, prescriber specialty, number of tablets dispensed and length of therapy. A second 13 Euphoria is described as a unique sense of well being that addicts experience when using their drug of choice. Grinstead, S., A.D., M.A., A.C.R.P.S., Understanding Addiction (hereinafter "Understanding Addiction"). Available at: http://www.addiction-free.com/pain management & addiction understanding addiction.htrn. According to the OxyContin package insert, the risk of experiencing euphoria when taking OxyContin q l 2h is very low and the potential for developing addiction is "rare." 14 C