OTC ACETAMINOPHEN WARNING FOR POTENTIAL LIVER TOXICITY AMONG ALCOHOLICS

OTC ACETAMINOPHEN WARNING FOR POTENTIAL LIVER TOXICITY AMONG ALCOHOLICS was recommended by FDA's Nonprescription Drug Advisory Committee on June 29. The committee voted 9-1 in favor of a motion to recommend that "a warning . . . be placed on acetaminophen OTC products that warns of a risk for use in chronic alcoholics or in alcoholics -- to be defined later."

The committee also asked FDA's Office of OTC Drugs to postpone putting such a warning into effect until the panel can consider whether an alcohol warning is appropriate for aspirin and OTC nonsteroidal anti-inflammatory agents (see following story). The advisory committee was concerned that requiring an acetaminophen hepatotoxicity warning might lead consumers that imbibe alcohol to switch to aspirin and ibuprofen, which may pose a higher safety risk for the alcoholic population given the association with those products and gastric bleeding.

Noting that he was "impressed . . . with some of the data that were presented," committee member Alan Sinaiko, MD, University of Minnesota Medical School, stated: "The issue here is we know that there is a problem [with the acetaminophen/alcohol interaction] and that we can potentially do something about that. I believe that we're obligated to put something on the label someplace about acetaminophen and alcohol."

In reaching its recommendation, the committee discussed animal toxicity data, several pharmacokinetic studies of alcohol and acetaminophen, epidemiology studies from the U.S. and overseas, and data from approximately 70 case reports of acetaminophen- induced hepatotoxicity in humans that abused alcohol.

In addition, the panel heard conflicting points of view from guest presenters Hyman Zimmerman, MD, George Washington University School of Medicine, and Barry Rumack, MD, Rocky Mountain Poison Control Center. Zimmerman reported on a total of 80 published cases of acetaminophen-induced hepatotoxicity in alcoholics and another 69 cases he had personally compiled. He also described the mechanism by which alcohol interacts with acetaminophen metabolism to create a potentially toxic situation for the liver. Rumack contended that acetaminophen/alcohol hepatotoxicity is a "false issue" based on the unreliability and sketchiness of the case reports and on the absence of scientifically verifiable events of liver toxicity in alcoholics in a large-scale prospective acetaminophen study.

During the open public hearing, the committee also heard presentations on behalf of Whitehall Labs from Willis Madrey, MD, Southwestern Medical Center, and Steven Schenker, MD, University of Texas Medical School. Madrey recommended that males drinking 60 g of alcohol a day and females drinking 30 g a day should limit their acetaminophen intake to 2 g/daily or half the recommended daily dose. Madrey acknowledged that no reports of acetaminophen hepatotoxicity have been seen in persons taking less than 2 g acetaminophen but said there have been cases reported at 4 g/daily. Schenker maintained that acetaminophen/alcohol hepatotoxicity is a "clinical situation" supported by clinical experience, basic science and new animal data that "at least" warrants efforts to educate physicians and medical providers.

Speaking on behalf of McNeil, hepatologist Gordon Benson, MD, Robert Wood Johnson Medical School, analyzed the case reports in the medical literature and suggested that of the 25 reports where blood levels of acetaminophen were available, 20 of those cases showed evidence of acetaminophen overdose. In addition, Benson reported that the patients in the case reports drank between 16-18 drinks a day, suggesting that the at-risk group does not include social drinkers.

The advisory committee felt that the process by which alcohol interacts with acetaminophen metabolism to make the ingredient hepatotoxic was sufficiently well understood and that the case reports were "compelling" and "consistent." Calling the basic science base "quite supportive," Committee Chairman Randy Juhl, PhD, University of Pittsburgh, said the data were strong enough "to explain what we think we are observing."

Wright described the profile of the consumer most at risk of liver damage from acetaminophen use as someone who consumes alcohol heavily and regularly, is malnourished, and has stopped drinking prior to taking more than the recommended daily dose of acetaminophen since acute alcohol can mitigate against the potential toxic effects of acetaminophen. However, several case reports presented by Zimmerman indicated that liver damage had occurred in a few alcoholic patients taking therapeutic doses of acetaminophen. Also, toxicity occurred in some moderate abusers of alcohol using acetaminophen.

The committee initially defined the population at risk of acetaminophen-associated liver toxicity as "chronic abusers of alcohol" and discussed identifying those abusers as "alcoholics" in the label warning. However, several members were concerned that alcohol abusers might not identify themselves with that term.

The committee also attempted to define those at risk by the number of drinks consumed a day but decided to leave it up to FDA to decide how to word the label warning.

Curtis Wright, MD, from FDA's Pilot Drug Review Staff, suggested to the committee that they "not try to be specific" in defining the at-risk population by the number of drinks a person consumes in a day. "What you're trying to say is that individuals who drink alcohol the way alcoholics do are the people who are at risk of this problem," Wright observed. He advised the committee to leave the development of appropriate warning language "to the [Office of OTC Drugs] staff and the companies."

However, committee member Joseph Veltri, PharmD, Intermountain Regional Poison Control Center, said he was "not convinced that it is just the alcoholic that is at risk." He suggested that the at- risk population "might include other people who take regular alcohol who are maybe fasting or have some other problem that could be at risk as well." Veltri said his "preference is somebody who drinks alcohol two-to-four drinks a day regularly is the population that we want to capture [and] not specifically somebody who identifies themself as an alcoholic."

Sinaiko, though agreeing with Veltri about the "potential here for problems," pointed out that the data the committee heard indicated that the risk from acetaminophen hepatotoxicity was confined to heavy drinkers. "I don't sense that people who do not drink heavily are at risk," he noted. "If they are, we haven't seen any data [to support an at-risk finding] and I suspect we would have." Summarizing the views of the committee, Chairman Randy Juhl, PharmD, University of Pittsburgh, said "we want the label to convey in a sense that the people who are going to be affected by the [warning] label are people who drink a lot."

Committee members advised FDA to make the warning organ specific -- that is, to specifically refer to the potential for liver damage or liver toxicity. The panel also decided it did not have enough data to make a recommendation on the appropriate acetaminophen dose for alcohol abusers.