Correspondence

Overdose of Extended-Release Acetaminophen

N Engl J Med 1995; 333:196July 20, 1995

Article

To the Editor:

A previously healthy 13-year-old girl arrived at the hospital 19 hours after ingesting two handfuls of Tylenol Extended Relief (McNeil Pharmaceuticals), a new extended-release formulation of acetaminophen containing 650 mg per caplet. Vomiting and abdominal pain began six hours after ingestion. Examination revealed tenderness of the epigastrium and right upper quadrant. The serum acetaminophen level was 89 μg per milliliter, with an alanine aminotransferase level of 180 IU per liter, a bilirubin level of 1.7 mg per deciliter, and an international normalized ratio of body weight of 1.5. The patient received an initial oral dose of 140 mg of acetylcysteine per kilogram of body weight followed by 6 doses of 70 mg per kilogram and 11 doses of 100 mg per kilogram. The alanine aminotransferase level (7459 μl per liter) and international normalized ratio (4.2) peaked 59 hours after the ingestion of acetaminophen. The patient remained clinically well and was sent home on day 4 with resolving liver-function values. Serial acetaminophen measurements showed a linear decline in drug concentrations, with an apparent elimination half-life of 11.08 hours (Figure 1Figure 1Time Course of Acetaminophen Levels in a 13-Year-Old Girl after an Overdose of Extended-Release Tylenol.).

Tylenol Extended Relief is formulated to maintain its analgesic effect for eight hours.1 There is no published experience with its overdose. Serum levels of immediate-release acetaminophen peak 20 to 90 minutes after ingestion, and the elimination half-life ranges from 1.9 to 2.5 hours.2 Peak levels of other sustained-release medications occur later than with immediate-release preparations.3 Peak levels occur up to 18 hours after an overdose of other sustained-release preparations.3 We were unable to determine in this patient the time or the level of the peak plasma value because of her delayed presentation. It is uncertain whether the slowed elimination of acetaminophen resulted from prolonged absorption or hepatic dysfunction.

Since drug levels tend to plateau rather than peak after the ingestion of sustained-release preparations, any given drug level in this setting is indicative of greater drug absorption (area under time–concentration curve) than that occurring after the ingestion of immediate-release preparations. Hence, measurement of acetaminophen levels after a massive overdose of Tylenol Extended Relief may lead to an underestimation of the need for antidotal therapy if the current nomogram based on an overdose of immediate-release acetaminophen is used. Delayed absorption may further limit the usefulness of the nomogram. Unless acetaminophen levels after an overdose of Tylenol Extended Relief are in the potentially toxic range, we doubt that the nomogram has any value in this setting. Even with serial findings of elevated, nontoxic levels of acetaminophen, it is unlikely that the possibility of subsequent hepatotoxicity can be excluded. Studies in animals indicate that the dose of acetylcysteine required to prevent hepatotoxicity is proportional to the dose of acetaminophen ingested.4 On the basis of area-under-the-curve considerations, we were concerned that the high acetaminophen levels in our patient represented a massive overdose and elected to give higher-than-usual doses of acetylcysteine.

Andis Graudins, M.B., B.S.
Cynthia K. Aaron, M.D.
Christopher H. Linden, M.D.
University of Massachusetts Medical Center, Worcester, MA 01655-0228

4 References

1. 1

   McNeil Consumer Products Company letter to physicians: Tylenol Extended-Relief product information, January 3, 1995.
   

2. 2

   Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 1982;7:93-107
   CrossRef | Web of Science | Medline

3. 3

   Dawson AH, Whyte IM. The assessment and treatment of theophylline poisoning. Med J Aust 1989;151:689-693
   Web of Science | Medline

4. 4

   Piperno E, Berssenbruegge DA. Reversal of experimental paracetamol toxicosis with N-acetylcysteine. Lancet 1976;2:738-739
   CrossRef | Web of Science | Medline

Citing Articles (8)

Citing Articles

1. 1

   Clifford Tan, Andis Graudins. (2006) Comparative pharmacokinetics of Panadol Extend and immediate-release paracetamol in a simulated overdose model. Emergency Medicine Australasia 18:4, 398-403
   CrossRef

2. 2

   Richard C. Dart, Andrew R. Erdman, Kent R. Olson, Gwenn Christianson, Anthony S. Manoguerra, Peter A. Chyka, E. Martin Caravati, Paul M. Wax, Daniel C. Keyes, Alan D. Woolf, Elizabeth J. Scharman, Lisa L. Booze, William G. Troutman. (2006) Acetaminophen Poisoning: an Evidence-Based Consensus Guideline for Out-of-Hospital Management. Clinical Toxicology 44:1, 1-18
   CrossRef

3. 3

   Richard C Dart, Jody L Green, Gregory M Bogdan. (2005) The Safety Profile of Sustained Release Paracetamol During Therapeutic Use and Following Overdose. Drug Safety 28:11, 1045-1056
   CrossRef

4. 4

   John Trinkhaus, Jay Nathan, Leona Beane, Barton Meltzer. (1997) Acetaminophen (Tylenol): Johnson & Johnson and Consumer Safety. The Journal of Law, Medicine & Ethics 25:1, 49-57
   CrossRef

5. 5

   Edward P. Krenzelok, Jerrold B. Leikin. (1996) Approach to the poisoned patient. Disease-a-Month 42:9, 514-607
   CrossRef

6. 6

   Keith K. Burkhart. (1996) The Acetaminophen Nomogram: Will It Withstand the Test of the Extended Relief Formulation?. Academic Emergency Medicine 3:8, 738-739
   CrossRef

7. 7

   (1995) More on Extended-Release Acetaminophen. New England Journal of Medicine 333:22, 1508-1509
   Full Text

8. 8

   &NA;. (1995) Paracetamol overdose. Reactions Weekly &NA;:561, 11
   CrossRef