Evrenzo Drug Interactions

Patients with CKD often use multiple medications concurrently. The following are drugs that require caution when used in conjunction with roxadustat: Phosphate binders, oral iron: Co-administration of roxadustat (200 mg) with sevelamer carbonate (2400 mg) or calcium acetate (1900 mg) decreased roxadustat AUC by 67% and 46% and C_max by 66% and 52%, respectively. Roxadustat should be taken at least 1 hour before or after the use of phosphate binders, oral iron, magnesium/aluminum-containing antacids, or other multivalent cation-containing drugs and mineral supplements. This restriction does not apply to lanthanum carbonate, as co-administration with lanthanum carbonate did not result in a clinically meaningful change in roxadustat AUC or C_max.
Activated adsorptive charcoal: Co-administration with oral adsorptive charcoal (Kremezin) does not have a clinically meaningful effect on roxadustat AUC or C_max.
Probenecid (UGT and OAT1/OAT3 inhibitor): Co-administration of roxadustat (100 mg) with probenecid (500 mg, BID) results in a 2.3-fold increase in roxadustat AUC and a 1.4-fold increase in C_max. Caution is advised when starting or stopping concurrent treatment with probenecid, other OAT1/OAT3 inhibitors (e.g., teriflunomide), UGT inhibitors (e.g., valproic acid), and UGT inducers (e.g., rifampin). Dose adjustment of roxadustat may be considered if necessary.
Statins: Co-administration of roxadustat (200 mg) with simvastatin (40 mg) increases the AUC and C_max of simvastatin by 1.8- and 1.9-fold, respectively, and the AUC and C_max of Simvastatin acid (the active metabolite of Simvastatin) by 1.9- and 2.8-fold, respectively. Time-separation of dosing by 2, 4, or 10 hours does not mitigate this interaction.
Co-administration of roxadustat (200 mg) with Rosuvastatin (10 mg) increases the AUC and C_max of Rosuvastatin by 2.9- and 4.5-fold, respectively.
Co-administration of roxadustat (200 mg) with Atorvastatin (40 mg) increases the AUC and C_max of Atorvastatin by 2.0- and 1.3-fold, respectively.
Interactions are also expected when co-administered with other statins (or an OATP1B1 substrate such as Glyburide).
To avoid statin overdose and potential effects on skeletal muscles (e.g., myalgia, myopathy, and rare rhabdomyolysis), it is recommended to consider reducing the dose of statin and to monitor for adverse reactions when used with roxadustat.
Gemfibrozil (CYP2C8 and OATP1B1 inhibitor): Co-administration of roxadustat (100 mg) with Gemfibrozil (600 mg BID) increased roxadustat AUC by 2.3-fold and C_max by 1.4-fold. Caution is advised when initiating or discontinuing concomitant treatment with Gemfibrozil, other OATP1B1 inhibitors (e.g., cyclosporine), CYP2C8 inhibitors, and CYP2C8 inducers (e.g., Rifampin). Dose adjustment of roxadustat may be considered if necessary.
Increased roxadustat plasma exposure could potentially lead to a rapid rise in Hb levels when roxadustat is used with Gemfibrozil or Probenecid. This risk can be mitigated by regular monitoring of Hb levels and appropriate dose adjustments. For information on the use of Probenecid or Gemfibrozil in patients with CKD, refer to relevant Package Inserts of these products.
Omeprazole (gastric acid inhibitor): Co-administration of roxadustat with Omeprazole did not show a clinically meaningful effect on roxadustat AUC or C_max. No interactions are anticipated between roxadustat and other proton pump inhibitors.
CYP450 inhibition/induction potential: Co-administration of roxadustat did not show a clinically meaningful effect on the AUC or C_max of drugs metabolized by CYP2B6 (bupropion), CYP2C8 (rosiglitazone), or CYP2C9 (S-warfarin) enzyme. No clinically significant interactions (CYP metabolism inhibition) are expected when roxadustat is used with drugs metabolized by CYP enzymes.
Roxadustat has shown no induction of CYP enzymes in vitro at clinically relevant concentrations.
In vitro CYP450 enzyme inhibition studies assessing the inhibition of a panel of CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/3A5) revealed that roxadustat is a mixed-type inhibitor of CYP2B6, 2C8, and 2C9, with K_i values of 110, 16, and 140 µmol/L, respectively. Roxadustat is a non-competitive inhibitor of CYP2A6 and 3A4/3A5, with K_i values of 340 and 460 µmol/L, respectively. Roxadustat shows minimal direct inhibition of CYP1A2, 2D6, and 2E1 (IC50 > 500 µmol/L). Although the effects of roxadustat on the pharmacokinetics of CYP1A2, 2A6, 2C19, 2D6, 2E1, and 3A4/3A5 substrates have not been assessed in humans, the absence of clinically meaningful drug interactions with CYP2C8, 2C9, and 2B6 probe substrates suggests that inhibition of other CYP enzyme substrates are unlikely.
Clopidogrel: Co-administration of roxadustat with Clopidogrel did not affect roxadustat exposure.