Drug Interactions between avatrombopag and fluvoxamine

ADJUST DOSE: Concomitant use of avatrombopag with moderate to potent dual inhibitors of CYP450 2C9 and 3A4 may increase the systemic exposure (AUC) to avatrombopag. This may lead to an increased risk of avatrombopag toxicities including thromboembolic events such as portal vein thrombosis and septic thrombophlebitis. Metabolic clearance via CYP450 2C9 appears be more significant than CYP450 3A4. An open-label study evaluated the pharmacokinetic and pharmacodynamic drug-drug interactions of avatrombopag in combination with dual or selective CYP450 2C9 and 3A4 interacting drugs. Administration of a single 20 mg dose of avatrombopag to healthy subjects (n=48) who had achieved steady-state concentrations of fluconazole (a moderate dual CYP450 3A4 and 2C9 inhibitor) led to a 2.16-fold increase in avatrombopag AUC, an increase in the terminal elimination phase half-life from 19.7 hours to 39.9 hours, and a clinically significant 1.66-fold increase in the maximum platelet count. In addition, pooled pharmacogenomic analysis of avatrombopag studies suggests that CYP450 2C9 polymorphisms may also impact the clearance of avatrombopag. Compared to normal metabolizers, intermediate and poor metabolizers for CYP450 2C9 showed a 1.4- and 2-fold increase in avatrombopag exposure, respectively .

MANAGEMENT: For the treatment of patients with chronic immune thrombocytopenia, the manufacturer recommends a reduced starting dose of avatrombopag 20 mg orally three times a week when used concomitantly with a moderate to potent dual inhibitor of CYP450 2C9 and 3A4. In patients already receiving avatrombopag therapy, monitoring of platelet counts is recommended when a moderate to potent dual CYP450 2C9 and 3A4 inhibitor is added, and the avatrombopag dose adjusted according to the manufacturer's product labeling as necessary. Dosage adjustments are not available for poor metabolizers of CYP450 2C9. Dose adjustments are not recommended when prescribed for the treatment of thrombocytopenia in adult patients with chronic liver disease undergoing a procedure.