Apixaban × Dronedarone

Dronedarone is a moderate inhibitor of the CYP3A4 enzyme and a strong inhibitor of the P-glycoprotein transporter, and apixaban is cleared through both routes. Dronedarone can therefore raise apixaban blood levels and the bleeding risk. The dronedarone SmPC does not class it as a strong inhibitor of both routes together, and the labels give no figures for the rise in apixaban levels (dronedarone SmPC of the European Medicines Agency, EMA).

Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

The combination is allowed with caution. Do not change the apixaban dose because of dronedarone: the dronedarone SmPC of the European Medicines Agency (EMA) says so directly, and the apixaban SmPC requires no dose adjustment with inhibitors that are not strong (dronedarone and apixaban SmPCs, EMA). The dronedarone SmPC requires monitoring of co-administered anticoagulants (dronedarone SmPC, EMA). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily if two of three criteria are present: age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher (apixaban SmPC, EMA). Dronedarone itself raises serum creatinine, on average by 10 µmol/L, usually within the first week. Measure creatinine before starting dronedarone and after 7 days, take the stable value as the new baseline, and then check kidney function regularly (dronedarone SmPC, EMA). Dronedarone is contraindicated with creatinine clearance below 30 mL/min (dronedarone 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).