PEDIATRICS Vol. 110 No. 3 September 2002, pp. 646
Acetaminophen Recommendation
To the Editor.—The American Academy of Pediatrics provides an important contribution with its recommendations for the safe use of medications in children.1 Unfortunately, the recent statement about acetaminophen contains some misinformation or worrisome suggestions that there may be new concerns regarding acetaminophen use in children that are inaccurate. As the manufacturer of Tylenol acetaminophen products, we believe it is important for physicians to have accurate and current information from which to draw their conclusions about the safe and appropriate use of analgesics.
We agree that "the safety and efficacy of acetaminophen in children are well established, especially in comparison with aspirin."1 When used as directed, acetaminophen has a superior safety profile compared to other over-the-counter pain relievers and has been used effectively by hundreds of millions of children over the past 40 years.
However, the statement cites 1997 American Association of Poison Control Centers (AAPCC) data and, as summarized, misrepresents the data. The mention of 94 death reports is largely irrelevant, because only 4 involved children <18 years of age.2 In addition, the vast majority of the 10 000+ N-acetyl-cysteine uses were in adults, and the antidote is routinely administered on an anticipatory basis while confirmatory laboratory results are pending. We have obtained additional detail from the AAPCC that stated that there were 422 exposures in which N-acetyl-cysteine treatments were reportedly administered to children 12 years of age and under (personal communication from AAPCC, September 27, 2001). It would be disappointing should others quote the statistics as originally stated without the pediatric-relevant detail.
We also believe that recent information provides a more accurate assessment and raises questions about the validity of information in Table 1. Recent human data show that only CYP2E1 plays a significant role in the cytochrome P450 pathway of acetaminophen metabolism.3 Consequently, any interaction of acetaminophen with the anticonvulsants listed in Table 1 is likely to be clinically insignificant because these drugs are metabolized primarily by cytochrome P450 isoenzymes other than CYP2E1. In addition, isoniazid (INH) is listed as a drug that induces CYP2E1 and therefore may increase susceptibility to acetaminophen hepatic toxicity. INH blocks the formation of acetaminophen’s toxic metabolite when the 2 drugs are given concurrently, suggesting that INH may protect against hepatotoxicity in acetaminophen overdose, making the actual risk very limited and probably only in cases of substantial overdose.4,5 In addition, the CYP2E1 induction is relatively short-lived, diminishing 12 to 24 hours after discontinuation of the INH.5, 6
The suggestions that obesity and poorly controlled diabetes might increase the risk of acetaminophen hepatoxicity also seems more alarming to readers than is warranted or supported by the references cited. The study regarding obesity was a pharmacokinetic evaluation of chlorazoxazone, a drug that is primarily (>50%) metabolized by CYP2E1 and has questionable relevance to acetaminophen toxicity.7 The human study referenced in poorly controlled insulin-dependent diabetic patients measured CYP2E1 levels in lymphocytes and is of unknown relevance to hepatic enzyme levels or acetaminophen metabolism.8
The statement’s comments regarding ethanol also may be incorrectly interpreted. A recent study shows that chronic alcoholics can take 4 g/d of acetaminophen for 2 days without alteration of their liver enzymes or evidence of hepatic injury when compared to placebo-treated alcoholics.9
Of critical importance, the Committee statement failed to discuss that, presently, pediatric acetaminophen products still do not include dosing information for children under 2 years of age. At least 1 Fellow of the Academy has supported the inclusion of this information in testimony before the Food and Drug Administration in the past.10 We hope that the Academy supports this very important public health measure by seeing that the Food and Drug Administration moves forward with the addition of under-2 dosing information to the label.
Mary Ellen Mortensen, MD, MS, FAAP
Jennifer L. Cullen, PharmD
McNeil Consumer & Specialty Pharmaceuticals
Fort Washington, PA 19034-2299, USA
REFERENCES
- American Academy of Pediatrics, Committee on Drugs. Acetaminophen toxicity in children.
Pediatrics.2001; 108
:1020
–1024
[Abstract/Free Full Text] - Litovitz TL, Klein-Schwartz W, Dyher KS, Lee S, Powers M. 1997 annual report of the american association of poison control centers toxic exposure surveillance system. Am J Emerg Med.1998; 16 :443 –497[CrossRef][Web of Science][Medline]
- Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther.2000; 67 :275 –282[CrossRef][Web of Science][Medline]
- Epstein MM, Nelson SD, Slattery JT, Kalhorn TF, Wall RA, Wright JM. Inhibition of the metabolism of paracetamol by isoniazid. Br J Clin Pharmacol.1991; 31 :139 –142[Web of Science][Medline]
- Zand R, Nelson SD, Slattery JT, et al. Inhibition and induction of cytochrome P450 2E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther.1993; 54 :142 –149[Web of Science][Medline]
- Chien JY, Peter RM, Nolan CM, et al. Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bioactivation with long-term isoniazid. Clin Pharmacol Ther.1997; 61 :24 –34[CrossRef][Web of Science][Medline]
- O’Shea D, Davis SN, Kim RB, Wilkinson GR. Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity. Clin Pharmacol Ther.1994; 56 :359 –367[Web of Science][Medline]
- Song BJ, Veech RL, Saenger P. Cytochrome P450IIE1 is elevated in lymphocytes from poorly-controlled insulin-dependent diabetics.
J Clin Endocrinol Metab.1990; 71
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[Abstract/Free Full Text] - Kuffner EK, Dart RC, Bogdan GM, Hill RE, Casper E, Darton L. Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial.
Arch Intern Med.2001; 161
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[Abstract/Free Full Text] - Labeling and dosing of over the counter pediatric analgesic/antipyretic drug products. Topic of discussion at the public meeting of the Nonprescription Drugs Advisory Committee. September 1997
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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