Apixaban with Phenobarbital Interaction Details

Brand Names Associated with Apixaban

Brand Names Associated with Phenobarbital

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Mar 04, 2024

Interaction Effect

Reduced apixaban exposure and increased risk of thrombotic events

Interaction Summary

Concomitant use of apixaban (a CYP3A4 substrate)[1] with phenobarbital (a CYP3A4 inducer) may lead to reduced apixaban levels, especially in the presence of other drugs that may cause reduced apixaban levels, [2] and may increase risk of thrombotic events [3]. Avoid concomitant administration [1]. Consider a vitamin K antagonist with close INR monitoring instead of a direct-acting oral anticoagulant (DOAC), or use an antiepileptic drug without known influence on P-glycoprotein or CYP3A4 [4]. If concomitant use of DOAC and an enzyme-inducing drug is necessary, monitoring of the DOAC concentration may be useful [5].

Severity

Major

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Concomitant use of apixaban (a CYP3A4 substrate)[1] with phenobarbital (a CYP3A4 inducer) may lead to reduced apixaban levels, especially in the presence of other drugs that may cause reduced apixaban levels [2], and may increase risk of thrombotic events [3]. Avoid concomitant administration [1]. Consider a vitamin K antagonist with close INR monitoring instead of a direct-acting oral anticoagulant (DOAC), or use an antiepileptic drug without known influence on P-glycoprotein or CYP3A4 [4]. If concomitant use of DOAC and an enzyme-inducing drug is necessary, monitoring of the DOAC concentration may be useful [5].

Mechanism Of Interaction

Induction of CYP3A4-mediated apixaban metabolism; possible induction of P-glycoprotein-mediated efflux transport of apixaban

Literature Reports

A) In a retrospective study (N=131) of patients receiving phenobarbital (n=4) or other enzyme-inducing antiseizure medications (EI-ASM; n=22) concomitantly with direct oral anticoagulant (DOAC) therapy, 37.5% experienced DOAC concentrations below the therapeutic range compared with 9.3% who were not receiving phenobarbital or other enzyme-inducing antiseizure medications (OR, 5.82; 95% CI, 2.03 to 16.66). Coadministration of apixaban and an EI-ASM significantly reduced the median apixaban peak concentration compared with patients not receiving an EI-ASM (106 vs 150 nanograms/mL). Apixaban was used by 85% (111 patients) of patients within the study, however, some patients received rivaroxaban (14 patients) or dabigatran (6 patients) [6].

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 [7].

C) In a retrospective evaluation (N=22), serum concentrations of direct-acting oral anticoagulants (DOACs) were found to be reduced in some patients concomitantly receiving enzyme-inducing drugs (EID), including phenytoin, carbamazepine, primidone, phenobarbital, St Johns wort, and oxcarbazepine. Apixaban concentrations ranged from 35.8 to 205.4 mcg/L in 10 patients with 5 of those patients having levels below the fifth percentile observed in the ARISTOTLE study population. Rivaroxaban levels were tested in 1 patient and found to be 148.1 mcg/L, which was below the fifth percentile based on the ROCKET-AF study population. Among the 11 patients with DOAC levels measured, 1 had the DOAC or EID discontinued, 3 received an increased DOAC dose, and the other 7 had no change to therapy [5].

D) An 82-year-old patient with a history of epilepsy was stable on phenobarbital 100 mg/day and began receiving renal-dose adjusted rivaroxaban (15 mg/day; CrCl about 49 mL/min) for atrial fibrillation. He developed an aneurysm of the left popliteal artery 7 months after initiation of rivaroxaban and was found to have a peak rivaroxaban concentration of 100 nanograms/mL (ng/mL); lower than the fifth percentile of values observed in phase III studies (189 to 419 ng/mL). He was discharged on enoxaparin after left leg amputation, and was then switched to apixaban 2.5 mg twice daily, with the dose based on his age and renal status. Apixaban peak concentration 3 hours postdose was found to be lower than the fifth percentile in multiple measurements (50 and 35.8 ng/mL versus expected range of 91 to 321 ng/mL). The patient's apixaban dose was doubled to 5 mg twice daily and levels increased to 120 ng/mL. The patient remained clinically stable at follow-up [8].

E) In a case report, a 77-year-old woman receiving low-dose phenobarbital experienced a cardioembolic stroke 6 months after starting apixaban 5 mg twice daily. Trough apixaban levels measured 11 hours postdose in this patient were 89 nanograms (ng)/mL (median predicted trough level in clinical trials was 103 ng/mL). The drug interaction probability score (DIPS) was 7, indicating a probably likelihood of a drug interaction [3].

References

1 ) Product Information: ELIQUIS(R) oral tablets, apixaban oral tablets. Bristol-Myers Squibb Company (per Manufacturer), Princeton, NJ, 2018.

2 ) Steffel J, Collins R, Antz M, et al: 2021 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace 2021; 23(10):1612-1676.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

3 ) King PK, Stump TA, Walkama AM, et al: Management of phenobarbital and apixaban interaction in recurrent cardioembolic stroke. Ann Pharmacother 2018; 52(6):605-606.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

4 ) Stollberger C & Finsterer J: Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs. Epilepsy Res 2016; 126:98-101.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

5 ) 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/...

6 ) Perlman A, Goldstein R, Choshen Cohen L, et al: Effect of enzyme-inducing antiseizure medications on the risk of sub-therapeutic concentrations of direct oral anticoagulants: a retrospective cohort study. CNS Drugs 2021; 35(3):305-316.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

7 ) 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/...

8 ) Dagan G , Perlman A , Hochberg-Klein S , et al: Managing direct oral anticoagulants in patients with antiepileptic medication. Can J Cardiol 2018; 34(11):1534-1534.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

Apixaban Overview

• 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.

Phenobarbital Overview

• Phenobarbital is used to control seizures. Phenobarbital is also used to relieve anxiety. It is also used to prevent withdrawal symptoms in people who are dependent ('addicted'; feel a need to continue taking the medication) on another barbiturate medication and are going to stop taking the medication. Phenobarbital is in a class of medications called barbiturates. It works by slowing 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:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

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.