Zemimet SR Drug Interactions

Co-administration of multiple doses of gemigliptin and metformin did not meaningfully alter the pharmacokinetics of either gemigliptin or metformin in patients with type 2 diabetes.
There have been no formal interaction studies for Zemimet SR. The following statements reflect the information available on the individual active substances.
Gemigliptin: In vitro assessment of interactions: The responsible enzyme for the metabolism of gemigliptin is CYP3A4. In vitro studies indicated that gemigliptin and its active metabolite are not inhibitors of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 and are not inducers 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 concentrations. Therefore, gemigliptin is unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.
In vivo assessment of interactions: Effects of gemigliptin on other medicinal products: In clinical studies, gemigliptin did not meaningfully alter the pharmacokinetics of metformin, pioglitazone and glimepiride, rosuvastatin, dapagliflozin, or empagliflozin providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP2C8, CYP2C9, CYP3A4, organic cation transporter (OCT), and UDP-glucuronosyltransferase (UGT).
Metformin: Repeated co-administration of 50 mg gemigliptin with 2,000 mg metformin, a substrate of OCT1 and OCT2, decreased the C_max of metformin by 13% but did not affect the AUC of metformin at steady state.
Pioglitazone: Repeated co-administration of 200 mg gemigliptin with 30 mg pioglitazone, a substrate of CYP2C8 and 3A4, decreased the AUC and C_max of pioglitazone by 15% and 17%, respectively. However, those of the active metabolites of pioglitazone were not changed at steady state.
Glimepiride: Co-administration of multiple doses of 50 mg gemigliptin with a single dose of 4 mg glimepiride, a substrate of CYP2C9, did not meaningfully alter the pharmacokinetics of glimepiride at steady state.
Rosuvastatin: Repeated co-administration of 50 mg gemigliptin with 20 mg rosuvastatin, a substrate of CYP2C9 and 3A4, did not meaningfully alter the pharmacokinetics of rosuvastatin at steady state.
Dapagliflozin: Repeated co-administration of 50 mg gemigliptin with 10 mg of dapagliflozin, a substrate of UGT1A9, did not meaningfully alter the pharmacokinetics of dapagliflozin at steady state.
Empagliflozin: Repeated co-administration of 50 mg gemigliptin with 25 mg of empagliflozin, a substrate of UGT2B7, UGT1A3, UGT1A8, and UGT1A9, did not meaningfully alter the pharmacokinetics of empagliflozin at steady state.
Effects of other medical products on gemigliptin: In clinical studies, metformin and pioglitazone did not meaningfully alter the pharmacokinetics of gemigliptin. Ketoconazole did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite. 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: Repeated co-administration of 50 mg gemigliptin with 2,000 mg metformin, a substrate of OCT1 and OCT2, did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state.
Pioglitazone: Repeated co-administration of 200 mg gemigliptin with 30 mg of pioglitazone, a substrate of CYP2C8 and 3A4, did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state.
Ketoconazole: Co-administration of multiple doses of 400 mg ketoconazole, a strong inhibitor of CYP3A4, 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 at steady state.
Rifampicin: Co-administration of multiple doses of 600 mg rifampicin, a strong inducer of CYP3A4, 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 36% at steady state.
Rosuvastatin: Repeated co-administration of 50 mg gemigliptin with 20 mg rosuvastatin did not meaningfully alter the pharmacokinetics of gemigliptin at steady state.
Dapagliflozin: Repeated co-administration of 50 mg gemigliptin with 10 mg of dapagliflozin did not meaningfully alter the pharmacokinetics of gemigliptin at steady state.
Empagliflozin: Repeated co-administration of 50 mg gemigliptin with 25 mg of empagliflozin did not meaningfully alter the pharmacokinetics of gemigliptin at steady state.
Metformin: Combinations not recommended: Alcohol: There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition, or hepatic impairment) due to the metformin active substance of Zemimet SR. Consumption of alcohol and medicinal products containing 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, Zemimet SR 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.
Combination requiring precautions for use: Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.
Glucocorticoids: Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsic hyperglycemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
ACE-inhibitors: ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the anti-hyperglycemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.
Levothyroxine: Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.
Organic cation transporters (OCT): Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with: Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.
Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.
Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered, as OCT inhibitors/inducers may alter the efficacy of metformin.