Acetaminophen with Phenytoin Interaction Details
Brand Names Associated with Phenytoin
- Dilantin®
- Phenytek®
- Phenytoin
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Feb 25, 2024
Interaction Effect
Decreased acetaminophen effectiveness and an increased risk of hepatotoxicity
Interaction Summary
Phenytoin has been demonstrated to increase the metabolism of acetaminophen by greater than 40% and to decrease the acetaminophen half-life by about 25%. Because of the production of toxic acetaminophen metabolites, patients may be at a greater risk for acetaminophen toxicity when taking phenytoin concurrently. In addition, the duration of analgesia may be shorter[1].
Severity
Moderate
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Patients receiving phenytoin therapy should avoid large and/or chronic doses of acetaminophen. Monitor the patient for evidence of hepatotoxicity.
Mechanism Of Interaction
Induction of CYP3A4-mediated acetaminophen hepatic metabolism
Literature Reports
A) Acetaminophen is hepatically metabolized in the liver via two separate pathways. Approximately 80% to 90% of an acetaminophen dose is conjugated by a phase II reaction to either glucuronic acid or sulfate, both of which are nontoxic. The remainder is metabolized by a phase I cytochrome P450 (CYP) reaction to a reactive, electrophilic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is rapidly conjugated with glutathione to form mercapturic acid and other nontoxic products which are eliminated in the urine. If glutathione stores are depleted or NAPQI production is increased, detoxification of NAPQI is reduced and NAPQI accumulates, binds to hepatic tissue macromolecules, and causes oxidative stress, tissue damage, or necrosis. Induction of the CYP system increases the rate of drug metabolism and also increases the rate of production of NAPQI. Therefore, the amount of NAPQI produced by a therapeutic dose of acetaminophen in a patient receiving a CYP-inducing drug may be the same as the amount of NAPQI produced by a toxic dose of acetaminophen in a non-induced person [2].
B) A 55-year-old female smoker with chronic obstructive pulmonary disease developed community-acquired pneumonia and was placed on cefprozil 500 mg twice daily. Other medications included phenytoin 400 mg alternating every other day with 300 mg, warfarin 6 mg daily, diltiazem 30 mg four times daily, cisapride 20 mg four times daily, famotidine 40 mg daily, and paroxetine 20 mg daily. On admission to the hospital for placement of an inferior vena cava (IVC) filter, hepatic transaminases, lactose dehydrogenase, and alkaline phosphatase were significantly elevated. Drug review showed that three different analgesics, all containing acetaminophen, were prescribed and used by the patient. Daily doses of acetaminophen ranged from 1300 mg to 6200 mg daily. Because phenytoin was also being given, acetaminophen-induced liver injury secondary to enzyme induction was suspected. All acetaminophen products were discontinued, and the patient's hepatic values were normal two and six weeks later [2].
References
1 ) 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.
2 ) Brackett CC & Bloch JD: Phenytoin as a possible cause of acetaminophen hepatotoxicity: case report and review of the literature. Pharmacotherapy 2000; 20:229-233.
Phenytoin Overview
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Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
Where Does Our Information Come From?
Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.