Apixaban with Phenytoin Interaction Details
Brand Names Associated with Apixaban
- Apixaban
- Eliquis®
Brand Names Associated with Phenytoin
- Dilantin®
- Phenytek®
- Phenytoin
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Mar 04, 2024
Interaction Effect
Decreased exposure of apixaban and increased risk thromboembolic events
Interaction Summary
Avoid concomitant use of apixaban with combined P-glycoprotein and strong CYP3A4 inducers, such as rifampin, carbamazepine, phenytoin, and St. John's Wort. Apixaban exposure and Cmax were decreased in pharmacokinetic studies when coadministered with the combined P-glycoprotein (P-gp) and strong CYP3A4 inducer rifampin[1] and concentration levels of apixaban were below the fifth percentile of expected values in half of patients receiving concomitant apixaban and an enzyme-inducing drug in a retrospective study. If concomitant use of a direct oral anticoagulant (DOAC) and an enzyme-inducing drug is necessary, monitoring of the DOAC concentration may be useful [2].
Severity
Major
Onset
Unspecified
Evidence
Established
How To Manage Interaction
Avoid concomitant use of apixaban with combined P-glycoprotein and strong CYP3A4 inducers, as this decreases apixaban exposure and increases the risk of stroke and other thromboembolic events[1]. If concomitant use of a direct oral anticoagulant (DOAC) and an enzyme-inducing drug is necessary, monitoring of the DOAC concentration may be useful [2].
Mechanism Of Interaction
Induction of CYP3A4- and p-glycoprotein-mediated metabolism of apixaban
Literature Reports
A) A significantly increased risk of stroke/systemic embolism was noted with administration of direct-acting oral anticoagulant (DOAC) drugs concomitantly with carbamazepine (adjusted OR, 2.15; 95% CI, 1.07 to 4.3) or phenytoin (OR, 4.46; 95% CI, 2.46 to 8.08) in a propensity-score adjusted nested case-control study of patients with atrial fibrillation or recent DVT/PE (N=89,284). Patients were new users of DOAC therapy and included 54.8% on apixaban, 31.3% on rivaroxaban, and 14% on dabigatran. Results were adjusted for demographic and lifestyle variables [3].
B) In a prospective cohort study of patients with nonvalvular atrial fibrillation receiving direct-acting oral anticoagulant therapy (DOAC) concomitantly with antiepileptic drugs (N=91), the composite outcome of ischemic stroke, transient ischemic attack, and systemic embolism occurred in 9 patients (5.7% patient-year; 3 fatalities) over a median follow up of 17.5 +/- 14.5 months; however, patients who experienced a thromboembolic event were older (75 years or greater), had a history of stroke, and a higher risk score (CHA(2)DS(2)-VASc greater than 3). Although no direct comparisons were made, this incidence of thromboembolic events was noted to be higher than rates in cohort studies of patients with atrial fibrillation treated with DOAC therapy alone. Major bleeding occurred in 3 patients (1.9% patient-year; 1 fatality). In the study, 46.2%, 27.5%, 16.5%, and 9.9% of patients received apixaban, rivaroxaban, dabigatran, and edoxaban, respectively. Concomitant antiepileptic therapy included 45% receiving levetiracetam, 22% valproic acid, 12% phenobarbital, 11% carbamazepine, and 10% other antiepileptic therapy [4].
C) In a retrospective study evaluating hospitalized patients who received concomitant direct oral anticoagulants (DOACs; apixaban, 77%; rivaroxaban, 15%; dabigatran, 8%) with an enzyme-inducing drug (total study population, 1596; 22 [1.4%] received the concomitant prescriptions), a DOAC concentration below the fifth percentile of expected concentration occurred in 6 of 11 patients who had measured DOAC levels. The peak apixaban concentrations ranged from 35.8 to 205.4 mcg/L in 10 patients, compared with a fifth percentile of 91 mcg/mL and a ninety-fifth percentile of 321 mcg/mL based on standard apixaban dosing from the ARISTOTLE study; 5 of the patients from the ARISTOTLE study had levels below the fifth percentile. The DOACs were prescribed for atrial fibrillation (86%) or VTE (14%) and the indication for the enzyme inducer was primarily for seizure (55%), but also for neuropathy, essential tremor, or depression [2].
D) Mean apixaban Cmax was decreased by 42% and AUC(0 to infinity) was decreased by 54% with coadministration of oral apixaban and oral rifampin in healthy subjects (N=20). Oral bioavailability of apixaban was decreased by 25% and mean apparent clearance was increased by 2.1-fold. Subjects received a single IV dose of apixaban 5 mg on Day 1 followed by a 10-mg oral dose on Day 3. Subsequently, rifampin 600 mg orally once daily was administered on Days 5 to 15. Finally, a single dose of apixaban 5 mg IV and 10 mg orally were administered separately on Days 12 and 14 in randomized sequence [5].
References
1 ) Product Information: ELIQUIS(R) oral tablets, apixaban oral tablets. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2019.
2 ) Perlman A, Hochberg-Klein S, Choshen Cohen L, et al: Management strategies of the interaction between direct oral anticoagulant and drug-metabolizing enzyme inducers. J Thromb Thrombolysis 2019; 47(4):590-595.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
3 ) Gronich N, Stein N, & Muszkat M: Association between use of pharmacokinetic-interacting drugs and effectiveness and safety of direct acting oral anticoagulants: nested case-control study. Clin Pharmacol Ther 2021; 110(6):1526-1536.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
4 ) Giustozzi M, Mazzetti M, Paciaroni M, et al: Concomitant use of direct oral anticoagulants and antiepileptic drugs: a prospective cohort study in patients with atrial fibrillation. Clin Drug Investig 2021; 41(1):43-51.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
5 ) Vakkalagadda B, Frost C, Byon W, et al: Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of Factor Xa. Am J Cardiovasc Drugs 2016; 16(2):119-127.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
Apixaban Overview
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Apixaban is used help prevent strokes or blood clots in people who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body and possibly causing strokes) that is not caused by heart valve disease. Apixaban is also used to prevent deep vein thrombosis (DVT; a blood clot, usually in the leg) and pulmonary embolism (PE; a blood clot in the lung) in people who are having hip replacement or knee replacement surgery. Apixaban is also used to treat DVT and PE and may be continued to prevent DVT and PE from happening again after the initial treatment is completed. Apixaban is in a class of medications called factor Xa inhibitors. It works by blocking the action of a certain natural substance that helps blood clots to form.
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.