Pediatric Acetaminophen Toxicity Literature Distribution Supported By AAP

Written information about acetaminophen toxicity should be given to parents at their children's regular medical check-ups and discussed at later visits, the American Association of Pediatrics' Committee on Drugs advises in a policy statement in the October issue of Pediatrics.

The policy statement recommends that the written information convey the possibility that "the perceived safety of acetaminophen may contribute to inappropriate dosing," as well as "failure to recognize children at increased risk and delay in diagnosis and treatment of acetaminophen intoxication."

Literature also "should include the dose, frequency, duration of therapy and the specific strength and formulation for the individual child," and dispel the notion that "more is better" when taking OTC drugs, the statement says.

Moreover, parents should be encouraged to notify their pharmacist of their child's use of acetaminophen when filling a new prescription, AAP says. The statement maintains parents should be made aware of the dangers of using more than one product containing acetaminophen, or of substituting adult for pediatric formulas, errors that could lead to liver damage.

Although the policy statement notes "the safety and efficacy of acetaminophen in children are well established" and "the risk of developing toxic reactions to acetaminophen appears to be lower in children than in adults," it asserts pediatricians must be aware of the drug's toxic potential due to its high level of use in children.

Hepatic toxicity levels in children have been hard to determine due to "inaccurate recollection of the ingested dose, doses administered during several days and prolonged-release products," AAP says.

Entitled "Acetaminophen Toxicity in Children," the policy statement also advises pediatricians to consider warning signs of hepatotoxicity when treating children, since many of its initial symptoms, such as nausea and vomiting, may "provoke administration of additional doses of acetaminophen."

Some children are at a higher risk for hepatotoxicity than others, and physicians should be aware of these increased risks, AAP continues, singling out children "with chronic diseases treated with several different medications or chronic undernutrition."

Tylenol manufacturer McNeil Consumer Healthcare responded to the statement by noting it has worked with AAP for years to ensure the public is properly informed about acetaminophen and other OTC drugs.

The company stressed that "acetaminophen is by far the pediatric pain and fever reducer most often recommended by pediatricians." As with any medication, consumers should "read labels carefully so they know which products contain acetaminophen in order to avoid inadvertent overdose" and use the product exactly as instructed, the firm said.

McNeil also supplies various educational materials to doctors for distribution to parents. The firm noted it provides physicians with brochures in both English and Spanish covering topics such as fevers and asthma. The materials include dosing charts, tips on fever management and instructions on taking temperatures.

Most recently, McNeil and J&J/Merck launched a national campaign encouraging consumers to "read, remove and restock" drugs in their medicine cabinets (¹ (Also see "P&G Vicks NyQuil Cough Features Up To 8-Hour Nighttime Cough Relief" - Pink Sheet, 1 Oct, 2001.)).

In an Aug. 15 supplemental filing with FDA, McNeil suggested acetaminophen dosing levels for children under six months be based on body weight (² (Also see "Weight-Based Pediatric Acetaminophen Dosing "Preferred," McNeil Says" - Pink Sheet, 3 Sep, 2001.)).

McNeil also funded a study appearing in the Oct. 8 Archives of Internal Medicine entitled "Effect of Maximal Daily Doses of Acetaminophen on the Liver of Alcoholic Patients."

The randomized, double-blind, placebo-controlled trial conducted by Edwin Kuffner, MD, Rocky Mountain Poison & Drug Center, et al., involved 201 patients at the Denver Comprehensive Alcohol Receiving & Emergency Services.

The treatment arm consisted of 102 subjects given 4,000 mg acetaminophen orally (the maximum daily OTC dose); the placebo arm included 99 people.

Nearly all the enrolled participants were inebriated at baseline. However, since previous studies have demonstrated that simultaneous consumption of alcohol and acetaminophen protects against acetaminophen-caused hepatotoxic reactions, the study did not begin until participants reached sobriety.

The researchers thus could be assured subjects were at "maximum vulnerability for developing a toxic reaction," thereby lending weight to any results indicating acetaminophen's safety, Kuffner et al. explain.

Participants were administered four separate doses of acetaminophen or placebo for two days. Over the next two days, liver tests were conducted to measure for minor variations in the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), two enzymes indicative of cell damage in the liver.

"Our study was designed to detect a small change in serum AST and ALT levels, should the administration of acetaminophen in therapeutic doses to an alcoholic subject produce any degree of hepatotoxic reaction," the researchers state. "We found no difference between placebo-treated and alcoholic subjects who received the maximum recommended daily dose of acetaminophen."

Although the study appears to contradict earlier findings, Kuffner et al. cite flaws in prior studies.

For example, previous trials depended on participants' medication histories, which Kuffner et al. note can be "incomplete and inaccurate" and lead to "missing and conflicting data," especially in alcoholic subjects. The researchers additionally contend that "other causes of liver injury were not evaluated" in many prior studies.

However, the researchers concede the limitations of their study, noting the doses used did not exceed maximum therapeutic daily dose and were administered for only two days. "It is possible that administration of acetaminophen for longer...is required for alcoholic patients to manifest a hepatotoxic reaction," they state.

"It is also possible that a hepatotoxic reaction...is an idiosyncratic and rare event that would only be detected in a study with an extremely large sample size," Kuffner et al. note.

Acetaminophen's safety has come under increased regulatory scrutiny in the past year, including an interest by FDA in examining ways to limit OTC access to large amounts of the analgesic, thereby reducing its hepatotoxic potential (³ (Also see "OTC Acetaminophen Access Limitations To Be Considered By FDA" - Pink Sheet, 19 Feb, 2001.)).