Apixaban × Clarithromycin

Apixaban is cleared partly through the CYP3A4 enzyme and the P-glycoprotein (P-gp) transporter, and clarithromycin inhibits both. The European Medicines Agency (EMA) does not class clarithromycin as a strong inhibitor of both pathways at once: at 500 mg twice daily it raised the apixaban area under the curve 1.6-fold and peak concentration 1.3-fold, compared with 2-fold and 1.6-fold for ketoconazole (apixaban SmPC, EMA). Higher apixaban levels mean a higher risk of bleeding.

Bleeding gums, nosebleeds, bruising without injury, blood in the urine or stool, heavy periods. In severe cases, gastrointestinal or intracranial bleeding. The risk is higher in patients aged 75 or over, with chronic kidney disease, previous bleeding or anaemia, and with concomitant antiplatelet drugs, non-steroidal anti-inflammatory drugs or systemic corticosteroids.

The combination can be used with caution. The European Medicines Agency (EMA) requires no apixaban dose change with inhibitors that do not strongly block both of its elimination pathways and names clarithromycin among them (apixaban SmPC, EMA). The US Food and Drug Administration (FDA) also requires no dose adjustment with clarithromycin (apixaban FDA label). Caution matters most in patients at high risk of bleeding (clarithromycin SmPC). The European Heart Rhythm Association (EHRA) advises particular caution with polypharmacy and when two or more risk factors are present, such as age 75 or over, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic corticosteroids or previous bleeding (EHRA 2021). In that case, first consider whether another anticoagulant or antibiotic with fewer interactions is suitable (EHRA 2021). Watch the patient for signs of bleeding and stop apixaban if severe bleeding occurs (apixaban SmPC, EMA).