Testimony on Acetaminophen Use and Liver Injury

Good afternoon and thank you for the opportunity to provide testimony here today. My name is Dr. Caroline Riely and I’m a professor of medicine and pediatrics at the University of Tennessee Health Sciences Center at Memphis.

I am providing testimony today on behalf of the American Liver Foundation -- the leading national voluntary health agency dedicated to the prevention, treatment and cure of hepatitis and other liver diseases through research, education, and advocacy. We are here today because we are concerned about the issue of adverse reactions in the liver to over-the-counter medications.

As a hepatologist caring for patients with both acute and chronic liver disease, I suggest both acetaminophen and non-steroidal anti-inflammatory drugs such as ibuprofen to my patients, depending on the setting. For example, acetaminophen is the antipyretic and analgesic of choice for patients with chronic non-alcohol related liver disease, despite its well-known association with hepatotoxicity, particularly in alcoholics. Ibuprofen is not a hepatotoxin, but can be toxic to the kidneys in patients with chronic liver disease.

Acetaminophen, normally a very safe drug, is a hepatotoxin when dosed incorrectly under certain conditions. The therapeutic window for this agent is narrow – the usual adult dose is 1gram (2 pills) PO q 4 hours, but a single dose of 20 grams (40 pills) can cause lethal hepatotoxicity. While many believe 4 grams (8 pills) is a safe level, even for those who regularly use alcohol, some suggested that this group might find it more prudent to look at a maximum dose of 2 grams in consultation with their physician.

Acetaminophen is a constituent of many combination medications, both over the counter and prescribed. So a patient may take two forms of acetaminophen without being aware of that fact – for example, a patient may use Tylenol PM and Percocet, and may inadvertently exceed the safe dose.

This is particularly a problem in the pediatric population. Well-meaning parents administering multiple doses can reach a toxic dose, inadvertently resulting in liver injury. In this age group the problem is magnified by the multiple formulations available. The parent may not be aware that the preparation advised for infants, a concentrated form given in drops, is much more potent than the syrup administered by the teaspoon in older children. Using the infant formula, but given by the spoonful, for toddlers may inadvertently result in injury to the liver.

We are concerned that present marketing practices make it very difficult to find the standard dose formulation, the 325 mg pills, on the shelf in the drug store or discount store. As a result, the consumer thinks that the “extra strength” preparation is the only one available. Given the narrow therapeutic window, this failure to market the lower dose may contribute to increased adverse events.

At the American Liver Foundation, we would like to encourage an active approach to this problem, and would like to participate in any way we can. There needs to be greater awareness on the part of all, the consumer (or their parents), the pharmacist, and the physician providing primary care for the consumer. We would advocate an innovative educational effort to help minimize this problem. For example, the package warnings in use now are too small, difficult to read, and thus, may appear to be unimportant to the consumer. An educational effort at the site of purchase would be useful. There could be signs or brochures, in Spanish as well as English, available at the display shelf, or at the check out counter. Pharmacists distributing acetaminophen-containing prescription drugs, such as Percocet, should label the bottle to indicate that the medication contains acetaminophen, with a warning that toxic doses may be attained if the patient is an alcohol user, or taking OTC acetaminophen. Public service announcements on TV would be helpful. And, the manufacturers should promote the use of the 325 mg tablets, or at least give them equal shelf space, with some informative guidelines as to which dose is appropriate for whom.

Likewise, physician education is important. Physicians need to know all of the medications, both OTC and prescribed, that their patients are taking. They need to be aware of the narrow therapeutic window for acetaminophen, and its interaction with alcohol. And pediatricians and family practitioners should go over with parents the appropriate dosing for the various pediatric formulations

We realize that discussion of over the counter medications in patients with chronic diseases is tomorrow’s topic. The ALF would like to take this opportunity to remind the panel that NSAIDS such as ibuprofen are potentially toxic in patients with chronic liver disease, leading to renal failure even at modest doses. Thus, in this setting acetaminophen is a better choice for the treatment of pain or fever.

Acetaminophen is a good drug, proven so over decades. Efforts at education of the consumer and the professional will result in an even better safety record for this agent.

The ALF wishes to thank the FDA for convening this panel to discuss the potential risks of acetaminophen and NSAIDS. It is our belief, however, that these products represent the tip of the iceberg in relation to the great need to get a better understanding of the potential hepatotoxicity in all therapeutic agents.

Thus, the ALF recommends the creation of a task force to examine the overall issue of hepatotoxicity so that appropriate review mechanisms and studies can be put in place to address the matter. As more and more data about hepatotoxicity accumulates, the ALF stands ready to assist in this initiative.

Thank you very much for allowing me this opportunity to share the American Liver Foundation’s views with you today.