Acetaminophen Interactions
- Acetaminophen
Antacids
Barbiturates
- Busulfan
- Carbamazepine
- Charcoal
- Cholestyramine
- Diflunisal
- Echinacea
- Ethanol
- Ethotoin
- Exenatide
- Fosphenytoin
- Imatinib, STI-571
- Isoniazid, INH
- Lamotrigine
- Oxcarbazepine
- Phenytoin
- Prilocaine
- Rifabutin
- Rifampin
Salicylates
- St. John’s Wort, Hypericum perforatum
- Sulfinpyrazone
- tobacco
- Warfarin
- Zidovudine, ZDV
Acetaminophen Interactions
Many prescription and non-prescription medicines contain acetaminophen. Avoid concurrent use of products that contain acetaminophen as the maximum daily dose (i.e., 4 g/day for adults; 75 mg/kg/day for infants and children) may be exceeded leading to an increased risk of hepatotoxicity. Also, high dosages of acetaminophen on a chronic basis can cause depletion of glutathione stores, which can lead to a greater production of the hepatotoxic metabolite, NAPQI. Advise patients to carefully read the ingredients of any other products they are taking with acetaminophen.
The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume ethanol. In these patients, hepatotoxicity is possible even at normal, therapeutic dosages of acetaminophen. Acute or chronic ethanol use increases acetaminophen-induced hepatotoxicity by inducing cytochrome P450 (CYP) 2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume ethanol regularly (see Acetaminophen Contraindications).
Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as carbamazepine, oxcarbazepine, barbiturates (including primidone), and phenytoin or fosphenytoin (and possibly ethotoin), may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen’s hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1000 mg daily and phenobarbital 100 mg daily and with acetaminophen 1300 - 6200 mg daily and phenytoin. In both cases, acetaminophen cessation led to serum transaminase normalization within 2 weeks.
The combination of isoniazid, INH and acetaminophen has caused severe hepatotoxicity. Isoniazid, while present in the body, induces the hepatic cytochrome P450 isoenzyme 2E1. In slow N-acetylators, induction of 2E1 occurs for about 2 weeks after INH clearance by the body. Induction of 2E1 activity may potentially increase the risk for acetaminophen-induced hepatotoxicity via enhanced generation of acetaminophen’s hepatotoxic metabolite, NAPQI. Concomitant use of INH and acetaminophen when given at the same time resulted in a markedly decreased formation clearance for NAPQI in patients who received INH daily for 6 months. However, decreased formation clearance for NAPQI only persisted in slow acetylators when acetaminophen was administered 12 hours after INH administration. Rapid acetylators had enhanced formation of NAPQI. Thus, the timing of acetaminophen administration and whether a person is a fast or slow acetylator appears to affect the likelihood of acetaminophen hepatotoxicity.
As cytochrome P450 isoenzyme inducers, rifampin and rifabutin could induce the metabolism of acetaminophen, altering the clinical response. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. Hepatic failure and encephalopathy has been attributed to the combination of rifampin and acetaminophen. A 32 year-old female with normal prothrombin time and liver function developed a serum alanine transaminase concentration of 450 IU, an international normalized ratio of 5.2, confusion, and agitation 2 days after starting rifampicin 600 mg twice daily. She had been taking 2 - 4 grams of acetaminophen on a daily basis for several weeks. Her liver dysfunction resolved with rifampicin and acetaminophen withdrawal and vitamin K and N-acetylcysteine administration.
Sulfinpyrazone can induce hepatic oxidative microsomal enzymes and the drug has been shown to increase acetaminophen clearance by roughly 23%. Theoretically, it is thought that the induction of acetaminophen metabolism by sulfinpyrazone may increase the risk of acetaminophen hepatotoxicity due to the formation of increased amounts of toxic acetaminophen metabolites, but there is no confirmatory evidence.
Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. In a case-controlled study of patients with early renal failure, the regular use of aspirin and acetaminophen was associated with an odds ratio of 2.2 (95% confidence interval 1.4 to 3.5) when regular aspirin users were the reference group. The trend toward greater risk with an increasing cumulative life-time dose of acetaminophen was statistically significant with a risk that was 2.4-times as high for subjects who had consumed a total > 500 g of acetaminophen in combination with aspirin than for those who had used aspirin alone. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
Acetaminophen is routinely considered safer than aspirin and is the agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin. However, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Both INR prolongation and clinical bleeding have been reported. Concomitant acetaminophen ingestion with warfarin may increase the INR in a dose-related fashion. The exact mechanism of this interaction is not known. Acetaminophen and R-warfarin are both metabolized by the cytochrome P450 (CYP)1A2 and CYP3A4 isoenzymes to varying degrees. In some patients, metabolism of acetaminophen may be shifted towards CYP1A2 and CYP3A4 due to genetic polymorphism of CYP2E1 resulting in the decreased metabolism of R-warfarin; although, this mechanism is theoretical. Single doses or short courses (i.e., several days) of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an interaction with warfarin if acetaminophen is co-administered daily in large doses (> 1.3 g/day) for longer than 10 - 14 days. Careful monitoring of a patient’s INR is recommended after initiation and cessation of acetaminophen.
Use of acetaminophen prior to (< 72 hours) or concurrently with busulfan may result in decreased clearance of busulfan due to acetaminophen-induced decreases in glutathione levels. Busulfan is metabolized in the liver through conjugation with glutathione, which is catalyzed by glutathione S-transferase. During high-dose busulfan treatment, glutathione hepatocellular concentrations may be depleted. As the hepatotoxic metabolite of acetaminophen, NAPQI, is inactivated by conjugation with glutathione, the risk of acetaminophen-related hepatotoxicity may be increased.
Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen has been associated with severe hepatotoxic reactions (see Acetaminophen Adverse Reactions); therefore, caution should be exercised when using these agents concomitantly
Prilocaine and acetaminophen each individually can cause methemoglobinemia. Patients treated with prilocaine who are receiving acetaminophen concurrently are at greater risk for developing methemoglobinemia.
Acetaminophen can be hepatotoxic (see Adverse Reactions), and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
Imatinib, STI-571 may affect the metabolism of acetaminophen. In a phase II trial, one death due to liver failure occurred within 12 days of beginning imatinib 600 mg/day. The patient had been receiving acetaminophen 3000 - 3500 mg daily for approximately 1 month. After 6 days of imatinib, the patient developed upper quadrant discomfort, jaundice, hyperbilirubinemia and elevated serum transaminase concentrations. Although imatinib was stopped on day 7 and tests for infection were negative, the patient’s condition deteriorated. The mechanism of the possible interaction between imatinib and acetaminophen has not been elucidated. No studies examining the potential interaction have been performed. Patients should be warned to limit their use of acetaminophen, including non-prescription products, while taking imatinib; chronic acetaminophen therapy should be avoided.
St. John’s wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 - 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes (CYP) 2E1 (major pathway), 3A4, and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI). Thus, theoretically St. John’s wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. Data suggest that acetaminophen glucuronidation is competitively inhibited by zidovudine, whereas zidovudine glucuronidation is only slightly inhibited by acetaminophen. As more acetaminophen is oxidized, glutathione reserves are needed to detoxify the hepatotoxic intermediate, NAPQI. Thus, the interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism. Also, patients taking an inducer of 2E1 or 1A2 with zidovudine and acetaminophen will have greater production of NAPQI and thus, a greater likelihood of hepatotoxicity.
Tobacco smoking induces the cytochrome P450 isoenzyme CYP1A2 and may potentially increase the risk for acetaminophen-induced hepatotoxicity during overdose via enhanced generation of acetaminophen’s hepatotoxic metabolite, NAPQI. In one study, current tobacco smoking was found to be very frequent in patients admitted with acetaminophen poisoning. Tobacco smoking appears to be an independent risk factor of severe hepatotoxicity, acute liver failure and death following acetaminophen overdose.
Cholestyramine has also been shown to decrease the absorption of acetaminophen by roughly 60%. Experts have recommended that cholestyramine not be given within 1 hour of acetaminophen if analgesic or antipyretic effect is to be achieved. The bile-acid sequestrant cholestyramine is well-known to cause drug interactions by binding and decreasing the oral administration of many drugs; to minimize drug interactions, the manufacturer recommends administering other drugs at least 1 hour before or at least 4 - 6 hours after the administration of cholestyramine.
Activated charcoal binds many drugs within the gut and is often therapeutically employed in the setting of acetaminophen overdose. Charcoal appears to bind acetaminophen more avidly than the orally-administered antidotes (acetylcysteine) employed in such poisoning; thus, coadministration of charcoal does not preclude the administration of such antidotes in the setting of acetaminophen overdose. However, since activated charcoal is available as a dietary supplement, patients should be aware that administering charcoal at the same time as a routine acetaminophen dosage would be expected to interfere with the analgesic and antipyretic efficacy of acetaminophen.
Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
When 1000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was increased from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter analgesic effectiveness of acetaminophen, patients should take acetaminophen at least one hour prior to exenatide SQ injection.
Although rare, hepatotoxicity has been reported with echinacea use. A proposed mechanism for the hepatotoxicity associated with echinacea is that some species may contain pyrrolizidine alkaloids; pyrrolizidine alkaloids deplete glutathione, which may increase the risk of liver toxicity, especially when used in conjunction with acetaminophen. The significance of echinacea-induced hepatotoxicity has been challenged as echinacea does not contain the 1,2 unsaturated necrine ring system that is typically associated with pyrrolizidine alkaloid hepatotoxicity. The hepatoxicity could be derived from contaminants, rather than the herb itself. Irregardless, clinicians and patients should monitor for signs of hepatoxicity if these drugs are coadministered.
[ Last revised: 7/11/2006 12:15:00 PM ]
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