Moderate
Apixaban × diltiazem
Direct oral anticoagulants (factor Xa inhibitors)×Calcium channel blocker, non-DHP (benzothiazepine derivative)
Mechanism
Diltiazem moderately inhibits CYP3A4 and P-glycoprotein; apixaban is substrate for both. Apixaban exposure rises by 40%, increasing bleeding risk.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.
Management
At standard apixaban dose (5 mg twice daily), the combination is acceptable in patients under 75 with normal renal function. In older patients, creatinine clearance below 50 mL/min, or body weight below 60 kg, reduce apixaban to 2.5 mg twice daily. Alternatives: verapamil with the same precaution, or a beta-blocker without CYP3A4 effect (metoprolol, bisoprolol).