Severe Supratherapeutic international normalized ratio (INR) following concomitant Ribociclib and warfarin therapy

BackgroundRibociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor used in metastatic breast cancer, is a time-dependent inhibitor of cytochrome P450 (CYP) 3A4. While interactions with direct oral anticoagulants (DOACs) are recognized, interactions with warfarin may be underrecognized.Case PresentationA woman in her late 70's taking warfarin for atrial fibrillation developed a critically elevated international normalized ratio (INR) of 16.4 and epistaxis approximately 2 weeks after initiation of ribociclib for breast cancer. She had been transitioned from apixaban to warfarin approximately 2 months earlier due to concern for a potential interaction between apixaban and ribociclib. Her INR had remained stable prior to ribociclib initiation, with a time in therapeutic range (TTR) of 78%.Management and OutcomeThe patient required reversal with vitamin K and 4-factor prothrombin complex concentrate (4F-PCC). Ribociclib-associated CYP3A4 inhibition was considered the most plausible contributing factor to the critically elevated INR. Warfarin was resumed at a reduced dose with close outpatient monitoring.DiscussionThis case highlights the risk of a clinically significant anticoagulant interaction following ribociclib initiation. Although warfarin allows monitoring via INR, insufficient early monitoring may increase patient risk. Weekly INR monitoring during the first 2 cycles of ribociclib may improve safety.