Correspondence

More on Extended-Release Acetaminophen

N Engl J Med 1995; 333:1508-1509November 30, 1995

Article

To the Editor:

Graudins et al. (July 20 issue)1 report a case of an overdose of extended-release acetaminophen (Tylenol Extended Relief, McNeil Pharmaceuticals). We would like to provide additional information to help physicians evaluate such cases.

With regard to the formulation, Tylenol Extended Relief is a bilayered extended-release caplet containing a total of 650 mg of acetaminophen. One side of the caplet contains 325 mg of immediate-release acetaminophen. The other side contains a matrix formulation of 325 mg of acetaminophen designed to be released more slowly. In vitro, 2 caplets containing a total of 1.3 g of acetaminophen release 88 percent of the agent within three hours and 95 percent within five hours; the respective values for 20 caplets containing a total of 13 g are 84 percent and 93 percent. These data indicate that in vitro release of acetaminophen from the caplets occurs as designed, even with large amounts of this product.

With regard to the case report, because of the delay between the overdose and the patient's arrival at the hospital, the data cannot be used to determine the length of time to the peak level or to assess the usefulness of the Rumack–Matthew nomogram2 of acetaminophen overdose (Figure 1Figure 1Superimposition of the Line on the Rumack–Matthew Nomogram Indicating Potential Toxicity on the Time Course of Acetaminophen Levels in a 13-Year-Old Girl First Seen 19 Hours after an Overdose of Extended-Release Acetaminophen.). The subsequent pattern of acetaminophen elimination in this case is similar to that seen with acute acetaminophen overdose when hepatotoxicity has developed. We believe that the nomogram is of value in situations involving an overdose of extended-release acetaminophen in which the initial plasma acetaminophen levels are not in the potentially toxic range. On the basis of in vitro dissolution data and plasma acetaminophen levels in other cases of overdose of extended-release acetaminophen reported to McNeil, and after consultation with toxicologists, we are currently advising the following in regard to measuring the plasma acetaminophen level. After an overdose with an extended-release acetaminophen product, plasma acetaminophen levels should be measured at least four hours after ingestion and again four to six hours later. If either of these values is above the line on the nomogram indicating potential toxicity, the entire course of antidotal therapy with acetylcysteine should be completed. If neither value is above the nomogram line, toxicity is unlikely. However, if the second value is higher than the first or lies close to the potentially toxic range, it would be prudent to consider obtaining additional acetaminophen measurements as well as initiating or continuing acetylcysteine therapy. If the specific type of acetaminophen product ingested is not known, managing the case as if it involved an extended-release product would be prudent. The Poisindex Information System3 should be referred to for complete information regarding the management of acute acetaminophen overdose, including overdose with extended-release products, and the use of acetylcysteine.

Anthony R. Temple, M.D.
Thomas J. Mrazik, Pharm.D.
McNeil Consumer Products, Fort Washington, PA 19034-2299

3 References

1. 1

   Graudins A, Aaron CK, Linden CH. Overdose of extended-release acetaminophen. N Engl J Med 1995;333:196-196
   Full Text | Web of Science | Medline

2. 2

   Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871-876
   Web of Science | Medline

3. 3

   Rumack BH, Spoerke DG, eds. POISINDEX Information System. Vol. 85. Denver: Micromedex, June 1–August 31, 1995.
   

Author/Editor Response

The authors reply:

To the Editor: Temple and Mrazik suggest that the rate-limiting step in drug absorption — tablet dissolution — is only minimally delayed after an overdose of tylenol Extended Relief. In one study,1 however, the rate and extent of dissolution of Tylenol Extended Relief tablets decreased with increasing numbers of tablets; with 50 tablets, only 64 percent dissolution was seen at eight hours. Our patient vomited “shrunken” Tylenol Extended Relief tablets six hours after ingestion. Prolonged drug absorption has been noted after actual and simulated overdoses of Tylenol Extended Relief.2,3 We are therefore concerned that the treatment approach suggested by Drs. Temple and Mrazik may not detect potentially toxic blood levels, since the time to the peak drug level after an overdose of Tylenol Extended Relief may depend on whether other products were also ingested and on other factors in addition to the dose.

On the basis of recent data showing little or no prolongation of the elimination of Tylenol Extended Relief after an overdose in patients without hepatotoxicity,3,4 we agree that slowed drug elimination in our patient was due to hepatic dysfunction rather than to unusually prolonged drug absorption.

There are now data to support our contention that drug levels after the ingestion of Tylenol Extended Relief reflect a greater degree of drug absorption than after an equivalent dose of immediate-release acetaminophen. Peak acetaminophen levels after supratherapeutic, nontoxic doses of Tylenol Extended Relief were only two thirds of those seen after equivalent doses of the immediate-release Tylenol, but the areas under the time–concentration curves were nearly identical.3

Until more information is available, our approach to the management of an overdose of Tylenol Extended Relief is to measure serum acetaminophen levels every 2 hours from 4 to 16 hours after ingestion. Treatment with acetylcysteine is begun if any value is more than two thirds of the potentially toxic level according to the nomogram. If the value never reaches the potentially toxic range delineated by the nomogram and if liver-function tests are normal 36 hours after ingestion, treatment is discontinued. If any value is found to be in the potentially toxic range, a full course of treatment is given.

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

4 References

1. 1

   Vraa EP, Watson WA, Neau SH. Dissolution of Tylenol dosage formulations under overdose conditions. J Toxicol Clin Toxicol 1995;33:510-510 abstract.
   

2. 2

   Bizovi K, Keys N, Rivas J, Aks S, Gross R, Paloucek F. Tylenol ER, late rise in APAP level after overdose. J Toxicol Clin Toxicol 1995;33:510-510 abstract.
   

3. 3

   Stork CM, Rees S, Howland MA, Kaplan L, Goldfrank L, Hoffman RS. Pharmacokinetics of extended Relief (ER) vs Regular Release (RR) Tylenol (APAP) in a simulated human overdose model. J Toxicol Clin Toxicol 1995;33:511-511 abstract.
   CrossRef

4. 4

   Cetaruk E, Horowitz R, Hurlbut K, McDonald F, Dart R. Tylenol Extended Relief overdose: a new headache? J Toxicol Clin Toxicol 1995;33:511-511 abstract.
   

Citing Articles (3)

Citing Articles

1. 1

   Howard S. Smith, Mike A. Royal. 2009. ACETAMINOPHEN. , 429-436.
   CrossRef

2. 2

   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

3. 3

   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