Glyhart Drug Interactions

The metabolism of dapagliflozin is primarily mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9.
In vitro studies have shown that dapagliflozin and dapagliflozin 3-O-glucuronide, an inactive metabolite of dapagliflozin, did not inhibit cytochrome P450 (CYP) isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4. Dapagliflozin also did not induce CYP1A2, 2B6 or 3A4 in vitro. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the organic anion transport (OAT) 3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not significantly inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.
Insulin and Insulin Secretagogues: Concomitant use may potentially result in hypoglycemia. A lower dose of insulin or insulin secretagogue (e.g., sulfonylurea) may be required to reduce the risk of hypoglycemia.
Bumetanide: Coadministration of dapagliflozin (10 mg once a day for 7 days) and a single dose of bumetanide (1 mg) increased bumetanide AUC and C_max by 13%.
Digoxin: Coadministration of dapagliflozin (20 mg loading dose, then 10 mg once a day for 7 days) and a single dose of digoxin (250 mcg), a P-gp substrate, did not have a clinically significant effect on the AUC or C_max of digoxin.
Glimepiride: Coadministration of a single dose of dapagliflozin (20 mg) and glimepiride (4 mg), a CYP2C9 substrate, increased glimepiride AUC by 13%.
Hydrochlorothiazide: Coadministration of a single dose of dapagliflozin (50 mg) and hydrochlorothiazide (25 mg) did not have a clinically significant effect on the pharmacokinetics of hydrochlorothiazide or dapagliflozin.
Mefenamic Acid: Concurrent use of a single dose of dapagliflozin (10 mg) and mefenamic acid (loading dose of 500 mg, then 250 mg every 6 hours for 14 doses), an inhibitor of UGT1A9, increased dapagliflozin C_max and AUC by 13% and 51%, respectively. No dosage adjustment is necessary.
Metformin: Coadministration of a single dose of dapagliflozin (20 mg) and metformin (1 g), an hOCT-1 and hOCT-2 substrate, did not have a clinically significant effect on the pharmacokinetics of dapagliflozin or metformin.
Pioglitazone: Coadministration of a single dose of dapagliflozin (50 mg) and pioglitazone (45 mg), a CYP2C8 (major) and CYP3A4 (minor) substrate, decreased pioglitazone C_max by 7%.
Rifampicin: Coadministration of a single dose of dapagliflozin (10 mg) and rifampicin (600 mg once a day for 6 days), an inducer of various active transporters and drug-metabolizing enzymes, decreased dapagliflozin C_max and AUC by 7% and 22%, respectively. A clinically relevant effect with other inducers (e.g., carbamazepine, phenytoin, phenobarbital) is not expected.
Simvastatin: Coadministration of a single dose of dapagliflozin (20 mg) and simvastatin (40 mg), a CYP3A4 substrate, increased simvastatin AUC by 19%.
Sitagliptin: Coadministration of a single dose of dapagliflozin (20 mg) and sitagliptin (100 mg), an hOAT-3 and P-gp substrate, did not have a clinically significant effect on the pharmacokinetics of dapagliflozin or sitagliptin.
Valsartan: Coadministration of a single dose of dapagliflozin (20 mg) and valsartan (320 mg) decreased C_max of valsartan and dapagliflozin by 6 and 12%, respectively, and increased valsartan AUC by 5%.
Voglibose: Coadministration of a single dose of dapagliflozin (10 mg) and voglibose (200 mcg three times a day), an α-glucosidase inhibitor, did not have a clinically significant effect on the pharmacokinetics of dapagliflozin.
Warfarin: Concurrent use of dapagliflozin (20 mg loading dose, 10 mg once a day for 7 days) and a single dose of warfarin (25 mg) did not have a clinically significant effect on the pharmacokinetics or anticoagulant activity of warfarin as measured by the prothrombin time [International Normalized Ratio (INR)].