Zemimet SR Drug Interactions

Co-administration of single dose of gemigliptin (50 mg) and metformin (1 g) given twice daily did not meaningfully alter the pharmacokinetics of either gemigliptin or metformin in healthy volunteers.
Pharmacokinetic drug interaction studies with Gemigliptin/Metformin HCl have not been performed; however, such studies have been conducted with the individual components.
Gemigliptin: The responsible enzyme for the metabolism of gemigliptin is CYP3A4. In vitro studies indicated that gemigliptin is not an inhibitor of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 and is not an inducer of CYP1A2, 2C8, 2C9, 2C19, or 3A4. Therefore, gemigliptin is unlikely to cause interactions with other drugs that utilize these metabolic pathways. In vitro studies further indicated that gemigliptin did not induce P-glycoprotein (P-gp) while mildly inhibited P-gp mediated transport at high concentration. Therefore, gemigliptin is unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.
Effects of gemigliptin on other drugs: 50 mg/1 g: In clinical studies, gemigliptin did not meaningfully alter the pharmacokinetics of metformin, pioglitazone, glimepiride, rosuvastatin, dapagliflozin, and empagliflozin providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP2C8, CYP2C9, CYP3A4, and organic cation transporter (OCT).
50 mg/500 mg: In clinical studies, gemigliptin did not meaningfully alter the pharmacokinetics of metformin, pioglitazone, glimepiride and rosuvastatin, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP2C8, CYP2C9, CYP3A4, and organic cation transporter (OCT).
Metformin: Co-administration of multiple doses of 50 mg gemigliptin with 2000 mg metformin, a substrate of OCT1 and OCT2, to steady state decreased the C_max of metformin by 13% but did not affect the AUC of metformin.
Pioglitazone: Co-administration of multiple doses of 200 mg gemigliptin with 30 mg pioglitazone, a substrate of CYP2C8 and 3A4, to steady state decreased the AUC and C_max of pioglitazone by 15% and 17%, respectively. However, those of the active metabolites of pioglitazone were not changed.
Glimepiride: Co-administration of multiple doses of 50 mg gemigliptin to steady state with a single dose of 4 mg glimepiride, a substrate of CYP2C9, did not meaningfully alter the pharmacokinetics of glimepiride.
Rosuvastatin: Co-administration of multiple doses of 50 mg gemigliptin with 20 mg rosuvastatin, a substrate of CYP2C9 and 3A4, to steady state did not meaningfully alter the pharmacokinetics of rosuvastatin.
50 mg/1 g: Repeated co-administration of 50 mg gemigliptin with 10 mg of dapagliflozin, substrate of UGT149, did not meaningfully alter the pharmacokinetics of dapagliflozin at steady state.
Repeated co-administration of 50 mg gemigliptin with 25 mg of empagliflozin, substrate of UGT2B7, UGT1A3, UGT1A8, and UGT1A9, did not meaningfully alter the pharmacokinetics of empagliflozin at steady state.
Effects of other drugs on gemigliptin: 50 mg/500 mg: In clinical studies, metformin, pioglitazone and rosuvastatin did not meaningfully alter the pharmacokinetics of gemigliptin. Ketoconazole did not meaningfully alter the pharmacokinetics of gemigliptin. Therefore, strong and moderate CYP3A4 inhibitors would not cause clinically meaningful drug interactions. Rifampicin (rifampin), on the other hand, significantly decreased exposure of gemigliptin. Therefore, co-administration with other strong CYP3A4 inducers, including rifampicin (rifampin), dexamethasone, phenytoin, carbamazepine, rifabutin and phenobarbital, is not recommended.
50 mg/1 g: In clinical studies, metformin, pioglitazone, rosuvastatin, dapagliflozin, and empagliflozin did not meaningfully alter the pharmacokinetics of gemigliptin. Ketoconazole did not meaningfully alter the pharmacokinetics of gemigliptin. Therefore, strong and moderate CYP3A4 inhibitors would not cause clinically meaningful drug interactions. Rifampicin (rifampin), on the other hand, significantly decreased exposure of gemigliptin. Therefore, co-administration with other strong CYP3A4 inducers, including rifampicin (rifampin), dexamethasone, phenytoin, carbamazepine, rifabutin and phenobarbital, is not recommended.
Metformin: Co-administration of 50 mg gemigliptin with 2000 mg metformin, a substrate of OCT1 and OCT2, to steady state did not meaningfully alter the pharmacokinetics of gemigliptin.
Pioglitazone: Co-administration of 200 mg gemigliptin with 30 mg of pioglitazone, a substrate of CYP2C8 and 3A4, to steady state did not meaningfully alter the pharmacokinetics of gemigliptin.
Ketoconazole: Co-administration of multiple doses of 400 mg ketoconazole once daily, a strong inhibitor of CYP3A4, to steady state with a single dose of 50 mg gemigliptin, increased the AUC of active moiety, the sum of gemigliptin and its active metabolite by 1.9-fold.
Rifampicin: Co-administration of multiple doses of 600 mg rifampicin once daily, a strong inducer of CYP3A4, to steady state, with a single dose of 50 mg gemigliptin, decreased the AUC and C_max of gemigliptin by 80% and 59%, respectively. The C_max of active metabolite of gemigliptin was not significantly affected while the AUC was decreased by 41%.
Rosuvastatin: Repeated administration of 20 mg of rosuvastatin, a strong inducer of CYP2C9 and 3A4, with 50 mg of gemigliptin to steady state did not meaningfully alter the pharmacokinetics of gemigliptin.
50 mg/1 g: Repeated co-administration of 50 mg gemigliptin with 10 mg of dapagliflozin, substrate of UGT1A9, did not meaningfully alter the pharmacokinetics of dapagliflozin at steady state.
Repeated co-administration of 50 mg gemigliptin with 25 mg of empagliflozin, substrate of UGT2B7, UGT1A3, UGT1A8, and UGT1A9, did not meaningfully alter the pharmacokinetics of empagliflozin at steady state.
Metformin: Concomitant medication(s) of below medicinal products may potential hypoglycemic or hyperglycemic effects of metformin. Therefore, co-administration should be based on a careful assessment of glucose level and patient monitoring.
Drugs that can potentiate the hypoglycemic effect of metformin: Insulin, sulfonylamides, sulfonylureas, alpha-glucosidase inhibitors, anabolic steroid, guanethidine, salicylates (aspirin), beta blockers (propranolol), MAO inhibitors, angiotensin receptor antagonists.
Drugs that can potentiate the hyperglycemic effect of metformin: Epinephrine, sympathomimetics, corticosteroids, thyroid hormones, follicle hormone, estrogen, oral contraceptives, thiazides and other diuretics, pyrazinamide, isoniazid, nicotinic acid, phenothiazines, phenytoin, calcium channel blocking drugs.
Alcohol: The risk of metformin accumulation and lactic acidosis increases in patients with acute alcohol intoxication in the following conditions: Fasted or malnourished state; Reduced hepatic function.
Intake of alcohol or medicinal products that contain alcohol should be avoided.
Iodinated contrast agents: The intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, Gemigliptin/Metformin HCl must be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
Glyburide: In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C_max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between metformin blood levels and pharmacodynamics effects, makes the clinical significance of this interaction uncertain.
Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C_max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C_max 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 coadministered chronically.
Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C_max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T_max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Drugs which may affect renal function, cause significant hemodynamic changes, or affect metformin such as organic cation transporter excreted through renal tubular secretion: Metformin is a substrate of organic cation transporter (OCT) 1 and OCT 2.
Concomitant use with OCT1 inhibitors (verapamil, etc.) may reduce the effect of metformin.
Concomitant use with OCT1 inducers (rifampicin, etc.) may increase the gastrointestinal uptake and effect of metformin.
Concomitant use with OCT2 inhibitors (cimetidine, dolutegravir, lanolazine, trimethoprim, vandetanib, isavuconazole, etc.) may reduce the renal excretion of metformin leading to increase in blood concentration of metformin.
Concomitant use with OCT2 & OCT1 co-inhibitors (crizotinib, olaparib, etc.) may affect the renal excretion and effect of metformin.
Therefore, as concomitant use with such medicines may increase the blood concentration of metformin, special caution is required, especially for patients with renal impairment. As OCT inhibitors/inducers may change the effect of metformin, dose adjustment of metformin may be considered if necessary.
In addition, non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, diuretics (especially loop diuretics), etc. may have adverse effects on renal function leading to increase in the risk of lactic acidosis, renal function should be closely monitored when they are administered concomitantly with metformin.
Others: In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, 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.