Apixaban × Verapamil

Verapamil inhibits the CYP3A4 enzyme and the P-glycoprotein transporter (verapamil SmPC), and apixaban is cleared through both routes. Apixaban blood levels may therefore rise, and with them the bleeding risk. The size of the effect is unknown: there are no pharmacokinetic data for this pair (practical guide of the European Heart Rhythm Association, EHRA 2021). The apixaban SmPC of the European Medicines Agency (EMA) lists verapamil among inhibitors expected to raise apixaban levels to a lesser degree than strong inhibitors.

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

The combination is allowed with caution. The apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names verapamil among them (apixaban SmPC, EMA). The verapamil SmPC notes a possible rise in bleeding risk with direct oral anticoagulants, especially in patients with risk factors, and advises reducing the anticoagulant dose if needed, following its own SmPC (verapamil SmPC). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily only by its own criteria: two of three (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or creatinine clearance 15–29 mL/min (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) advises caution, especially with polypharmacy. If at least one more risk factor is present (age 75 years or older, body weight 60 kg or less, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic steroids, previous bleeding, anaemia or low platelets, frailty or falls), EHRA suggests considering an anticoagulant with fewer interactions or replacing the other drug (EHRA 2021).