FDA is looking for risk-management solutions to liver problems linked to the misuse of acetaminophen in OTC and prescription products, and will convene a joint advisory panel to discuss potential steps to take.

The Nonprescription Drugs, Drug Safety and Risk Management and Anesthetic and Life Support Drugs advisory committees will meet June 29-30 in Adelphi, Md., a Washington suburb.

Acetaminophen, best known in Johnson & Johnson's analgesic/fever reducer Tylenol , is widely used in single-ingredient and combination OTC products for headaches, aches and fever. In Rx products it is often combined with narcotic painkillers.

In an April 24 Federal Register ¹ notice announcing the meeting, the Center for Drug Evaluation and Research says it appointed a multidisciplinary working group in 2007 to evaluate issues associated with acetaminophen-related liver injuries.

FDA says it expects to release in May the working group's report with recommendations on strategies to reduce acetaminophen-related liver injuries.

"Given the complex nature of the underlying problem of acetaminophen liver toxicity," CDER Director Janet Woodcock and the working group agreed that the options identified in the report should be presented for public discussion prior to action by FDA, according to the notice.

In its deliberations, the working group considered detailed reviews from the Office of Nonprescription Products, the Office of Surveillance and Epidemiology and the Division of Anesthesia, Analgesia and Rheumatology Drug Products.

Risk And Communication

FDA's notice emphasizes that additional research is needed on factors such as unsafe dosing levels and how variables such as ethnicity, genetics or nutrition influence a person's susceptibility to adverse effects.

For instance, CDER says, "There is scientific agreement that taking a large amount of acetaminophen over a short period of time causes liver injury, but there is limited agreement as to the specific thresholds for toxicity."

Issues outlined in the notice suggest the panel discussion may focus strongly on communication issues, such as raising awareness of potential overdose risks, improving effective communication of label warnings and educational efforts.

For example, CDER says consumers are not sufficiently aware that acetaminophen can cause serious liver injury.

Even those who may be aware may not realize when it occurs in multiple products - another communication issue.

FDA notes that many cases of inadvertent overdose are caused by taking more than one product containing acetaminophen, such as an Rx drug and an OTC, or multiple acetaminophen products to treat different symptoms.

Consumers "may reasonably attempt to treat different conditions and symptoms with multiple choices among products containing acetaminophen, but may not realize" the ingredient is "common to each," FDA says.

In some cases, Rx products containing the ingredient are labeled as containing "APAP," the agency notes, and consumers may not be aware of redundant dosing when taking other products.

Labeling Issues On The Table

CDER also says that consumers may overlook current labeling on OTC products, as well as the patient information provided with dispensed prescriptions. Programs to educate the public about safe use of acetaminophen have been small and encountered a number of obstacles, according to FDA.

Possible labeling questions extend to pediatric acetaminophen products, particularly liquid formulations, which "are typically more concentrated" to facilitate proper dosing while using less liquid, FDA says. But consumers may administer those products at the higher dosing levels used for less concentrated products because they are not aware of the greater potency, according to the notice.

In December 2007, FDA issued a proposed ² rule to require OTC acetaminophen product labeling to include warnings about potential liver damage and that the container and outer carton identify acetaminophen when it is an ingredient. The final version of the regulation is currently under review (³ 'The Tan Sheet' Feb. 2, 2009, In Brief).

Conveying Risk In OTC Ads

FDA hopes to counter perceptions that acetaminophen is unlikely to be harmful, and cites some factors it says create that impression. In one example, the ingredient is available in retail outlets in large quantities, including 500-tablet bottles.

Consumers' perceptions may also be influenced by OTC ads, which are not subject to the same requirements imposed on Rx ads, the center says.

CDER staff explained that while OTC marketing commonly emphasizes the products' effectiveness, those ads are not subject to the requirement that prescription product ads offset such messages by providing warning information about possible risks and side affects associated with a drug.

This suggests FDA may be looking for a strategy that involves conveying risk information in ads for OTC acetaminophen products.

Federal Trade Commission regulations require that OTC drug advertising claims, like marketing for all consumer products, are backed by reliable scientific evidence; however, FTC regulations do not require warnings about possible risks associated with an OTC product.

Regulation of OTC drug advertising has been a concern for prominent Democrats on Capitol Hill.

House Energy and Commerce Committee Chairman Henry Waxman, Calif., and Senate Health, Education, Labor and Pensions Chairman Edward Kennedy, Mass., introduced matching bills in the 110th Congress to subject OTC drug advertising to certain provisions and regulations applied to prescription drug direct-to-consumer advertising, including some elements of the FDA Amendments Act of 2007.

The bills, neither of which moved out of committee, sought to give FDA authority to quickly amend or repeal OTC drug monographs without being required to pursue notice and comment rulemaking, as currently mandated under the Administrative Procedures Act (⁴ Also see "Waxman Bill Would Alter OTC Ad Rules, Streamline FDA Monograph Authority" - Pink Sheet, 12 November, 2007., p. 4).

The Consumer Healthcare Products Association opposes legislation to increase FDA's enforcement authority over OTC advertising.

Waxman has not taken up the issue again since he became Energy and Commerce chairman before the 111th Congress convened. He has focused his FDA-related legislation on giving the agency authority over tobacco products and on licensing biosimilar and biogeneric biological products.

Nor has Kennedy revived the bill. His public health focus this session shows in bills he has authored to reauthorize the National Cancer Institute and National Cancer Program in order to enhance and improve cancer research and to review the safety of certain antibiotics for non-therapeutic purposes in food-producing animals.

Risk Management In The Title

Convening DSRM with the other two committees indicates FDA is looking at a strategy used primarily for prescription drug issues - risk management.

According to FDA's Web site, the DSRM panel advises the agency on "risk management, risk communication, and quantitative evaluation of spontaneous reports for drugs for human use and for any other product" FDA regulates.

The FDA Amendments Act of 2007 required FDA to implement Risk Mitigation and Evaluation Strategies to detail how a drug can be sold, when the agency determines it is necessary based on indications of a serious risk with a drug. So far, REMS have been used only for Rx products.

However, FDA is considering the need for any regulatory action - including potential label changes or a REMS - in its evaluation of the safety of orlistat, the active ingredient in Roche's Rx diet drug Xenical and GlaxoSmithKline's OTC weight-loss product alli .

The agency in February added rectal bleeding as a potential safety issue for orlistat to its list of new safety information, based on adverse events reported between April 2008 and June 2008 (⁵ Also see "FDA Evaluating Orlistat For Potential Serious Risks" - Pink Sheet, 9 February, 2009., p. 8).

- Malcolm Spicer (m.spicer@elsevier.com)

Acetaminophen Risk Management On Tap For Joint Advisory Panel

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