FDA Caves In to Industry, Fails to Adequately Address Tylenol Overdoses

Most of us remember the 1982 debacle in which Tylenol capsules laced with cyanide were held responsible for seven deaths. These tragic events led to a reimagining of tamper-resistant drug packages. Yet a far greater Tylenol-related tragedy has been unfolding before and since 1982—preventable deaths due to overdoses from acetaminophen (the active ingredient in Tylenol and many other prescription and over-the-counter drugs) and the resultant liver damage. In fact, acetaminophen is the leading cause of toxic drug ingestions in the U.S.

The impact of acetaminophen overdoses on the health care system is daunting: 108,102 calls to Poison Control Centers in 1999; an average of 56,680 Emergency Department visits per year; an average of 26,256 hospitalizations per year; an average of 458 deaths per year. And deaths appear to have doubled between 1995 and 1999, according to one data source. By any measure, this is a major national health problem.

Yet, for decades the Food and Drug Administration (FDA) has watched this tragedy unfold. As long ago as 1977, the FDA’s Advisory Review Panel recommended the following warnings for acetaminophen-containing products: “Do not exceed recommended dosage because severe liver damage may occur” and “Do not exceed recommended dosage or take for more than 10 days, because severe liver damage may occur.” This wise advice went unheeded.

On September 19 and 20, 2002, a little-heralded war broke out inside the Hilton Hotel in Silver Spring, Maryland. The occasion was two days of hearings on the safety of acetaminophen, aspirin and non-
steroidal anti-inflammatory drugs such as ibuprofen. Representatives of all three camps lobbed missiles of self-serving data at one another, each asserting that its drug was safer but professing concern that unwitting consumers might go unwarned about the dangers of their competitors’ products.

Public Citizen’s Health Research Group was also present to testify
(see the testimony at http://www.
citizen.org/publications/release.cfm?ID=7202 or write to us for a copy).
In testimony before the FDA’s Nonprescription Drugs Advisory Committee, the group bunkered down at the Hilton, Dr. Peter Lurie, deputy director of Public Citizen’s Health Research Group noted
that the FDA had estimated that at least 57—74 percent of ingestions are intentional. Nonetheless, the FDA had framed the issue as “Unintentional Acetaminophen Hepatotoxicity,” an illogical restriction of the debate that summarily excluded most overdoses from discussion. Dr. Lurie described this as “a capitulation to the notion that nothing can be done for those making suicide attempts,” adding that, “This ignores the facts that many suicide attempts are impulsive ‘cries for help’ and most are not fatal but may leave significant residual disability.” He cited data from the United Kingdom in which restrictions on
the numbers of acetaminophen tablets per pack appear to have reduced acetaminophen-related overdoses, liver transplants and deaths.

Public Citizen put forward several recommendations that went well beyond the circumscribed debate the FDA wished to have. These included:

Greatly Expanded Warnings for Consumers

Current over-the-counter acetaminophen labeling is inadequate, excluding the liver toxicity warning that was recommended 25 years ago by FDA advisers. In addition to including a general warning about liver toxicity, the label should mention the early symptoms of liver toxicity and instruct patients to discontinue the drug and seek medical attention should such symptoms appear. The symptoms of liver toxicity include: unusual tiredness, abdominal pain, or yellow discoloration of the eyes or skin (jaundice). If these symptoms develop while taking acetaminophen or any drug, you should stop the drug and contact your doctor as soon as possible. The label should also warn against the simultaneous use of multiple acetaminophen-containing products.

Pharmacists should be required to distribute FDA-approved written risk information with each new and refill prescription for acetaminophen. This type of information, known as a Medication Guide, is already required for some drugs (see the August 2002 issue of Worst Pills, Best Pills News).

A Reduction in the FDA-recommended Maximum Daily Dose

In unintentional adult acetaminophen-associated liver toxicity cases reported to the FDA or published in the medical literature, a total of 282 between January 1, 1998 and July 25, 2001, the median daily dose was 5 grams per day. This amount is not much above the FDA-recommended maximum daily dose for acetaminophen of 4 grams per day. This is a small margin of safety and is even smaller for those with underlying risks such as heavy alcohol use. Restrictions on daily doses should be considered by the FDA for acetaminophen.

Restricting the Number of Milligrams of Acetaminophen in Tablets

There is a relationship between the amount of drug ingested and the incidence of serious overdose and death. Because there is a practical limit on how many pills a suicidal patient can take, it would be logical to limit the maximum tablet strength to 325 milligrams of acetaminophen, the most common strength currently available. Such a restriction is likely to also benefit pediatric patients who ingest acetaminophen-containing products as well as those unknowingly taking multiple acetaminophen- containing products.

Remove Irrational Acetaminophen- containing Combinations from the Market

Much of the problem with acetaminophen overdoses stems from the absurd way in which it is sold. Manufacturers emphasize brand names over generic names in their packaging and unwitting consumers may wind up taking two or even three medications containing the drug. Approximately 25 percent of patients with acetaminophen-associated liver toxicity collected by the FDA had taken more than one acetaminophen-containing product.

Forty-nine percent of over-the-counter acetaminophen sales is in the form of combination products. Most, if not all, of these combinations are irrational. Here are just a partial list of Tylenol (Johnson and Johnson) products, some containing as many as four active ingredients: Tylenol PM, Tylenol Simply Sleep (doesn’t even contain acetaminophen), Women’s Tylenol, Tylenol Flu, Tylenol Cold, and Tylenol Sore Throat (regular Tylenol in liquid form). Patients (and their parents) should be encouraged to use only the active ingredient they need, not lapse into this shotgun approach to drug therapy.

Standardize Liquid Products for Children

Pediatric acetaminophen formulations confuse both doctors and parents. Cases of liver toxicity reported to the FDA or reported in the medical literature between January 1, 1998 and July 25, 2001 included 25 pediatric cases. In at least four of these, teaspoonfuls of medication were administered, instead of dropperfuls. Acetaminophen suspension contains one-third as much drug per milliliter as acetaminophen drops, ample opportunity for an unintentional overdose. All liquid forms of the drug should be required to have the same concentration, Public Citizen testified.

The great war of words ended, as many wars do, with the battlefield only minimally changed. The Ad-visory Committee recommended modest changes in acetaminophen labeling (Johnson and Johnson had already agreed to do this prior to the meeting, in order to ward off worse regulation), but stopped well short of the measures that would actually have had an impact (but which would have undermined the companies’ sales).

It was left to the British Medical Journal to have the final word on the matter in its September 28, 2002 issue. A confidential draft document obtained by the Journal showed that FDA officials wanted the United Kingdom experience to be raised before the committee. They also sought a committee discussion of whether the “maximum tablet strength should be decreased,” whether “combination products [should] be reformulated without acetaminophen,” and whether there was “a need to standardize the various pediatric formulations.” The Journal reports that these issues were removed from discussion so as not to offend Johnson and Johnson.