Zemimet SR Drug Interactions

There have been no formal interaction studies for Zemimet SR 50/1000 mg. The following statements reflect the information available on the individual active substances.
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 50/1000 mg (see Precautions). 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 50/1000 mg 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 (see Precautions).
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 cyclo-oxygenase (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 (see Precautions).
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.
In vitro assessment of interactions: Gemigliptin: 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 but maybe affected by CYP3A inhibitors or inducers. Gemigliptin mildly inhibited P-gp mediated transport at a high concentration.
Effects of gemigliptin on other medicinal products: In clinical studies, gemigliptin did not meaningfully alter the pharmacokinetics of metformin, pioglitazone and glimepiride.
Metformin: Repeated co-administration of 50 mg gemigliptin with 2000 mg metformin 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, 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 did not meaningfully alter the pharmacokinetics of glimepiride at steady state. The effect of co-administration of gemigliptin on the AUC and C_max of glimepiride was less than 3%.
Effects of other medical products on gemigliptin: In clinical studies, metformin and pioglitazone did not meaningfully alter the pharmacokinetics of gemigliptin. Ketoconazole alters the pharmacokinetics of gemigliptin and its active metabolite but extended interaction was not considered clinically significant, and no dose adjustment is required. 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 2000 mg metformin did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state. The AUC and C_max of gemigliptin were decreased by 9% and 8%, respectively, and AUC and C_max of LC15-0636 were decreased by 5%.
Pioglitazone: Repeated co-administration of 200 mg gemigliptin with 30 mg of pioglitazone did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state. The AUC of gemigliptin was increased by 6% while C_max was decreased by 3%. The AUC and C_max of active metabolite were increased by 3% and 9%, respectively.
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 (see Contraindications and Precautions).
Metformin: Phenprocoumon: Metformin may decrease the anti-coagulant effect of phenprocoumon. Therefore, a 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.