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FDA Advisory Panel Tightens Controls on Acetaminophen Products 
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A joint advisory committee to the Food and Drug Administration has voted to urge the FDA to take a number of steps that will change the way acetaminophen products are marketed to consumers in the United States.

Following a day and half of listening to testimony from a variety of experts in the field, including key AASLD members Dr. Will Lee, who was a guest speaker, and Dr. Tim Davern, who was the lead-off witness during public testimony, the joint advisory committee voted to make the following recommendations to the FDA:

  • In what was probably the biggest decision of the meeting, the committee voted 20-17 to recommend to the FDA that it eliminate prescription acetaminophen combination products.
  • By a vote of 21-16, the committee voted to recommend that the FDA lower the current maximum daily dose of acetaminophen from its current level of 4000 mg/day. No specific dose was specified.
  • By a vote of 24-13, the committee then recommended that the single, non-prescription adult dose be reduced to 650 mg.
  • Following those two actions, the committee then voted 26-11 to recommend that the current maximum single dose (2 x 500 mg) become available only by prescription.
  • By a vote of 36-1, the committee voted to recommend that there be only one concentration of non-prescription acetaminophen liquids for pediatric patients, although there was mixed opinion on whether it should be at the more concentrated infants formulation or the less concentrated children’s version.
  • By a vote of 27-10, the committee recommended that “unit of use” packaging be required for any prescription acetaminophen products that remain on the market.
  • By a vote of 36-1, the committee recommended a black box warning be included for any prescription acetaminophen products that remain on the market.

There were two options discussed that were defeated in votes by the joint committee:

  • In a 17-20 vote, the committee opted not to recommend that the FDA seek to change the maximum size of the packaging for non-prescription acetaminophen.
  • In a 13-24 vote, the committee recommended against eliminating non-prescription acetaminophen combination products from the market.

Following these votes, the committee was asked to advise the FDA of what actions they put the highest priority on achieving. On that question:

  • 13 supported reducing the maximum daily single and daily dose and/or switching the 2 x 500 mg dose to prescription.
  • 7 felt the single OTC pediatric formulation was most important.
  • 7 indicated that eliminating prescription acetaminophen combination products was most important.
  • 7 thought the boxed warning for prescription combination products that remain on the market was most important.
  • 2 members cited the elimination of OTC combination products, and
  • 1 thought that “unit of use” packaging should be the highest priority.

This meeting was a joint session of three FDA advisory committees: Drug Safety and Risk Management; Nonprescription Drugs; and, Anesthetic and Life Support Drugs, involving a total of 37 members. The recommendations made by the joint advisory committee are not binding on the FDA, which makes the final decision. However, most often, the agency follows those recommendations of expert panels that it constitutes.

Additional information about the meeting will be posted on the FDA’s website (www.fda.gov) and is also available from various trade and general press sources.

AASLD first partnered with FDA and PhRMA in 2001 to initiate the hallmark conference on drug-induced hepatotoxicity:

2001:

The FDA/CDER, in co-sponsorship with AASLD and PhRMA, planned a workshop regarding drug-induced hepatotoxicity.  The FDA had several issues with drug-induced hepatotoxicity; thus an in-depth review of the state of knowledge on the issue of interactions between drugs and the liver was explored at a national level.  The Hepatotoxicity Steering Committee was comprised of FDA, PhRMA and AASLD senior level personnel formed to explore many issues with respect to drug-induced hepatotoxicity.  Specifically, what could be done better to detect it in animals and people; the use of in vitro systems to predict it; the design of clinical studies to detect it; detecting it during NDA review; and detecting and characterizing it post-approval.  This event brought together nationally known experts in the field of hepatotoxicity to share their knowledge.  The event was a two-day conference, with approximately 600 people.  The target audience for the workshop was scientists in government, industry and academia interested in mechanisms of pharmaceutical hepatotoxicity from a clinical, pre-clinical, and post-marketing perspective.

Event: Drug-Induced Liver Injury:  A National and Global Problem
Date: Monday and Tuesday, February 12-13, 2001
Location: Westfields Conference Center, Chantilly, VA 

From 2002 to 2006, a Steering Committee that met annually (approximately 30 people) to discuss new and evolving information was convened.  Interest continued to grow, and the Special Interest Group decided that it was important to expand the area of influence to a broader population once again.  AASLD provided access to experts in the field, and PhRMA companies had an interest in the outcome of any new discoveries.

After the steering committee met in 2006, it was determined that a larger workshop regarding drug-induced Hepatotoxicity should be planned in 2007.  The Hepatotoxicity Special Interest Group (formerly the Hepatotoxicity Steering Committee) was formed and was comprised of members from FDA, the National Institutes of Health (NIH), PhRMA and AASLD senior level personnel to explore many issues with respect to drug-induced hepatotoxicity.  The event purpose was to bring together nationally known experts in the field of hepatotoxicity to share their knowledge. The target audience was scientists in government, industry and academia interested in pharmaceutical hepatotoxicity from a clinical, non-clinical and post-marketing perspective.

Event: Issues and Controversies in Drug-Induced Liver Injury (DILI)
#pp: 129
Date: Wednesday and Thursday, January 24-25, 2007
Location: Brookside Gardens Conference Center, Wheaton, MD

In 2008, the group convened again: 

Event: Issues and Controversies in Drug-Induced Liver Injury (DILI)
#pp: 226
Date: Wednesday and Thursday, March 26-27, 2008
Location: George Meany Center at the National Labor College, Silver Spring, MD

2009:

Event: Recent Research Advances in Drug-Induced Liver Injury 2009
#pp: 151
Date: Wednesday and Thursday, April 8-9, 2008
Location: George Meany Center at the National Labor College, Silver Spring, MD

Importance of Event to CDER/FDA, AASLD and PhRMA

Drug-induced liver injury is now the most frequent cause of acute liver failure in the United States, exceeding all other causes combined.  We do not know how to detect in advance the individuals who are idiosyncratically different from most people, but active research is increasingly underway.

The FDA (CDER and CBER) developed a Guidance for Industry entitled “Premarketing Evaluation of Drug-induced Liver Injury”

The Guidance was published for comment in the Federal Register in October 2007 (www.fda.gov/cber/guidelines.htm).  Comments received were considered for incorporation into the final Guidance.  The final Guidance is expected to be published in the Spring of 2009.

This event is designed to convene known experts to discuss many aspects of DILI, as well as the Guidance.