No drug interaction studies have been performed with GLYXAMBI and other medicinal products; however, such studies have been conducted with the individual active substances. Based on results of pharmacokinetic studies, no dose adjustment of GLYXAMBI is recommended when co-administered with commonly prescribed medicinal products, except those mentioned as follows.
Pharmacodynamic interactions: Insulin and sulphonylureas: Insulin and sulphonylureas may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or sulphonylureas may be required to reduce the risk of hypoglycaemia when used in combination with GLYXAMBI (see Dosage & Administration, Precautions and Adverse Reactions).
Diuretics: Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see Precautions).
Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.
Pharmacokinetic interactions: Effects of other medicinal products on empagliflozin: Empagliflozin is mainly excreted unchanged. A minor fraction is metabolised via uridine 5'-diphosphoglucuronosyltransferases (UGT); therefore, a clinically relevant effect of UGT inhibitors on empagliflozin is not expected (see Pharmacology: Pharmacokinetics under Actions). The effect of UGT induction on empagliflozin has not been studied. Co-administration with known inducers of UGT enzymes should be avoided because of a risk of decreased efficacy of empagliflozin.
Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and OAT3, resulted in a 26 % increase in peak empagliflozin plasma concentrations (Cmax) and a 53 % increase in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful.
An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that empagliflozin Cmax increased by 15 % and AUC increased by 59 % following co-administration. These changes were not considered to be clinically meaningful.
Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75 % increase in Cmax and a 35 % increase in AUC of empagliflozin. These changes were not considered to be clinically meaningful.
Interaction studies suggest that the pharmacokinetics of empagliflozin were not influenced by co-administration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide.
Effects of empagliflozin on other medicinal products: Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives.
Effects of other medicinal products on linagliptin: Co-administration of rifampicin decreased linagliptin exposure by 40 %, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-glycoprotein (P-gp) or cytochrome P450 (CYP) isozyme CYP3A4 inducer, particularly if these are administered long-term (see Pharmacology: Pharmacokinetics under Actions). Co-administration with other potent inducers of P-gp and CYP3A4, such as carbamazepine, phenobarbital and phenytoin, has not been studied.
Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and Cmax of linagliptin approximately twofold and threefold, respectively. The unbound concentrations, which are usually less than 1 % at the therapeutic dose of linagliptin, were increased 4 to 5-fold after co-administration with ritonavir. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir indicated that the increase in exposure will be not associated with an increased accumulation. These changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-glycoprotein/CYP3A4 inhibitors.
Interaction studies conducted in healthy volunteers suggest that the pharmacokinetics of linagliptin were not influenced by co-administration with metformin and glibenclamide.
Effects of linagliptin on other medicinal products: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxin with low potency.
Linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, empagliflozin or oral contraceptives providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).