Xigduo XR Drug Interactions

Co-administration of multiple doses of dapagliflozin and metformin did not meaningfully alter the pharmacokinetics of either dapagliflozin or metformin in healthy subjects.
There have been no formal interaction studies for XIGDUO XR. The following statements reflect the information available on the individual active substances.
Drug interactions with dapagliflozin: The metabolism of dapagliflozin is primarily mediated by UGT1A9-dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide, is not an SGLT2 inhibitor.
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes, and drugs that inhibit or induce these enzymes are not expected to alter the metabolic clearance of dapagliflozin. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.
Effect of Other Drugs on Dapagliflozin: In studies conducted in healthy subjects, the pharmacokinetics of dapagliflozin were not altered by pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (an hOAT-3 substrate and P-glycoprotein substrate), glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. Following Co-administration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolizing enzymes) or mefenamic acid (an inhibitor of UGT1A9), a 22% decrease and a 51% increase, respectively, in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24- hour urinary glucose excretion in either case.
Pioglitazone: Co-administration of a single dose of dapagliflozin (50 mg) and pioglitazone (45 mg), a CYP2C8 (major) and CYP3A4 (minor) substrate, did not alter the pharmacokinetics of dapagliflozin. Therefore, meaningful interactions of dapagliflozin with other CYP2C8 substrates would not be expected.
Sitagliptin: Co-administration of a single dose of dapagliflozin (20 mg) and sitagliptin (100 mg), an hOAT-3 substrate, did not alter the pharmacokinetics of dapagliflozin. Therefore, meaningful interactions of dapagliflozin with other hOAT-3 substrates would not be expected.
Glimepiride: Co-administration of a single dose of dapagliflozin (20 mg) and glimepiride (4 mg), a CYP2C9 substrate, did not alter the pharmacokinetics of dapagliflozin. Therefore, meaningful interactions of dapagliflozin with other CYP2C9 substrates would not be expected.
Voglibose (α-glucosidase inhibitor): Co-administration of a single dose of dapagliflozin (10 mg) and voglibose (0.2 mg three times per day) did not alter the pharmacokinetics of dapagliflozin.
Hydrochlorothiazide: Co-administration of a single dose of dapagliflozin (50 mg) and hydrochlorothiazide (25 mg) did not alter the pharmacokinetics of dapagliflozin.
Bumetanide: Co-administration of multiple once-daily doses of dapagliflozin (10 mg) and multiple once-daily doses of bumetanide (1 mg) did not alter the pharmacokinetics of dapagliflozin. Co-administration of dapagliflozin and bumetanide did not meaningfully change the pharmacodynamic effect of dapagliflozin to increase urinary glucose excretion in healthy subjects.
Valsartan: Co-administration of a single dose of dapagliflozin (20 mg) and valsartan (320 mg) did not alter the pharmacokinetics of dapagliflozin.
Simvastatin: Co-administration of a single dose of dapagliflozin (20 mg) and simvastatin (40 mg), a CYP3A4 substrate, did not alter the pharmacokinetics of dapagliflozin. Therefore, meaningful interactions of dapagliflozin with other CYP3A4 substrates would not be expected.
Rifampin: Co-administration of a single dose of dapagliflozin (10 mg) and rifampin (rifampicin), an inducer of various active transporters and drug-metabolizing enzymes, dosed to steady-state (600 mg/day) resulted in a decrease in dapagliflozin Cmax and AUC by 7% and 22%, respectively. The mean amount of glucose excreted in the urine over 24 hours following administration of dapagliflozin alone (51 g) was not markedly affected by rifampin Co-administration (45 g). No dose adjustment of dapagliflozin is recommended when dapagliflozin is co-administered with rifampin.
Mefenamic Acid: Co-administration of a single dose of dapagliflozin (10 mg) and mefenamic acid, an inhibitor of UGT1A9, dosed to steady-state (250 mg every 6 hours) resulted in an increase in dapagliflozin Cmax and AUC by 13% and 51%, respectively. The mean amount of glucose excreted in the urine over 24 hours following administration of dapagliflozin alone was not markedly affected by mefenamic acid Co-administration. No dose adjustment of dapagliflozin is recommended when dapagliflozin is co-administered with mefenamic acid.
Effect of Dapagliflozin on Other Drugs: In studies conducted in healthy subjects, as described as follows, dapagliflozin did not alter the pharmacokinetics of pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, simvastatin, digoxin, or warfarin.
Pioglitazone: Co-administration of a single dose of dapagliflozin (50 mg) and pioglitazone (45 mg), a CYP2C8 (major) and CYP3A4 (minor) substrate, did not alter the pharmacokinetics of pioglitazone. Therefore, dapagliflozin does not meaningfully inhibit CYP2C8-mediated metabolism.
Sitagliptin: Co-administration of a single dose of dapagliflozin (20 mg) and sitagliptin (100 mg), an hOAT-3 substrate, did not alter the pharmacokinetics of sitagliptin. Therefore, dapagliflozin is not an inhibitor of hOAT-3 transport pathway.
Glimepiride: Co-administration of a single dose of dapagliflozin (20 mg) and glimepiride (4 mg), a CYP2C9 substrate, did not alter the pharmacokinetics of glimepiride. Therefore, dapagliflozin is not an inhibitor of CYP2C9-mediated metabolism.
Hydrochlorothiazide: Co-administration of a single dose of dapagliflozin (50 mg) and hydrochlorothiazide (25 mg) did not alter the pharmacokinetics of hydrochlorothiazide.
Bumetanide: Co-administration of a multiple once-daily doses of dapagliflozin (10 mg) and multiple once-daily doses of bumetanide (1 mg) increased both Cmax and AUC bumetanide values by 13%. Co-administration of dapagliflozin did not meaningfully alter the steady-state pharmacodynamics responses (urinary sodium excretion, urine volume) to bumetanide in healthy subjects.
Valsartan: Co-administration of a single dose of dapagliflozin (20 mg) and valsartan (320 mg) did not alter the pharmacokinetics of valsartan.
Simvastatin: Co-administration of a single dose of dapagliflozin (20 mg) and simvastatin (40 mg), a CYP3A4 substrate, did not affect the Cmax of simvastatin but increased the AUC by 20%, which was not considered to be clinically relevant. Therefore, dapagliflozin does not meaningfully inhibit CYP3A4-mediated metabolism.
Digoxin: Co-administration of dapagliflozin (10 mg once daily following a 20-mg loading dose) and a single dose of digoxin (0.25 mg), a P-glycoprotein substrate, did not affect the pharmacokinetics of digoxin. Therefore, dapagliflozin does not meaningfully inhibit or induce P-gp-mediated transport.
Warfarin: Co-administration of dapagliflozin (10 mg once daily following a 20-mg loading dose) and a single dose of warfarin (25 mg) did not affect the pharmacokinetics of S-warfarin, a CYP2C19 substrate. Therefore, dapagliflozin does not meaningfully inhibit or induce CYP2C19-mediated metabolism. Dapagliflozin also did not affect the pharmacokinetics of R-warfarin. Additionally, dapagliflozin did not affect the anticoagulant activity of warfarin as measured by the prothrombin time (International Normalized Ratio [INR]).
Lithium: Concomitant use of dapagliflozin and lithium may lead to a reduction in serum lithium concentrations due to a possible increased urinary clearance of lithium. The dose of lithium may need to be adjusted.
Drug interactions with metformin: Cationic Drugs: Metformin hydrochloride: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Glyburide: Metformin hydrochloride: In a single-dose interaction study in type 2 diabetes patients, Co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and maximum concentration (Cmax) were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects make the clinical significance of this interaction uncertain.
Furosemide: Metformin hydrochloride: A single-dose, metformin-furosemide drug-interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by Co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
Nifedipine: Metformin hydrochloride: A single-dose, metformin-nifedipine drug-interaction study in normal healthy volunteers demonstrated that Co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Use with Other Drugs: Metformin hydrochloride: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin, the patient should be closely observed for loss of blood glucose control.
When such drugs are withdrawn from a patient receiving metformin, the patient should be observed closely for hypoglycemia.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.
Metformin is negligibly bound to plasma proteins and, therefore, is less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.
Other interactions: The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of dapagliflozin have not been specifically studied.
Interference with 1.5-anhydroglucitol (1.5.AG) Assay: Monitoring glycemic control with 1.5-AG assay is not recommended as measurements of 1.5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.