Drug Interaction Report

ADJUST DOSE: Coadministration with moderate inhibitors of CYP450 2C8 may significantly increase the plasma concentrations and the risk of adverse effects associated with daprodustat, which is primarily metabolized by the isoenzyme. When gemfibrozil (600 mg twice daily for 5 days), a potent CYP450 2C8 inhibitor, was administered with a single daprodustat dose of 100 mg on day 4 of gemfibrozil administration, daprodustat peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.9-fold and 18.6-fold, respectively. In addition, daprodustat Cmax and AUC are predicted to increase by at least 3-fold and 4-fold, respectively, following concomitant administration with clopidogrel 75 mg once daily (a moderate CYP450 2C8 inhibitor).

MANAGEMENT: Daprodustat starting dose should be reduced by half if it is coadministered with moderate CYP450 2C8 inhibitors, except in patients whose starting dose is already 1 mg. Close monitoring of hemoglobin levels and adjusting the dose of daprodustat is advised following initiation or discontinuation of treatment with moderate CYP450 2C8 inhibitors.

GENERALLY AVOID: The consumption of alcohol during therapy with leflunomide may potentiate the risk of liver injury. Leflunomide has been associated with hepatotoxicity, including elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis,

MANAGEMENT: Patients should be advised to avoid excessive alcohol use during leflunomide treatment.

MONITOR: Smoking and alcohol consumption during therapy with daprodustat may increase the risk of gastric or esophageal erosions. Serious erosions, including gastrointestinal bleeding and the need for red blood cell transfusions, have been reported during daprodustat clinical trials. Patients with a history of gastrointestinal erosion, peptic ulcer disease, and current tobacco smokers and alcohol drinkers may be at higher risk of gastrointestinal injury.

MANAGEMENT: Caution is advised if daprodustat is prescribed to current tobacco smokers or alcohol drinkers. Patients should be advised to contact their physician if they develop potential signs and symptoms of gastrointestinal injury such as abdominal pain, hematemesis, trouble swallowing, chest or throat pain, and/or black, tarry stools.