Major
ritonavir × Warfarin
HIV protease inhibitor / pharmacokinetic booster×Vitamin K antagonist anticoagulants
Mechanism
Complex mechanism. Ritonavir inhibits CYP3A4 but simultaneously induces CYP1A2, CYP2C9, and CYP2C19 (long-term effect). The net effect on warfarin varies: in some patients INR rises, in others it falls.
Symptoms
If INR rises: gum bleeding, epistaxis, bruising without trauma, blood in urine or stool. If INR drops: thromboembolic risk (deep vein thrombosis, stroke in atrial fibrillation).
Management
When ritonavir starts, is escalated, or is withdrawn, check INR at 1, 2, and 4 weeks and titrate warfarin to effect. Alternative anticoagulant in HIV-positive patients: low molecular weight heparin for short courses (no CYP interactions).