There were no studies on drug interactions of the preparation GENTADUETO. However, pharmacokinetic studies were conducted on the drug interactions of the components of the preparation GENTADOUEDO: linagliptin and metformin.
Linaglyptin
Evaluation of drug interactions in vitro
Linagliptin is a weak competitive inhibitor of isoenzyme CYP3A4, has a weak or moderate ability to irreversibly inhibit the isoenzyme CYP3A4, but does not inhibit other isoenzymes CYP. Linagliptin is not an inducer of isozymes CYP.
Linagliptin is a substrate for glycoprotein-P and to a small extent inhibits glycoprotein-P-mediated digoxin transport. Based on these results and data obtained in studies of drug interactions in vivo, the ability of linagliptin to interact with other substrates for glycoprotein-P is considered unlikely.
Evaluation of drug interaction in vivo
Linagliptin had no clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, and oral contraceptives, which was consistent with those obtained under conditions in vivo data on low ability to drug interactions with substrates for isoenzymes CYP3A4. CYP2C9, CYP2C8, glycoprotein-P and carriers of organic cations.
Metformin. The simultaneous use of metformin (repeated use in a dose of 850 mg 2-3 times a day) and linagliptin (10 mg once a day) in healthy volunteers did not lead to clinically significant changes in the pharmacokinetics of linagliptin or metformin.
Derivatives of sulfonylureas. Simultaneous single administration of glibenclamide (1.75 mg) and repeated use of linagliptin (5 mg) did not affect the pharmacokinetics of linagliptin. However, there was a clinically insignificant decrease (by 14%) in the value AUC and CmOh glibenclamide. Because the glibenclamide is mainly metabolized with the participation of isoenzyme CYP2C9. These data also support the conclusion that linaglyptin is not an inhibitor of isoenzyme CYP2C9. Clinically significant interactions are not expected with other derivatives of sulfonylureas (for example, glipizide, tolbutamide and glimepiride), which, like glibenclamide. mainly metabolized with the participation of isoenzyme CYP2C9. Thiazolidinediones. Simultaneous multiple application of linagliptin in a dose exceeding the recommended therapeutic (10 mg) and repeated use of pioglitazone in a daily dose of 45 mg, which is a substrate for isoenzymes CYP2C8 and CYP3A4, did not lead to clinically significant changes in the pharmacokinetics of linagliptin or pioglitazone (and also active metabolites of pioglitazone). This indicates that linaglyptin in vivo It is not an inhibitor of isoenzyme mediated metabolism CYP2C8, and confirms the conclusion that in conditions in vivo inhibition of isoenzyme CYP3A4 linagliptin is insignificant.
Ritonavir. The effect of ritonavir, an active inhibitor of glycoprotein-P and isoenzyme CYP3A4, on the pharmacokinetics of linagliptin. Simultaneous single application of linagliptin inside at a dose of 5 mg and repeated application of ritonavir inside at a dose of 200 mg resulted in an increase in the values AUC and CmOh linagliptin, respectively, approximately 2 and 3 times. The observed changes in the pharmacokinetics of linagliptin were not considered clinically significant. Therefore, when using other glycoprotein-P inhibitors and / or CYP3A4 clinically significant interactions are not expected, and dose adjustment is not required.
Rifampicin. The effect of rifampicin (an active inducer of glycoprotein-P and isoenzyme CYP3A4) on the pharmacokinetics of linagliptin taken in a dose of 5 mg. Simultaneous multiple use of linagliptin and rifampicin resulted in a decrease in the values of AUC and CmOh linagliptin during the equilibrium plasma concentration, respectively, by 39.6% and 43.8%, and to a decrease in inhibition of DPP-4 by approximately 30%. Thus, the clinical efficacy of linagliptin in the case of simultaneous use of active inducers of glycoprotein-P will persist, although, perhaps, not completely.
Digoxin. Joint repeated use in healthy volunteers of linagliptin (5 mg per day) and repeated use of digoxin (0.25 mg) did not affect the pharmacokinetics of digoxin. Therefore, it is considered that in vivo linagliptin is not an inhibitor of digoxin transport mediated by glycoprotein-P.
Warfarin. Multiple doses of linagliptin (5 mg per day) did not alter the pharmacokinetics of warfarin. which is a substrate for CYP2C9, which confirms the lack of ability to inhibit linagliptin CYP2C9.
Simvastatin. In healthy volunteers, repeated administration of linagliptin at a dose of 10 mg per day exceeding the recommended therapeutic dose had minimal effect on the pharmacokinetics of simvastatin, which is the substrate for CYP3A4. After simultaneous application of linagliptin in a dose of 10 mg and simvastatin at a dose of 40 mg for 6 days, the value AUC Simvastatin in plasma increased by 34%, and CmOh - on 10%. Concerning linaglyptin is considered a weak inhibitor of metabolism, which is carried out with the participation of isoenzyme CYP3A4. Dose correction with simultaneous use of linagliptin and drugs metabolized with the participation of isoenzyme CYP3A4, is not required.
Oral contraceptives. The combined use of linagliptin with levonorgestrel or ethinylestradiol did not alter the pharmacokinetics of these drugs.
Metformin
The use of metformin during acute alcohol intoxication increases the risk of developing lactic acidosis (especially in case of fasting, malnutrition or liver failure). Therefore, when using the drug GENTTADOUTO should avoid the use of alcohol and medications containing ethanol.
Cationic drugs, secreted in the renal tubules (for example, cimetidine), compete with metformin for tubular transport systems and can lead to an increase in CmOh metformin. Therefore, with the simultaneous use of the drug GENTADUETO and cationic drugs, careful monitoring of blood glucose concentration is required, since a change in the dose of metformin may be required.
On the background of functional renal failure in patients with diabetes mellitus, a radiological study using iodine-containing radiopaque agents can cause the development of lactic acidosis. The drug must cancel DZHENTADUETO depending on renal function for 48 hours before or at the time of X-ray studies using iodinated contrast media, and not to resume previously after 48 hours under the condition that the survey renal function was considered normal.
Glucocorticosteroids, beta-2-adrenergic agonists and diuretics have a hyperglycemic effect. Patients should be informed of the need for more frequent monitoring of blood glucose,especially at the beginning of therapy with the above drugs.
Danazol: It is not recommended to take danazol concurrently to avoid hyperglycemic action of the latter. If it is necessary to treat danazol and after stopping the latter, a correction of the dose of Gentadueto is required under the control of the glucose concentration in the blood.
Chlorpromazine: when taken in high doses (100 mg per day) increases the concentration of glucose in the blood, reducing the release of insulin. When treating with antipsychotics and after stopping the intake of the latter, a correction of the dose of Gentadueto under the control of the concentration of glucose in the blood is required.
Angiotensin converting enzyme inhibitors and other antihypertensive drugs can reduce the concentration of glucose in the blood. If necessary, the dose of Gentadueto should be adjusted.
With the simultaneous use of the drug GENTADOUETO with derivatives of sulfonylurea, insulin, acarbose, salicylates possible development hypoglycemia.
Nifedipine increases absorption and CmOh metformin.
Simultaneous reception "loop "diuretics can lead to the development of lactic acidosis because of the possible functional renal failure.