Ritonavir × Warfarin

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.

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).

The combination can be used with closer coagulation monitoring. The US ritonavir label (FDA) recommends frequent INR checks at the start of co-administration. The European ritonavir SmPC asks for monitoring of anticoagulation parameters both at antiretroviral doses and at the low dose used to boost other protease inhibitors. Adjust the warfarin dose to the INR. The Spanish warfarin SmPC requires close coagulation control whenever a concomitant medicine is added or stopped, so check the INR more often after ritonavir is stopped as well (warfarin SmPC).