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Potential Drug-Drug Interactions
The package label for adult TYLENOL® acetaminophen products contains an alcohol warning that states, "If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage."
Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive acetaminophen use, although reports of this event are rare. Although some authors suggest that alcoholics may be at increased risk from therapeutic doses, reports usually involve cases of severe chronic alcoholics and the dosages of acetaminophen most often exceed recommended doses and often involve substantial overdose.108-110 Studies evaluating the metabolism of doses up to 20 mg/kg of acetaminophen in chronic alcohol abusers and a study evaluating the effects of 2 days of acetaminophen dosing at 4000 mg daily in chronic alcoholics undergoing detoxification do not support an increased risk of hepatotoxicity with recommended doses of acetaminophen.111-115
Healthcare professionals should alert their patients who regularly consume large amounts of alcohol not to exceed recommended doses of acetaminophen.
Some reports have suggested that patients taking long-term anticonvulsants, who overdose on acetaminophen, may be at increased risk of hepatotoxicity because of accelerated metabolism of acetaminophen.137,138 Available data are conflicting. A 7-year retrospective study of acetaminophen overdose admissions indicates that the overall mortality rate was not significantly different for patients taking concomitant anticonvulsant medications.139
At usual oral therapeutic doses of acetaminophen and hydantoins, no special dosage adjustment or monitoring is generally required. Pharmacokinetic studies indicate that phenytoin primarily induces the glucuronidation pathway, whereas glutathione-derived metabolites are not increased in patients on chronic phenytoin therapy.140 Additionally, recent data demonstrate that phenytoin is metabolized primarily by CYP2C9 and CYP2C19,141 whereas acetaminophen is primarily metabolized by CYP2E1. These data indicate that there is no increased risk from an acetaminophen overdose in patients on chronic hydantoin therapy.
At usual oral therapeutic doses of acetaminophen and carbamazepine, no special dosage adjustment is generally required. Carbamazepine is primarily metabolized by CYP3A4, whereas acetaminophen is metabolized primarily via CYP2E1.141 It is not known whether there is increased risk from an acetaminophen overdose in patients on chronic carbamazepine therapy.
Professional literature from the manufacturer of diflunisal cautions that concomitant administration with acetaminophen produces an approximate 50% increase in plasma levels of acetaminophen in normal volunteers.142 Acetaminophen had no effect on diflunisal plasma levels. The clinical significance of these findings has not been established. However, caution should be used with concomitant administration of diflunisal and acetaminophen and patients should be monitored carefully.
Some reports suggest that patients on chronic isoniazid therapy may be at risk for developing hepatotoxicity from an acetaminophen overdose at doses that would not have been expected to produce toxicity.143-145 Since patients on isoniazid therapy may develop hepatic effects from isoniazid alone, data from individual case reports are unclear as to whether chronic administration of isoniazid may increase the risk of acetaminophen toxicity. Volunteer studies demonstrate that isoniazid inhibits the formation of the toxic metabolite of acetaminophen when taken concurrently, indicating that isoniazid could actually protect against hepatotoxicity from an acetaminophen overdose.146,147 However, it also appears that isoniazid acetylation genotype may play a role in the activity of CYP2E1,148 and based on acetylation genotype, inhibition or induction may be present following discontinuation of isoniazid therapy. In two studies of induction, any evidence suggesting increase of activity was only seen during a brief period from 12 to 48 hours after discontinuation of isoniazid.147,148
Many factors, including diet, medications, and environmental and physical states, may affect how a patient responds to anticoagulant therapy.142 There have been several reports that suggest that acetaminophen may produce hypoprothrombinemia (elevated international normalized ratio [INR] or prothrombin time) when administered with coumarin derivatives.149-151 In other studies, prothrombin time did not change.152-154 Reported changes have been generally of limited clinical significance, however, periodic evaluation of prothrombin time should be performed when these agents are administered concurrently. In the period immediately following discharge from the hospital or whenever other medications are initiated, discontinued, or taken regularly, it is important to monitor patient response to anticoagulation therapy with additional prothrombin time or INR determinations.142
108. Sch°idt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997;337:1112-1117.
109. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepototoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med. 1986;104:399-404.
110. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology. 1995;22:767-773.
111. Critchley JA, Dyson EH, Scott AW, Jarvie DR, Prescott LF. Is there a place for cimetidine or ethanol in the treatment of paracetamol poisoning? Lancet. 1983;1:1375-1376.
112. Critchley JA, Cregeen RJ, Balali-Mood M, Pentland B, Prescott LF. Paracetamol metabolism in heavy drinkers. Br J Clin Pharmacol. 1982;13:276P-277P.
113. Kuffner E, Bogdan GM, Dart RC. Evaluation of hepatotoxicity in alcoholics from therapeutic doses of acetaminophen (abstract). J Toxicol Clin Toxicol. 1997;35:561.
114. Skinner MH, Matano R, Hazle W, Blaschke TF. Acetaminophen metabolism in recovering alcoholics. Methods Find Exp Clin Pharmacol. 1990;12:513-515.
115. Villeneuve JP, Raymond G, Bruneau J, Colpron L, Pomier-Layrargues G. Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic, and cirrhotic subjects. Gastroenterol Clin Biol. 1983;7:898-902.
137. Bray GP, Harrison PM, O'Grady JG, Tredger JM, Williams R. Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. Hum Exp Toxicol. 1992;11:265-270.
138. Miners JO, Attwood J, Birkett DJ. Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways. Clin Pharmacol Ther. 1984; 35:480-486.
139. Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995;109:1907-1916.
140. Prescott LF, Critchley JA, Balali-Mood M, Pentland B. Effects of microsomal enzyme induction on paracetamol metabolism in man. Br J Clin Pharmacol. 1981;12:149-153.
141. Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36(suppl 5):S8-S13.
142. Physicians' Desk Reference®. 53rd ed. Montvale, NJ: Medical Economics Company; 1999.
143. Murphy R, Swartz R, Watkins PB. Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med. 1990;113:799-800. [Correction: Acetaminophen toxicity. Ann Intern Med. 1991; 114:253.]
144. Crippin JS. Acetaminophen hepatotoxicity: potentiation by isoniazid. Am J Gastroenterol. 1993;88:590-592.
145. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr. 1997;130:300-304.
146. 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.
147. Zand R, Nelson SD, Slattery JT, et al. Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther. 1993;54:142-149.
148. Chien JY, Peter RM, Nolan CM, et al. Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bio-activation with long-term isoniazid. Clin Pharmacol Ther. 1997;61:24-34.
149. Antlitz AM, Mead JA Jr, Tolentino MA. Potentiation of oral anticoagulant therapy by acetaminophen. Curr Ther Res. 1968;10:501-507.
150. Boeijinga JJ, Boerstra EE, Ris P, Breimer DD, Jeletich-Bastiaanse A. Interaction between paracetamol and coumarin anticoagulants (letter). Lancet. 1982;1:506.
151. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998; 279:657-662.
152. Antlitz AM, Awalt LF. A double-blind study of acetaminophen used in conjunction with oral anticoagulant therapy. Curr Ther Res. 1969;11:360-361.
153. Kwan D, Bartle WR, Walker SE. The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol. 1999;39:68-75.
154. Udall JA. Drug interference with warfarin therapy. Clin Med. 1970:20-25.
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Last reviewed on RxList: 11/9/2007
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