Apixaban and Primidone: 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
Primidone
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.
Primidone can make apixaban (Eliquis) work less well. Apixaban is a blood thinner that helps prevent dangerous clots. Primidone (Mysoline) is a seizure medicine that speeds up the body's system for breaking down apixaban. When your body clears apixaban faster, there is less of it in your blood, so it may not protect you as well against clots like strokes or clots in the legs and lungs.
The good news is that your care team can manage this. Please don't stop either medicine on your own. Talk with your doctor or pharmacist. They may switch one of the medicines or watch you more closely to keep you protected.
Effect: Primidone (a hepatic enzyme inducer, partly via its phenobarbital metabolite) can induce CYP3A4 and possibly P-gp, increasing apixaban clearance and lowering apixaban exposure (AUC/Cmax), which raises thrombotic risk.
- Direction: Reduced apixaban effect (neither drug is a prodrug here).
- Evidence: Probable; onset unspecified.
- Severity: Major.
Management: Avoid concomitant use. Consider a vitamin K antagonist with INR monitoring instead of a DOAC, or an antiepileptic lacking CYP3A4/P-gp induction. If co-administration is unavoidable, DOAC concentration monitoring may be useful, and dosing should be individualized by the care team.
What happens
Reduced apixaban exposure and an increased risk of thrombotic events
Interaction Deep Dive
Taking apixaban, which is a CYP3A4 substrate,1 together with PHENobarbital, a CYP3A4 inducer, can lower apixaban concentrations, particularly when additional agents that also reduce apixaban levels are present 2, and this may heighten the likelihood of thrombotic events 7. These drugs should not be given together. As an alternative, consider using a vitamin K antagonist with careful INR monitoring rather than a direct-acting oral anticoagulant (DOAC), or select an antiepileptic agent that has no known effect on P-glycoprotein or CYP3A4 3. When combining a DOAC with an enzyme-inducing medication cannot be avoided, checking 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
Keep taking both medicines as prescribed until your care team advises otherwise, and raise this combination with your pharmacist or prescriber.
Because primidone can lower apixaban levels, your team may:
- Consider a different blood thinner, such as a vitamin K antagonist (warfarin) with regular INR checks.
- Consider a seizure medicine that does not speed up apixaban breakdown.
- Monitor you more closely, including possibly checking apixaban levels, if both drugs must be used together.
Also tell them right away about signs of a clot: sudden leg swelling or pain, chest pain, shortness of breath, or stroke symptoms (face droop, arm weakness, speech trouble).
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, showed no difference in the risk of thromboembolic events when compared with non-EI-ASMs (adjusted HR, 1.1 [95% CI, 0.82 to 1.46]). A secondary analysis (n=14,158 eligible episodes) demonstrated a significant decrease in major bleeding events with concurrent use of DOACs with EI-ASMs relative to non-EI-ASMs (adjusted HR, 0.63 [95% CI, 0.44 to 0.89]) 4.
b) In a retrospective study (N=131) of patients given PHENobarbital (n=4) or other enzyme-inducing antiseizure medications (EI-ASM; n=22) alongside direct oral anticoagulant (DOAC) therapy, 37.5% had DOAC concentrations below the therapeutic range versus 9.3% of those not receiving PHENobarbital or other enzyme-inducing antiseizure medications (OR, 5.82; 95% CI, 2.03 to 16.66). Combined administration of apixaban and an EI-ASM significantly lowered the median apixaban peak concentration relative to patients not on an EI-ASM (106 vs 150 nanograms/mL). Apixaban was taken by 85% (111 patients) of the study participants, though some patients received rivaroxaban (14 patients) or dabigatran (6 patients) 6.
c) In a prospective cohort study of patients with nonvalvular atrial fibrillation on direct-acting oral anticoagulant therapy (DOAC) together with antiepileptic drugs (N=91), the composite endpoint of ischemic stroke, transient ischemic attack, and systemic embolism developed 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 the rates reported 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). Within the study, 46.2%, 27.5%, 16.5%, and 9.9% of patients received apixaban, rivaroxaban, dabigatran, and edoxaban, respectively. Concurrent antiepileptic therapy comprised 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 shown to be lowered in some patients receiving enzyme-inducing drugs (EID) at the same time, including phenytoin, carBAMazepine, primidone, PHENobarbital, St Johns wort, and OXcarbazepine. Apixaban concentrations spanned 35.8 to 205.4 mcg/L in 10 patients, with 5 of those patients having levels beneath 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 fell below the fifth percentile based on the ROCKET-AF study population. Of the 11 patients with DOAC levels measured, 1 had the DOAC or EID stopped, 3 had an increased DOAC dose, and the remaining 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), which was 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 subsequently 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 below 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 rose to 120 ng/mL. The patient remained clinically stable at follow-up 9.
f) In a case report, a 77-year-old woman on low-dose PHENobarbital had a cardioembolic stroke 6 months after beginning apixaban 5 mg twice daily. Trough apixaban levels taken 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 Primidone together?
Primidone can lower apixaban levels and weaken its clot protection, so don't combine them without medical guidance; your care team may switch a medication or monitor you closely. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Apixaban and Primidone 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 Primidone interaction managed?
Keep taking both medicines as prescribed until your care team advises otherwise, and raise this combination with your pharmacist or prescriber. Because primidone can lower apixaban levels, your team may: Consider a different blood thinner, such as a vitamin K antagonist (warfarin) with regular INR checks. Consider a seizure medicine that does not speed up apixaban breakdown. Monitor you more close… 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 Primidone 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 Primidone
Keep reading about Apixaban
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