Apixaban and Phenobarbital: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Aug 8, 2026 · Source data updated Jul 11, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Phenobarbital
Apixaban
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Here's what's going on. Apixaban (Eliquis) is a blood thinner that helps prevent dangerous clots. Phenobarbital speeds up the way your body breaks apixaban down, so less of the blood thinner stays in your system. That means it may not protect you as well, and your risk of a clot (like a stroke or a clot in the legs or lungs) could go up.
Please don't stop or change either medicine on your own. This is a manageable situation. Talk with your pharmacist or doctor, because they may pick a different blood thinner or a different seizure medicine, or watch you more closely so you stay protected.
Effect: Phenobarbital (a potent CYP3A4 and P-gp inducer) increases clearance of apixaban (a CYP3A4/P-gp substrate), reducing apixaban exposure (AUC/Cmax) and increasing thrombotic risk. Neither drug is a prodrug, so induction directly lowers the active anticoagulant effect.
- Direction: reduced apixaban effect (possible treatment failure)
- Evidence: probable; severity major; onset unspecified
- Management: Avoid concomitant use. Consider a vitamin K antagonist with INR monitoring instead of a DOAC, or an antiepileptic without CYP3A4/P-gp induction. If co-use is unavoidable, DOAC concentration monitoring may help guide an individualized regimen.
What happens
Reduced apixaban exposure and an increased risk of thrombotic events
Interaction Deep Dive
When apixaban (a CYP3A4 substrate)1 is taken together with PHENobarbital (a CYP3A4 inducer), apixaban concentrations may fall, particularly when additional agents capable of lowering apixaban levels are also present 2, which may heighten the risk of thrombotic events 7. Do not administer these drugs together. As an alternative, consider a vitamin K antagonist with close INR monitoring rather than a direct-acting oral anticoagulant (DOAC), or select an antiepileptic drug that has no recognized effect on P-glycoprotein or CYP3A4 3. Should combined use of a DOAC and an enzyme-inducing agent be unavoidable, measuring the DOAC concentration may be helpful 8.
Why it happens (mechanism)
Induction of CYP3A4-mediated apixaban metabolism; possible induction of P-gp-mediated efflux transport of apixaban
How to manage this interaction
The good news: your care team can manage this. Keep taking both medicines exactly as prescribed until they advise you otherwise.
- Your team may switch you to a different blood thinner, such as a vitamin K antagonist (warfarin) with regular INR blood tests.
- Or they may choose a seizure medicine that doesn't speed up apixaban's breakdown.
- If you do need both, they may monitor your apixaban levels and individualize your care.
What to do: Ask your pharmacist or prescriber before making any changes, and report any signs of a clot (leg swelling or pain, chest pain, shortness of breath, sudden weakness, or trouble speaking) right away.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
6 reports — tap to read
a) A retrospective cohort study of propensity score-matched adults (n=14,078 eligible episodes) taking direct-acting oral anticoagulant (DOAC) therapy (apixaban, dabigatran, or rivaroxaban) together with enzyme-inducing antiseizure medications (EI-ASMs), including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, or topiramate, found no difference in the risk of thromboembolic events compared with non-EI-ASMs (adjusted HR, 1.1 [95% CI, 0.82 to 1.46]). A secondary analysis (n=14,158 eligible episodes) showed a significant decrease in major bleeding events with concurrent use of DOACs and EI-ASMs versus non-EI-ASMs (adjusted HR, 0.63 [95% CI, 0.44 to 0.89]) 4.
b) In a retrospective study (N=131) of patients taking PHENobarbital (n=4) or other enzyme-inducing antiseizure medications (EI-ASM; n=22) along with direct oral anticoagulant (DOAC) therapy, 37.5% had 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). Giving apixaban together with an EI-ASM significantly lowered the median apixaban peak concentration relative to patients not taking an EI-ASM (106 vs 150 nanograms/mL). Apixaban was used by 85% (111 patients) of patients in the study, while some patients received rivaroxaban (14 patients) or dabigatran (6 patients) 6.
c) In a prospective cohort study of patients with nonvalvular atrial fibrillation receiving direct-acting oral anticoagulant therapy (DOAC) together 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 had 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 performed, this rate of thromboembolic events was observed 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 5.
d) In a retrospective evaluation (N=22), serum concentrations of direct-acting oral anticoagulants (DOACs) were reduced in some patients who were also 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 seen in the ARISTOTLE study population. Rivaroxaban levels were measured 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 stopped, 3 received an increased DOAC dose, and the other 7 had no change to therapy 8.
e) An 82-year-old patient with a history of epilepsy was stable on PHENobarbital 100 mg/day and started 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 starting 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 following left leg amputation, and was then changed 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 increased to 5 mg twice daily and levels rose to 120 ng/mL. The patient remained clinically stable at follow-up 9.
f) In a case report, a 77-year-old woman taking low-dose PHENobarbital had 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 probable likelihood of a drug interaction 7.
Common questions
Can I take Apixaban and Phenobarbital together?
Phenobarbital can lower apixaban levels and leave you less protected from clots. Don't change anything yourself, but talk to your doctor or pharmacist soon about a safer combination. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Apixaban and Phenobarbital interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Apixaban and Phenobarbital interaction managed?
The good news: your care team can manage this. Keep taking both medicines exactly as prescribed until they advise you otherwise. Your team may switch you to a different blood thinner, such as a vitamin K antagonist (warfarin) with regular INR blood tests. Or they may choose a seizure medicine that doesn't speed up apixaban's breakdown. If you do need both, they may monitor your apixaban levels and… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Apixaban or Phenobarbital need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (9)
- Product Information: ELIQUIS(R) oral tablets, apixaban oral tablets. Bristol-Myers Squibb Company (per manufacturer), Princeton, NJ, 2021. DailyMed
- 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.
- Stollberger C & Finsterer J: Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs. Epilepsy Res 2016; 126:98-101. PubMed
- Acton EK, Hennessy S, Gelfand MA, et al: Direct-acting oral anticoagulants and antiseizure medications for atrial fibrillation and epilepsy and risk of thromboembolic events. JAMA Neurol 2024; Epub:Epub. DOI
- 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. DOI
- 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
- 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. DOI
- 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
- 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. DOI
Keep reading about Phenobarbital
Keep reading about Apixaban
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