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QUALITY & COMPLIANCE FDA’s Acetaminophen Notice: A Snapshot of the Current Regulatory Environment By Kevin D. Healy, PhD, RAC As part of an ongoing safety initiative, the US Food and Drug Administration (FDA) recently announced that it is asking manufacturers to limit the maximum amount of acetaminophen allowed in prescription products to 325 mg/ unit.1 Acetaminophen is an active ingredient found in many common over-the-counter (OTC) products (e.g., Tylenol, Excedrin, Nyquil) and prescribed combination products (e.g., Percocet, Vicodin). FDA’s action will directly impact several highly prescribed drug products in the US, and it is possible that future FDA actions will impact the substantial OTC acetaminophen market. The regulatory activity surrounding acetaminophen illustrates FDA’s continued focus on drug safety and exemplifies the tools and tactics being utilized in the wake of Food and Drug Administration Amendments Act (FDAAA) of 2007. As summarized in an FDA Advisory Committee briefing document, nearly 20 billion OTC doses of acetaminophen-containing products are sold in the US per year. About half of these are single-ingredient products and half are combination products. On the prescription side, combination drugs containing acetaminophen include some of the most highly prescribed drug products—11 billion doses of drugs containing acetaminophen were prescribed in the US in 2005, and the hydrocodone/ acetaminophen combination has been the most highly prescribed product in the US since 1997.2 Acetaminophen is widely recognized as an effective and well-tolerated drug when used as directed, and has been used successfully to treat ailments in millions of patients. Notably, acetaminophen use is not associated with gastrointestinal problems that are associated with many other pain drugs, such as aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs).3 However, acetaminophen safety concerns, primarily related to overdose, date back to the early 1990s. Specifically, acetaminophen overdose (more than 4000 mg/day) can lead to hepatotoxicity and, in the most severe cases, lead to acute liver failure (ALF) or death. In the 1990s, acetaminophen poisoning was responsible for 56,000 emergency room visits per year, approximately 1,600 annual cases of ALF, and about 26 June 2011 450 deaths annually.4 A 2006 study concluded that unintentional acetaminophen overdose accounted for about one-quarter of the ER visits and deaths, and other studies have concluded that unintentional overdose contributes to about half of the cases of acetaminophen-induced ALF.5,6,7 An array of factors can contribute to unintentional overdosing (See Box 1). FDA’s Acetaminophen Safety Initiative was created in the early 1990s to reduce acetaminophen-related injuries, and recent activities serve as an example of the agency’s expanded authority and focus on safety in the post-FDAAA era. The 2007 FDAAA granted FDA the authority to require safety-related labeling changes to prescription drugs based upon safety information that becomes available postapproval. In January 2011, FDA published a notice in the Federal Register requesting manufacturers to reduce the maximum dosage strength of acetaminophen in prescribed products to 325 mg/unit and requiring safety labeling changes, including a new black box warning. Per the notice, the agency determined that the scientific literature provided new safety information that acetaminophen overdose is a major cause of ALF in the US, and that postmarketing reports and Box 1: Overdose Factors Nearly 500 Americans per year die as a result of acetaminophen-related poisoning. FDA has outlined several possible contributing factors:8 • large number of products ŊŊ simultaneous use of multiple acetaminophen-containing products • varying dosage forms (liquids, tablets, etc) • varying dosage concentrations (250 – 750 mg/tablet) • confusing prescription labeling (use of abbreviations such as “APAP” and “ACET”) • lack of public awareness of which products contain acetaminophen the scientific literature contained additional new safety information—cases of hypersensitivity reactions and anaphylaxis associated with acetaminophen. Consistent with Section 505(o)(4)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), sponsors were given 30 days from their receipt of a Safety Labeling Change Notification to submit revised labeling or a response detailing the reasons that such a labeling change is unwarranted. Based on Section 505(e)(2) of the FD&C Act, the agency has authority to withdraw approval of New Drug Applications (NDAs) or Abbreviated NDAs (ANDAs) based on the consideration of new evidence. However, consistent with recent practice, in this instance, FDA has chosen to rely on voluntary sponsor activity for product withdrawals of any prescription acetaminophen-containing products. At the time of publication of the Federal Register notice, there were 189 approved active applications containing acetaminophen in the list of Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), spanning seven different combinations from 26 sponsors. The majority of these applications, including the most highly prescribed products, have more than 325 mg acetaminophen/unit,9 and, thus, limiting the maximum unit dosage strength to 325 mg has widespread implications. In an apparent effort to minimize the regulatory burden while focusing on patient safety and access, the agency opted to request that sponsors voluntarily withdraw their products containing more than 325 mg acetaminophen/unit over the next three years, after which time they may be subject to FDA action.10 Further, the Federal Register notice advised sponsors on appropriate steps for developing and obtaining approval for reformulated, lower-strength products, and directly welcomed related consultations. The voluntary withdrawal route is analogous to a previous high-profile change in the pain arena. In 2004 and 2005, the COX-2 antagonists Vioxx and Bextra were withdrawn by Merck and Pfizer, respectively. In each case, the sponsor voluntarily withdrew the product following communications with FDA regarding new postmarketing clinical trial data. Thus, while FDA has long had the authority to withdraw drug approvals, the preferred path appears to be suggesting voluntary withdrawals on the part of sponsors, an approach more likely to reduce legal and regulatory burden. Another trend evident in recent regulatory activity is FDA’s increased use of Advisory Committees, particularly the Drug Safety and Risk Management (DSRM) Advisory Committee. FDA has long relied upon Advisory Committees to provide independent expert advice; there are currently 49 separate committees and panels that periodically meet and discuss regulatory matters.11 At least two Advisory Committee meetings have played prominent roles in the Acetaminophen Safety Initiative. A Nonprescription Drugs Advisory Committee meeting in September 2002 led to labeling changes for OTC acetaminophen products in 2009, and a DSRM Advisory Committee meeting in June 2009 held jointly with the Anesthetic and Life Support Drugs Advisory Committee was cited as a primary driver of the recent changes to prescription acetaminophen products. FDA has acknowledged its growing reliance on the DSRM Committee, which convened for 13 days last year as opposed to six days in 2009.12 FDA’s Center for Drug Evaluation and Research convened 51 days of Advisory Committee meetings per year in 2009 and 2010, approximately double the number of meeting days held per year from 2006 to 2008.13 In summary, FDA’s actions of January 2011 will not only affect several of the most highly prescribed drug products in the US, but also illustrate the safety-oriented regulatory environment and broad range of tools and tactics that the agency is employing. FDA is focused on ensuring the public’s health, while also striving to work with pharmaceutical companies to minimize disruptions to the healthcare system. This balancing act is exemplified by the acetaminophen case: While stating that prescription acetaminophen products should no longer contain greater than 325 mg/unit and strengthening Regulatory Focus 27 label warnings, FDA is also utilizing potential voluntary withdrawals, an extended timeframe of three years, and offering consultation with manufacturers on product reformulation issues. Future changes are possible, as FDA continues to evaluate ways to reduce the risk of acetaminophen-related liver injury from OTC products.14 Once again, FDA likely will give great weight to recommendations of the DSRM Advisory Committee; a majority of its members previously recommended reducing the amount of acetaminophen per dose to 650 mg.15 Implementing changes to OTC products would require altering the OTC monograph and FDA drawing upon another set of tools from its regulatory toolbox. If acetaminophen-containing OTC product changes are determined necessary, recent trends indicate FDA will work diligently to make any changes to that massive market as smooth as possible for the American public, the healthcare system and the pharmaceutical industry. Box 2: The Regulatory Toolbox FDA can rely on a number of tools to help ensure the public’s health. Several different tactics have been utilized to ensure safe use of acetaminophen. • Acetaminophen Safety Initiative Ŋ Ongoing umbrella program • Advisory Committee Meetings Ŋ Nonprescription Drugs Advisory Committee (September 2002) Ŋ Drug Safety and Risk Management Advisory Committee (June 2009) • Safety Labeling Updates Ŋ Authority granted through FDAAA 2007 • Sponsor Withdrawals of NDAs / ANDAs Ŋ Section 505(e)(2) grants authority of FDA to withdraw applications Ŋ Voluntary withdrawals appear to be the preferred route References 1. Federal Register Docket No. FDA-2011-N-0021, 14 Jan 2011. 2. Briefing Information for the June 29-30, 2009 Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee. www.fda.gov/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. DrugSafetyandRiskManagementAdvisoryCommittee/ ucm161515.htm Op cit 1. Nourjah P et al. ”Estimates of Acetaminophen (Paracetamol)-induced Overdoses in the United States.’’ Pharacoepidemiological Drug Safety, 6: 406-409, 2006. Op cit 4 Bower WA et al. “Population-Based Surveillance for Acute Liver Failure.” American Journal of Gastroenterology, (102(11)):2459-63, 2007. Larson, AM et al. “Acetaminophen-Induced Acute Liver Failure: Results of A United States Multicenter, Prospective Study.” Hepatology, 42:1364-72, 2005. Op cit 1. Op cit 1. Op cit 1. www.fda.gov/AdvisoryCommittees/default.htm The Pink Sheet, “Where FDA Is Paying The Most Attention: Drug Safety Advisory Committee Had The Most Meetings In 2010.” Sue Sutter. 20 Jan 2011. Op cit 11. www.fda.gov/ForConsumers/ConsumerUpdates/ ucm239747.htm Summary Minutes of the Joint Meeting of the Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee, June 29 and 30, 2009. www.fda.gov/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ DrugSafetyandRiskManagementAdvisoryCommittee/ ucm126014.htm. Author Kevin Healy, PhD, RAC, is a manager of regulatory affairs within the specialty pharmaceuticals division at Covidien, a global healthcare company that develops pharmaceuticals, medical devices and medical supplies. Healy has extensive experience with drug development in a number of therapeutic areas, and has supported products from the pre-IND stage through postapproval. He is currently focused on advancing innovative products intended for the management of pain. 28 June 2011