Acetaminophen “Black Box” Warning Would “Scare” Users, NDAC Rep Says

Use of a "black box" warning on OTC acetaminophen labeling would be an inappropriate means for alerting consumers about potential liver damage, two consultants to FDA's Nonprescription Drugs Advisory Committee said Sept. 19.

"I'd be a little concerned about the equivalent of a black box warning just because I think we'd scare people away from the product unnecessarily," hepatologist Paul Watkins, MD, University of North Carolina, said during NDAC's meeting on acetaminophen safety in Silver Spring, Md.

Such a warning "would cause more harm than good from a public health standpoint," added New Rochelle, N.Y.-based anaesthesiologist Nathaniel Katz, MD.

The comments responded to measures proposed by NDAC consultant and rheumatologist John Cush, MD, Presbyterian Hospital, Dallas, to reduce instances of liver toxicity related to use of the analgesic.

Cush said that in addition to including a bolded label statement that the product contains acetaminophen, "I'd also maybe go so far as to say we should think about a bold, big box warning, just like the Surgeon General's warning for tobacco, saying, 'Combined use of acetaminophen-containing products may be harmful to your liver.'"

Public Citizen Health Research Group Deputy Director Peter Lurie, MD, also referenced cigarette label warnings in his prepared remarks to NDAC.

Acetaminophen labeling should include not only a general warning about liver toxicity, but also mention the early symptoms of toxicity, instruct patients to discontinue use and seek medical help if such symptoms occur, and warn against simultaneous use of multiple products containing the ingredient, Lurie maintained.

"As many of these elements as possible should appear, in sufficiently large type, on the container itself," Lurie's prepared statement says. "If the box warning becomes unwieldy, consideration should be given to a system of rotating warnings, as has become standard on tobacco products."

NDAC members and consultants voted 21-1 that changes to acetaminophen labeling should be made now, rather than waiting until additional studies are completed and more data are available.

Many panel members cited the need for a liver damage warning separate from the current "alcohol warning."

Acetaminophen labeling currently mentions liver damage solely in the alcohol warning, thereby implying that only consumers who use alcohol are at risk for hepatotoxicity, gastroenterologist and consultant Loren Laine, MD, University of Southern California, asserted.

The current alcohol warning, adopted in 1998, states: "If you consume three or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage."

Laine and several committee reps cited a need to separate the liver damage warning from the alcohol warning to inform consumers who do not drink about the potential consequences of an acetaminophen overdose.

Labeling should demonstrate that acetaminophen is not a "benign" product, NDAC consultant Eric Brass, MD/PhD, Harbor-UCLA Medical Center, said. He suggested the directions for use section should advise consumers not to exceed the recommended dose unless instructed by a doctor, and that exceeding the recommended amount may cause liver damage.

NDAC member Julie Johnson, University of Florida, cautioned against limiting the liver damage warning language to "overdose" because the term might be interpreted only in connection with a suicide attempt.

Several hours before NDAC voted on whether to recommend immediate labeling changes, McNeil Consumer & Specialty Pharmaceuticals said it will modify its newly implemented "overdose warning" to include a specific hepatic damage advisory.

In briefing materials submitted prior to the meeting, McNeil said it has instituted a new warning for Tylenol single-ingredient and cough/cold combination products that states, in part: "Taking more than the recommended dose (overdose) could cause serious health problems" (¹ (Also see "Voluntary Acetaminophen Labeling Revisions Include Overdose Warning" - Pink Sheet, 16 Sep, 2002.), p. 6).

Bayer Consumer Care also has implemented similar OD labeling on its acetaminophen-containing products.

"We are stating here today that we will modify it further so that it says taking an overdose may cause liver damage," McNeil VP-Medical & Regulatory Sciences Anthony Temple, MD, said at the NDAC meeting. "We think others in the industry should follow and put similar types of warnings on all of their pain relievers."

McNeil said it began considering inclusion of a liver damage statement in the overdose warning after FDA's Aug. 21 proposed rule to add ibuprofen to the OTC internal analgesics tentative final monograph. In that proposal, the agency called for adding organ-specific warnings regarding renal failure and gastrointestinal problems on labeling of the non-steroidal anti-inflammatory drug (² (Also see "Ibuprofen Detailed Renal, GI Warnings Required For Monograph Inclusion" - Pink Sheet, 26 Aug, 2002.), p. 3).

FDA's actions signal the agency is moving away from its position in the TFM against including more specific warning language on OTC analgesics, according to McNeil.

The new warning language suggested by NDAC reps and McNeil closely resembles that of an FDA advisory panel which, in 1977, recommended acetaminophen products carry the statement: "Do not exceed recommended dosage because severe liver damage may occur."

The agency, however, did not adopt the panel's recommended language.

In the 1988 TFM, FDA concluded that warnings need not specify toxic effects on particular organs of the body caused by acute overdose, William Gilbertson, associate director of drug monographs with FDA's Division of OTC Drug Products, told the committee.

McNeil said it will work to include the overdose warning liver damage statement on product labeling as quickly as possible.

In addition to recommending the liver injury warning, panel members suggested a number of other labeling changes for acetaminophen single- and multi-ingredient products.

For instance, the committee called for prominently listing active ingredients, their purposes, and dosage or concentration on the principal display panel of packaging and bottles. McNeil and Bayer already have implemented some of these measures.

Committee members and consultants also cited the need for mandatory warnings advising against use with other acetaminophen products and improved pediatric dosing directions. However, NDAC concluded there were insufficient data to support adding label warnings for special populations (see ³ (Also see "Acetaminophen Special Populations Toxicity Data Lacking, NDAC Says" - Pink Sheet, 23 Sep, 2002.) ).