SelgiMet PRO (Tablets) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

ATC Code

A10BD07 (Metformin and Sitagliptin)

Active Substances

Metformin (Rec.INN registered by WHO)

Sitagliptin (Rec.INN registered by WHO)

Dosage Forms

	SelgiMet PRO	Film-coated tablets 500 mg+50 mg
		Film-coated tablets 850 mg+50 mg
		Film-coated tablets 1000 mg+50 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – jars – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – By prescription
14 pcs. – jars – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – By prescription
14 pcs. – blister packs (7 pcs.) – cardboard packs (98 pcs.) – By prescription
28 pcs. – jars – cardboard packs (28 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
56 pcs. – jars – cardboard packs (56 pcs.) – By prescription
60 pcs. – jars – cardboard packs (60 pcs.) – By prescription
84 pcs. – jars – cardboard packs (84 pcs.) – By prescription
90 pcs. – jars – cardboard packs (90 pcs.) – By prescription
98 pcs. – jars – cardboard packs (98 pcs.) – By prescription

Film-coated tablets

10 pcs. – jars – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – By prescription
14 pcs. – jars – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – By prescription
14 pcs. – blister packs (7 pcs.) – cardboard packs (98 pcs.) – By prescription
28 pcs. – jars – cardboard packs (28 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
56 pcs. – jars – cardboard packs (56 pcs.) – By prescription
60 pcs. – jars – cardboard packs (60 pcs.) – By prescription
84 pcs. – jars – cardboard packs (84 pcs.) – By prescription
90 pcs. – jars – cardboard packs (90 pcs.) – By prescription
98 pcs. – jars – cardboard packs (98 pcs.) – By prescription

Film-coated tablets

10 pcs. – jars – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – By prescription
14 pcs. – jars – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – By prescription
14 pcs. – blister packs (7 pcs.) – cardboard packs (98 pcs.) – By prescription
28 pcs. – jars – cardboard packs (28 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
56 pcs. – jars – cardboard packs (56 pcs.) – By prescription
60 pcs. – jars – cardboard packs (60 pcs.) – By prescription
84 pcs. – jars – cardboard packs (84 pcs.) – By prescription
90 pcs. – jars – cardboard packs (90 pcs.) – By prescription
98 pcs. – jars – cardboard packs (98 pcs.) – By prescription

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; combinations of oral hypoglycemic drugs

Pharmacological Action

The drug is a combination of two hypoglycemic drugs with complementary mechanisms of action, intended to improve glycemic control in patients with type 2 diabetes mellitus: sitagliptin, an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, and metformin, a representative of the biguanide class.

Metformin

Metformin is a hypoglycemic drug that increases glucose tolerance in patients with type 2 diabetes mellitus by reducing basal and postprandial blood glucose concentrations. Its pharmacological mechanisms of action differ from those of other classes of oral hypoglycemic drugs.

Metformin reduces hepatic glucose synthesis, reduces intestinal glucose absorption, and increases insulin sensitivity by enhancing peripheral glucose uptake and utilization. Unlike sulfonylurea derivatives, Metformin does not cause hypoglycemia in patients with type 2 diabetes mellitus or in healthy individuals (except under certain circumstances) and does not cause hyperinsulinemia. During treatment with metformin, insulin secretion does not change, while fasting insulin concentration and the daily plasma insulin concentration may decrease.

Sitagliptin

Sitagliptin is an orally active, highly selective inhibitor of the DPP-4 enzyme, intended for the treatment of type 2 diabetes mellitus. The pharmacological effects of the class of DPP-4 inhibitor drugs are mediated by the activation of incretins. By inhibiting DPP-4, Sitagliptin increases the concentration of two known active hormones of the incretin family: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins are part of the intrinsic physiological system regulating glucose homeostasis. At normal or elevated blood glucose concentrations, GLP-1 and GIP promote increased synthesis and secretion of insulin by pancreatic β-cells. GLP-1 also suppresses glucagon secretion by pancreatic α-cells, thereby reducing hepatic glucose synthesis. This mechanism of action differs from that of sulfonylurea derivatives, which stimulate insulin release even at low blood glucose concentrations, which carries the risk of sulfonylurea-induced hypoglycemia not only in patients with type 2 diabetes mellitus but also in healthy individuals. Sitagliptin at therapeutic concentrations does not inhibit the activity of the related enzymes DPP-8 or DPP-9. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogs, insulin, sulfonylurea derivatives or meglitinides, biguanides, peroxisome proliferator-activated receptor γ (PPARγ) agonists, alpha-glucosidase inhibitors, and amylin analogs.

Pharmacodynamics

Oral administration of a single dose of sitagliptin to patients with type 2 diabetes mellitus results in inhibition of DPP-4 enzyme activity for 24 hours, accompanied by a 2- to 3-fold increase in the concentration of circulating active GLP-1 and GIP, an increase in plasma insulin and C-peptide concentrations, a decrease in glucagon concentration and fasting plasma glucose concentration, and a reduction in glycemic fluctuations after a glucose or meal load.

Administration of sitagliptin at a daily dose of 100 mg for 4-6 months significantly improved pancreatic β-cell function in patients with type 2 diabetes mellitus, as evidenced by corresponding changes in such markers as HOMA-β (homeostasis model assessment-β), the proinsulin/insulin ratio, and the assessment of pancreatic β-cell response based on a repeated meal tolerance test panel. According to phase II and III clinical studies, the glycemic control efficacy of sitagliptin when used at a dose of 50 mg twice daily was comparable to the efficacy when using sitagliptin at a dose of 100 mg once daily.

In a randomized, placebo-controlled, double-blind, four-period, crossover, two-day study involving healthy adult volunteers, the effect of the combination of sitagliptin and metformin compared with sitagliptin monotherapy, metformin monotherapy, or placebo on changes in plasma concentrations of active and total GLP-1 hormone and glucose after a meal was studied. The weighted mean incremental concentration of active GLP-1 hormone over 4 hours after a meal increased approximately 2-fold after taking sitagliptin alone or metformin alone compared to placebo. Simultaneous administration of sitagliptin and metformin provided an additive effect with an approximately 4-fold increase in the concentration of active GLP-1 hormone compared to placebo. Taking sitagliptin alone was accompanied by an increase in the concentration of only the active GLP-1 hormone due to inhibition of the DPP-4 enzyme, while taking metformin alone was accompanied by a symmetrical increase in the concentration of both active and total GLP-1 hormone. These data are consistent with the different mechanisms of action of sitagliptin and metformin responsible for increasing the concentration of active GLP-1 hormone. The results of this study also showed that it is Sitagliptin, not Metformin, that increases the concentration of active GIP hormone.

In studies involving healthy volunteers, sitagliptin administration was not accompanied by a decrease in blood glucose concentration and did not cause hypoglycemia. This suggests that the insulinotropic and glucagon-suppressive effects of the drug are glucose-dependent.

Effect on Blood Pressure

In a randomized, placebo-controlled, crossover study involving patients with arterial hypertension, the simultaneous administration of antihypertensive drugs (one or more of the following: ACE inhibitors, angiotensin II receptor antagonists, slow calcium channel blockers, beta-blockers, diuretics) with sitagliptin was generally well tolerated by patients. In this category of patients, Sitagliptin demonstrated a slight hypotensive effect: at a dose of 100 mg/day, Sitagliptin reduced the mean 24-hour ambulatory systolic BP by approximately 2 mm Hg compared to the placebo group. Similar changes were not observed in patients with normal blood pressure.

Effect on Cardiac Electrophysiology

In a randomized, placebo-controlled, crossover study, healthy volunteers took Sitagliptin orally as a single dose of 100 mg, 800 mg (8 times the recommended dose), and placebo. After taking the recommended dose (100 mg), no effect of the drug on the QTc interval duration was observed either at the time of its maximum plasma concentration or at other time points throughout the study. After taking 800 mg, the maximum increase in the placebo-corrected mean change in QTc interval duration 3 hours after drug administration compared to baseline was 8.0 ms. Such a slight increase was assessed as clinically insignificant. After taking 800 mg, the C_max of sitagliptin in plasma was approximately 11 times higher than the corresponding value after a 100 mg dose.

In patients with type 2 diabetes mellitus, no significant changes in QTc interval duration were detected with the use of sitagliptin at a dose of 100 mg/day or 200 mg/day (based on electrocardiographic data obtained at the expected C_max of sitagliptin in plasma).

Pharmacokinetics

Results of a bioequivalence study in healthy volunteers demonstrated that the combined Metformin+Sitagliptin 500 mg+50 mg and 1000 mg+50 mg tablets are bioequivalent to the separate administration of sitagliptin and metformin at the corresponding doses.

Given the proven bioequivalence of the tablets with the lowest and highest dose of metformin, the tablets with the intermediate dose of metformin (Metformin+Sitagliptin) 850 mg+50 mg were also assigned bioequivalence provided the combination of fixed doses of the drugs in the tablet.

Metformin

The absolute bioavailability of metformin when taken on an empty stomach at a dose of 500 mg is 50-60%. Results of studies of single-dose administration of metformin tablets in doses from 500 mg to 1500 mg and from 850 mg to 2550 mg indicate a lack of dose proportionality with increasing dose, which is more likely due to reduced absorption rather than accelerated elimination. Simultaneous administration of the drug with food reduces the rate and extent of metformin absorption, as evidenced by a decrease in plasma C_max by approximately 40%, a decrease in AUC by approximately 25%, and a 35-minute delay in reaching C_max after a single dose of metformin 850 mg taken with food compared to the values of the corresponding parameters after taking the same dose of the drug on an empty stomach. The clinical significance of the reduction in pharmacokinetic parameter values has not been established.

The V_d of metformin after a single oral dose of 850 mg averaged 654±358 L. Metformin binds to plasma proteins to a very small extent. Metformin is partially and temporarily distributed in erythrocytes. When metformin is used at recommended doses, steady-state plasma concentrations (usually <1 μg/ml) are reached in about 24-48 hours. According to controlled studies, the plasma C_max of the drug did not exceed 5 μg/ml even after taking the drug at maximum doses.

After a single intravenous administration to healthy volunteers, almost the entire administered dose of metformin was excreted unchanged by the kidneys. Metabolic conversion of the drug in the liver and its excretion with bile do not occur.

The renal clearance of metformin exceeds the glomerular filtration rate by 3.5 times, indicating active renal secretion as the main route of elimination. After taking metformin, about 90% of the absorbed drug is excreted by the kidneys within the first 24 hours with a plasma half-life of approximately 6.2 hours; in blood, this value is prolonged to 17.6 hours, indicating the possible involvement of erythrocytes as a potential distribution compartment.

Sitagliptin

The absolute bioavailability of sitagliptin is approximately 87%. Taking sitagliptin simultaneously with a high-fat meal does not affect the pharmacokinetics of the drug.

The mean V_d at steady state after a single intravenous administration of 100 mg sitagliptin in healthy volunteers is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma proteins is relatively small (38%).

Approximately 79% of sitagliptin is excreted unchanged by the kidneys; metabolic transformation of the drug is minimal.

After oral administration of ¹⁴C-labeled sitagliptin, approximately 16% of the administered radioactivity was excreted as metabolites of sitagliptin. Trace concentrations of 6 metabolites of sitagliptin were identified, which do not contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In in vitro studies, the cytochrome isoenzymes CYP3A4 and CYP2C8 were identified as the main enzymes involved in the limited metabolism of sitagliptin.

After oral administration of ¹⁴C-labeled sitagliptin to healthy volunteers, almost all of the administered radioactivity was eliminated from the body within a week, including 13% via the intestine and 87% via the kidneys; the mean T_1/2 of sitagliptin after oral administration of a 100 mg dose is approximately 12.4 hours, renal clearance is approximately 350 ml/min.

Elimination of sitagliptin occurs primarily by renal excretion via active tubular secretion. Sitagliptin is a substrate of the human organic anion transporter-3 (hOAT-3), which is involved in the renal elimination of sitagliptin. The clinical significance of hOAT-3 involvement in sitagliptin transport has not been established. P-glycoprotein may be involved in the renal elimination of sitagliptin (as a substrate); however, the P-glycoprotein inhibitor cyclosporine does not reduce the renal clearance of sitagliptin.

Pharmacokinetics in Special Patient Groups

The pharmacokinetics of sitagliptin in patients with type 2 diabetes mellitus is similar to that in healthy individuals. With preserved renal function, the pharmacokinetic parameters after single and repeated doses of metformin are the same in patients with type 2 diabetes mellitus and healthy individuals, and no accumulation of the drug occurs at therapeutic doses.

The drug should not be prescribed to patients with renal failure. In patients with moderate renal impairment, an approximately 2-fold increase in the plasma AUC of sitagliptin was noted, and in patients with severe and end-stage renal failure (on hemodialysis), the increase in AUC value was 4-fold compared to control values in healthy volunteers. In patients with reduced renal function (by glomerular filtration rate), the T_1/2 of the drug is prolonged, and renal clearance decreases proportionally to the decrease in glomerular filtration rate.

In patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale), the mean AUC and C_max values of sitagliptin after a single 100 mg dose increase by approximately 21% and 13%, respectively, compared to healthy individuals. This difference is not clinically significant. There are no clinical data on the use of sitagliptin in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale). However, based on the predominantly renal route of elimination of the drug, significant changes in the pharmacokinetics of sitagliptin in patients with severe hepatic impairment are not predicted.

According to the analysis of pharmacokinetic data from phase I and II clinical studies, gender did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin. The pharmacokinetic parameters of metformin did not differ significantly between healthy volunteers and patients with type 2 diabetes mellitus based on gender. According to controlled clinical studies, the hypoglycemic effects of metformin were similar in men and women.

According to population pharmacokinetic analysis of Phase I and II clinical trial data, patient age did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin. The concentration of sitagliptin in elderly patients (65-80 years) was approximately 19% higher than in younger patients. Limited data from controlled pharmacokinetic studies of metformin in healthy elderly volunteers suggest that the total plasma clearance of the drug is decreased, the T_1/2 is prolonged, and the C_max value is increased compared to young healthy individuals. These data indicate that the age-related changes in the drug’s pharmacokinetics are due to a decrease in renal excretory function. Treatment with the drug is not indicated for the elderly aged >80 years, except for individuals whose creatinine clearance indicates that renal function is not reduced.

According to the analysis of pharmacokinetic data from Phase I and II clinical trials, race did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin, including in Caucasians, Mongoloids, Latin Americans, and other ethnic and racial groups. According to controlled studies of metformin in patients with type 2 diabetes mellitus, the hypoglycemic effect of the drug was comparable among Caucasians, Negroids, and Latin Americans.

According to complex and population analyses of pharmacokinetic parameters from Phase I and II clinical trials, BMI did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin.

Extended-release tablets

Results from a study in healthy volunteers showed that the combination drug (Metformin and Sitagliptin) in the form of extended-release tablets in doses of 500 mg+50 mg and 1000 mg+100 mg is bioequivalent to the combination of single-component sitagliptin and extended-release metformin in corresponding doses. Bioequivalence was also demonstrated between taking 2 extended-release tablets at a dose of 500 mg+50 mg and 1 extended-release tablet at a dose of 1000 mg+100 mg.

In a crossover study in healthy volunteers, the AUC and C_max values of sitagliptin and the AUC value of metformin after taking 1 extended-release tablet at a dose of 500 mg+50 mg and after taking 1 standard-release tablet at a dose of 500 mg+50 mg were similar. After taking 1 extended-release tablet at a dose of 500 mg+50 mg, the mean C_max value of metformin decreased by 30%, and the median time to maximum concentration (T_max) value increased by 4 hours compared to the corresponding values after taking 1 standard-release tablet at a dose of 500 mg+50 mg, which is consistent with the expected mechanism of extended release of metformin. When healthy adult volunteers took 2 extended-release tablets at a dose of 1000 mg+50 mg once daily in the evening with food for 7 days, the C_ss of sitagliptin and metformin in the blood was reached on days 4 and 5, respectively. The median T_max value for sitagliptin and metformin at steady state after administration was about 3 hours and 8 hours, respectively, while the median T_max value for sitagliptin and metformin after taking 1 standard-release tablet was 3 hours and 3.5 hours, respectively.

After taking the drug in the form of extended-release tablets simultaneously with a high-fat breakfast, the AUC value of sitagliptin did not change. The mean C_max value decreased by 17%, although the median T_max value did not change compared to the corresponding parameters when taking the drug on an empty stomach. After taking the drug in the form of extended-release tablets with a high-fat breakfast, the AUC value of metformin increased by 62%, the C_max value of metformin decreased by 9%, and the median T_max value of metformin increased by 2 hours compared to the corresponding parameters when taking the drug on an empty stomach.

Taking the single-component metformin with delayed release simultaneously with low-fat and high-fat food increased the systemic exposure of metformin (measured by AUC value) by approximately 38% and 73%, respectively, compared to the corresponding value of this parameter when taking the drug on an empty stomach. Taking any food, regardless of its fat content, increased the T_max value of metformin by approximately 3 hours, while the C_max value did not change.

Indications

Monotherapy

As initial therapy for patients with type 2 diabetes mellitus to improve glycemic control, if diet and exercise do not provide adequate control; as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus who have not achieved adequate control with metformin or sitagliptin monotherapy, or after unsuccessful combination therapy with two drugs.

Combination therapy

For patients with type 2 diabetes mellitus to improve glycemic control in combination with sulfonylurea derivatives (triple combination: Metformin + Sitagliptin + sulfonylurea derivative), when diet and exercise in combination with two of these three drugs (Metformin, Sitagliptin, or sulfonylurea derivatives) do not lead to adequate glycemic control; in combination with thiazolidinediones (PPARγ receptor agonists), when diet and exercise in combination with two of these three drugs (Metformin, Sitagliptin, or thiazolidinedione) do not lead to adequate glycemic control; in combination with insulin, when diet and exercise in combination with insulin do not lead to adequate glycemic control.

ICD codes

Dosage Regimen

The dosage regimen of the drug is selected individually, based on current therapy, efficacy and tolerability, but not exceeding the maximum recommended daily dose of metformin 2000 mg and sitagliptin 100 mg.

The drug in the form of standard-release tablets is available in the following dosages: 850 mg metformin + 50 mg sitagliptin and 1000 mg metformin + 50 mg sitagliptin. The drug is taken twice daily with meals.

The drug in the form of extended-release tablets is available in dosages of 500 mg+50 mg, 1000 mg+50 mg, and 1000 mg+100 mg. The drug with a dosage of 500 mg+50 mg or 1000 mg+50 mg should be taken as 2 tablets simultaneously once daily; 1000 mg+100 mg – 1 tablet once daily, with meals, preferably in the evening. To ensure the extended release of metformin, the tablet should not be split, broken, crushed, or chewed before swallowing. There have been reports of finding incompletely dissolved tablets in stool. It is not known whether this material contained active substances. The patient should be warned to report to the attending physician cases of repeated detection of tablets in stool. Upon receiving such reports, the attending physician should assess the adequacy of the patient’s glycemic control. Extended-release tablets, film-coated.

The dose of the drug should be increased gradually to reduce gastrointestinal adverse reactions associated with the action of metformin.

The initial dose of the drug depends on the current hypoglycemic therapy.

In patients with type 2 diabetes mellitus with inadequate glycemic control on diet and exercise, the recommended starting dose is 500 mg metformin + 50 mg sitagliptin twice daily. Subsequently, the dose can be increased to 1000 mg metformin + 50 mg sitagliptin twice daily.

The starting dose of the drug in the form of extended-release tablets should be equivalent to 1000 mg of metformin and 100 mg of sitagliptin. In patients taking the drug at the above dose who have not achieved adequate glycemic control, a gradual (to reduce the number of gastrointestinal adverse reactions associated with the action of metformin) increase in the drug dose up to the maximum recommended daily dose of metformin 2000 mg is possible.

In patients who have not achieved adequate control on metformin monotherapy, the recommended initial dose of the drug should be equivalent to 100 mg of sitagliptin and the dose of metformin taken.

In patients who have not achieved adequate control on sitagliptin monotherapy, the recommended initial dose is 500 mg metformin + 50 mg sitagliptin twice daily. Subsequently, the dose may be increased to 1000 mg metformin + 50 mg sitagliptin twice daily. The recommended initial dose of the drug in the form of extended-release tablets should be equivalent to 1000 mg of metformin and 100 mg of sitagliptin. The metformin dose may be adjusted to achieve adequate glycemic control. It should be taken into account that to reduce the number of gastrointestinal adverse reactions associated with the action of metformin, the metformin dose must be increased gradually. The drug is contraindicated in patients with renal failure taking an adjusted dose of sitagliptin in monotherapy due to this condition.

In patients taking a combination of Sitagliptin and Metformin drugs, when switching from combination therapy with sitagliptin and metformin, the initial dose of the drug may be equivalent to the doses of sitagliptin and metformin taken.

In patients taking two of the three listed hypoglycemic drugs (Sitagliptin, Metformin, or sulfonylurea derivatives), the initial dose of the drug should provide the recommended therapeutic daily dose of sitagliptin 100 mg. When determining the starting dose of metformin, the level of glycemic control and the current (if the patient is taking Metformin) dose of metformin should be taken into account. It should also be taken into account that to reduce the number of gastrointestinal adverse reactions associated with the action of metformin, the metformin dose must be increased gradually. Patients taking or starting to take a sulfonylurea derivative may require a reduction in the dose of the sulfonylurea derivative to reduce the risk of sulfonylurea-induced hypoglycemia.

In patients taking two of the three listed hypoglycemic drugs (Sitagliptin, Metformin, or PPARγ receptor agonists (thiazolidinediones)), the initial dose of the drug should correspond to a daily dose of sitagliptin 100 mg. When determining the starting dose of metformin, the level of glycemic control and the current (if the patient is taking Metformin) dose of metformin should be taken into account. It should also be taken into account that to reduce the number of gastrointestinal adverse reactions associated with the action of metformin, the dose must be increased gradually.

In patients taking two of the three listed hypoglycemic drugs (Sitagliptin, Metformin, or insulin), the initial dose of the drug should correspond to a daily dose of sitagliptin 100 mg. When determining the starting dose of metformin, the level of glycemic control and the current (if the patient is taking Metformin) dose of metformin should be taken into account. It should also be taken into account that to reduce the number of gastrointestinal adverse reactions associated with the action of metformin, the metformin dose must be increased gradually. Patients receiving or starting to receive insulin therapy may require a reduction in the insulin dose to reduce the risk of insulin-induced hypoglycemia.

No specific studies have been conducted to evaluate the safety and efficacy of therapy with the drug in patients previously treated with other oral hypoglycemic agents and switched to therapy with the combination drug. Any changes in therapy for type 2 diabetes mellitus should be carried out with caution and under the control of relevant parameters, taking into account possible changes in glycemic control.

The drug should not be used in patients with renal failure or renal dysfunction, for example, with serum creatinine concentration >1.5 mg/dl (in men) and >1.4 mg/dl (in women), respectively, or with decreased creatinine clearance.

The use of the drug in patients with severe hepatic impairment is not recommended.

The drug should be used with caution in elderly patients, since Metformin and Sitagliptin are excreted by the kidneys. Renal function should be monitored to prevent the development of Metformin-associated lactic acidosis, especially in elderly patients.

The safety of the drug in children and adolescents under 18 years of age has not been studied.

Adverse Reactions

In studies, combination treatment with sitagliptin and metformin was generally well tolerated by patients with type 2 diabetes mellitus. The incidence of side effects with combination treatment with sitagliptin and metformin was comparable to the incidence with metformin in combination with placebo.

Combination treatment with sitagliptin and metformin

Initial therapy. In a 24-week placebo-controlled factorial study of initial therapy, in the group of patients taking Sitagliptin at a dose of 50 mg twice daily in combination with metformin at a dose of 500 mg or 1000 mg twice daily, the following drug-related adverse reactions were observed with an incidence of ≥1% and more frequently compared to the groups of metformin monotherapy at a dose of 500 mg or 1000 mg twice daily or sitagliptin at a dose of 100 mg once daily, or placebo: diarrhea – 3.5% (3.3%, 0.0%, 1.1% – in the metformin monotherapy, sitagliptin monotherapy, and placebo groups, respectively), nausea – 1.6% (2.5%, 0.0%, 0.6%), dyspepsia – 1.3% (1.1%, 0.0% and 0.0%), flatulence – 1.3% (0.5%, 0.0% and 0.0%), vomiting – 1.1% (0.3%, 0.0% and 0.0%), headache – 1.3% (1.1%, 0.6% and 0.0%) and hypoglycemia – 1.1% (0.5%, 0.6% and 0.0%).

Addition of sitagliptin to current metformin therapy. In a 24-week placebo-controlled study, Sitagliptin was added to ongoing metformin therapy: 464 patients took Metformin with the addition of sitagliptin at a dose of 100 mg once daily, and 237 patients took placebo and Metformin. The only drug-related adverse reaction in the sitagliptin and metformin treatment group, observed with an incidence of ≥1% and exceeding that in the placebo group, was nausea (1.1% – in the combination therapy group with metformin and sitagliptin, 0.4% – in the placebo with metformin group).

Hypoglycemia and gastrointestinal adverse reactions. In placebo-controlled studies of combination therapy with sitagliptin and metformin, the incidence of hypoglycemia (regardless of causality) in patients receiving the combination of sitagliptin and metformin was comparable to the incidence in the group of patients taking Metformin in combination with placebo. In the initial therapy study with sitagliptin and metformin, the incidence of hypoglycemia was 1.6% in the combination therapy group with metformin and sitagliptin and 0.8% in the metformin therapy group. In the study of metformin therapy with the addition of sitagliptin, the incidence of hypoglycemia was 1.3% in the combination therapy group with metformin and sitagliptin and 2.1% in the metformin therapy group. In the initial therapy study with sitagliptin and metformin, the incidence of tracked gastrointestinal adverse reactions (regardless of causality) in patients receiving the combination of sitagliptin and metformin was comparable to the incidence in the group of patients taking Metformin with placebo: diarrhea (7.5% – in the combination therapy group with sitagliptin and metformin, 7.7% – in the metformin group), nausea (4.8%, 5.5%), vomiting (2.1%, 0.5%), abdominal pain (3.0%, 3.8%). In the study of metformin therapy with the addition of sitagliptin, the incidence of tracked gastrointestinal adverse reactions (regardless of causality) in patients receiving the combination of sitagliptin and metformin was comparable to the incidence in the group of patients taking Metformin with placebo: diarrhea (2.4% – in the combination therapy group with sitagliptin and metformin, 2.5% – in the metformin group), nausea (1.3%, 0.8%), vomiting (1.1%, 0.8%), abdominal pain (2.2%, 3.8%).

In all studies, adverse reactions in the form of hypoglycemia were recorded based on all reports of clinically significant symptoms of hypoglycemia. Additional measurement of blood glucose concentration was not required.

Combination treatment with sitagliptin, metformin and a sulfonylurea derivative

In a 24-week placebo-controlled study, when adding sitagliptin at a daily dose of 100 mg to current combination therapy with glimepiride at a daily dose of ≥4 mg and metformin at a daily dose of ≥1500 mg, the following drug-related adverse reactions were observed with an incidence of ≥1% in the sitagliptin treatment group and more frequently than in the placebo group: hypoglycemia (13.8% – in the sitagliptin group and 0.9% – in the placebo group) and constipation (1.7% and 0.0%).

Combination therapy with sitagliptin, metformin and a PPARγ agonist

In a placebo-controlled study, when adding sitagliptin at a daily dose of 100 mg to current combination therapy with rosiglitazone and metformin at 18 weeks of treatment, the following drug-related adverse reactions were observed with an incidence of ≥1% in the sitagliptin treatment group and more frequently than in the placebo group: headache (2.4% – in the sitagliptin group, 0.0% – in the placebo group), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0.0%), vomiting (1.2%, 0.0%). At 54 weeks of therapy, the following drug-related adverse reactions were observed with an incidence of ≥1% in the sitagliptin treatment group and more frequently than in the placebo group: headache (2.4%, 0.0%), hypoglycemia (2.4%, 0.0%), upper respiratory tract infections (1.8%, 0.0%), nausea (1.2%, 1.1%), cough (1.2%, 0.0%), fungal skin infections (1.2%, 0.0%), peripheral edema (1.2%, 0.0%), vomiting (1.2%, 0.0%).

Combination therapy with sitagliptin, metformin and insulin

In a 24-week placebo-controlled study, when adding sitagliptin at a daily dose of 100 mg to current combination therapy with metformin at a daily dose of ≥1500 mg and insulin at a constant dose, the only drug-related adverse reaction observed with an incidence of ≥1% in the treatment group with sitagliptin and more frequently than in the placebo group was hypoglycemia (10.9% – in the sitagliptin group, 5.2% – in the placebo group). In another 24-week study, in which patients received Sitagliptin as add-on therapy during ongoing insulin therapy intensification (with or without metformin), the only drug-related adverse reaction observed with an incidence of ≥1% in the sitagliptin and metformin therapy group and more frequently than in the placebo and metformin group was vomiting (1.1% – in the sitagliptin and metformin therapy group, 0.4% – in the placebo and metformin group).

Pancreatitis

According to a pooled analysis of the results of 19 double-blind, randomized clinical trials, which included data from patients receiving Sitagliptin at a daily dose of 100 mg or a corresponding control drug (active or placebo), the incidence of unconfirmed acute pancreatitis was 0.1 cases per 100 patient-years of treatment in each group.

No clinically significant deviations in vital signs or ECG (including QTc interval duration) were observed during combination therapy with sitagliptin and metformin.

Adverse reactions associated with sitagliptin intake

No adverse reactions associated with sitagliptin intake were observed in patients with a frequency of ≥1%.

Adverse reactions associated with metformin intake

Adverse reactions (regardless of causality) observed with a frequency of >5% in patients in the extended-release metformin therapy group and more frequently than in the placebo group are diarrhea, nausea/vomiting, flatulence, asthenia, dyspepsia, abdominal discomfort, and headache.

Effect on the cardiovascular system (TECOS safety study)

The clinical study assessing the effect of sitagliptin on the cardiovascular system (TECOS) included 7332 patients with type 2 diabetes mellitus receiving Sitagliptin at a daily dose of 100 mg (or 50 mg/day if the baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 ml/min/1.73 m²), and 7339 patients receiving placebo, among patients who received at least one dose of the study drug. The study drug (Sitagliptin or placebo) was prescribed in addition to baseline treatment aimed at controlling cardiovascular risk factors and achieving the target level of glycated hemoglobin (HbA1c), according to local standards of patient management. The study included 2004 patients aged ≥75 years, 970 of whom received Sitagliptin, 1034 received placebo. Overall, the incidence of serious adverse events in the group of patients receiving Sitagliptin was comparable to the incidence of adverse events in the placebo group. When assessing predefined complications due to diabetes mellitus, a comparable frequency of infections (18.4% in the sitagliptin therapy group, 17.7% in the placebo group) and renal failure (1.4% in the sitagliptin therapy group and 1.5% in the placebo group) was found between the groups. The adverse event profile in patients aged ≥75 years was generally comparable to the profile of the general population.

In the intention-to-treat population (patients who took at least one dose of the study drug), who were initially receiving insulin and/or a sulfonylurea drug, the incidence of severe hypoglycemia in the sitagliptin therapy group was 2.7%, in the placebo group – 2.5%. In patients not initially receiving insulin and/or a sulfonylurea derivative, the incidence of severe hypoglycemia in the sitagliptin therapy group was 1.0%, in the placebo group – 0.7%. The incidence of confirmed pancreatitis in patients receiving sitagliptin therapy was 0.3%, in the placebo group – 0.2%. The incidence of confirmed malignant neoplasms in patients receiving sitagliptin therapy was 3.7%, in the placebo group – 4.0%.

Post-marketing observations

During post-marketing monitoring of the use of the Metformin + Sitagliptin combination or its component sitagliptin, in monotherapy and/or in combination therapy with other hypoglycemic agents, additional adverse reactions were identified. Since these data were obtained voluntarily from a population of uncertain size, it is generally not possible to reliably determine the frequency and causal relationship of these adverse reactions with therapy.

These include: hypersensitivity reactions, including anaphylaxis, angioedema, skin rash, urticaria, cutaneous vasculitis and exfoliative skin conditions, including Stevens-Johnson syndrome, acute pancreatitis, including hemorrhagic and necrotizing forms with and without fatal outcome, worsening of renal function, including acute renal failure (sometimes requiring dialysis), upper respiratory tract infections, nasopharyngitis, constipation, vomiting, headache, arthralgia, myalgia, limb pain, back pain, pruritus, pemphigoid.

Changes in laboratory parameters

Sitagliptin. The frequency of laboratory parameter deviations in the sitagliptin and metformin therapy groups was comparable to the frequency in the placebo and metformin therapy groups. In most, but not all, clinical studies, a slight increase in white blood cell content (approximately 200/μl compared to placebo, mean baseline content approximately 6600/μl) was noted, due to an increase in neutrophil count. This change is not considered clinically significant.

Metformin. In controlled clinical trials of metformin lasting 29 weeks, a decrease in the normal concentration of cyanocobalamin (vitamin B₁₂) in blood serum to subnormal values without clinical manifestations was observed in approximately 7% of patients. This decrease, probably due to selective impairment of vitamin B₁₂ absorption (namely, impaired formation of the complex with intrinsic factor, the so-called complex intrinsic complex necessary for vitamin B₁₂ absorption), is very rarely accompanied by the development of anemia and is easily corrected by discontinuing metformin or by additional intake of vitamin B₁₂.

Contraindications

Type 1 diabetes mellitus; kidney disease or impaired renal function (with serum creatinine concentration >1.5 mg/dl and >1.4 mg/dl in men and women, respectively, or decreased CrCl (<60 ml/min), including due to cardiovascular collapse (shock), acute myocardial infarction or septicemia; acute conditions with a risk of developing renal dysfunction, such as dehydration (with diarrhea, vomiting), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, renal infections, bronchopulmonary diseases); acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without coma); clinically significant manifestations of acute and chronic diseases that can lead to tissue hypoxia (including cardiac or respiratory failure, acute myocardial infarction); extensive surgical operations and trauma, when insulin therapy is indicated; hepatic failure, impaired liver function; chronic alcoholism, acute alcohol poisoning; pregnancy, lactation period; lactic acidosis (including in history); use for at least 48 hours before and 48 hours after radioisotope or X-ray examinations with the administration of iodine-containing contrast medium; adherence to a hypocaloric diet (less than 1000 kcal/day); children and adolescents under 18 years of age; hypersensitivity to sitagliptin, metformin or any component of the drug.

With caution

Since the main route of elimination of sitagliptin and metformin is the kidneys, and because excretory renal function decreases with age, caution should be exercised when prescribing the drug to elderly patients. The dose should be carefully selected and renal function should be regularly monitored to prevent the development of Metformin-associated lactic acidosis.

According to clinical studies, the efficacy and safety of sitagliptin in elderly (over 65 years) patients were comparable to the efficacy and safety in younger (under 65 years) patients.

The number of elderly patients among participants in controlled metformin studies was insufficient to draw a formal conclusion about age-related differences in the efficacy and safety of the drug, although according to available data, no such differences were observed. Since Metformin is excreted primarily by the kidneys, and the risk of serious adverse reactions increases with impaired renal function, the drug should be prescribed only to patients with confirmed normal renal function.

Use in Pregnancy and Lactation

No adequately controlled studies of the drug or its components have been conducted in pregnant women; therefore, there are no data on its safety during pregnancy. The drug, like other oral hypoglycemic drugs, is not recommended for use during pregnancy.

No experimental studies of the combination drug have been conducted to assess its effect on reproductive function. Only available data from studies of sitagliptin and metformin are provided.

No teratogenic effect of sitagliptin was detected during the organogenesis period when administered orally to rats at doses up to 250 mg/kg or to rabbits at doses up to 125 mg/kg, which exceeds the exposure of the drug in humans after taking the recommended adult daily dose of 100 mg by 32 and 22 times, respectively. A slight increase in the incidence of rib malformations (absence, hypoplasia, curvature) was observed in the offspring of rats when the drug was administered orally at daily doses of 1000 mg/kg to pregnant females, which exceeds the exposure of the drug in humans after taking the recommended adult daily dose of 100 mg by approximately 100 times. When the drug was administered orally to females at a daily dose of 1000 mg/kg, a slight decrease in body weight was observed in both sexes of rat offspring during breastfeeding and a decrease in weight gain rate after the end of breastfeeding in males. However, the results of animal reproduction studies do not always predict the effect of the drug in humans.

No teratogenic effect of metformin was detected when administered to rats and rabbits at daily doses up to 600 mg/kg, which exceeds the plasma exposure of the drug in humans by 2 and 6 times (in rats and rabbits, respectively) after taking the maximum recommended daily therapeutic dose of 2000 mg. Determination of metformin concentration in fetal plasma indicates partial permeability of the placental barrier.

Experimental studies to determine the secretion of the components of the combination drug into breast milk have not been conducted. According to studies of individual drugs, both Sitagliptin and Metformin are secreted into the breast milk of rats. There are no data on the secretion of sitagliptin into human breast milk. Therefore, the drug should not be prescribed during lactation.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic failure, impaired liver function.

Use in Renal Impairment

The use of the drug is contraindicated in kidney disease or impaired renal function (with serum creatinine concentration >1.5 mg/dl and >1.4 mg/dl in men and women, respectively, or decreased CrCl (<60 ml/min).

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Caution should be exercised when prescribing the drug to elderly patients.

Special Precautions

Pancreatitis

Reports have been received of cases of acute pancreatitis, including hemorrhagic or necrotizing with and without fatal outcome, in patients taking Sitagliptin. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis resolved after discontinuation of sitagliptin. If pancreatitis is suspected, it is necessary to discontinue the drug and other potentially dangerous drugs.

Monitoring of renal function

Metformin and Sitagliptin are excreted primarily by the kidneys. The risk of metformin accumulation and the development of lactic acidosis increases in proportion to the degree of renal impairment, so the drug should not be prescribed to patients with serum creatinine concentrations above the upper age limit of normal. In elderly patients, due to age-related decline in renal function, the minimum dose of the drug should be used to achieve adequate glycemic control. In elderly patients, especially those aged ≥80 years, regular monitoring of renal function is performed. Before starting therapy with the drug, and at least once a year after starting treatment, normal renal function should be confirmed using appropriate tests. In patients at risk of developing renal dysfunction, renal function should be monitored more frequently, and if symptoms of renal dysfunction are detected, the drug should be discontinued.

Development of hypoglycemia when used concomitantly with sulfonylurea derivatives or insulin

As with the use of other hypoglycemic agents, hypoglycemia has been observed with the concomitant use of sitagliptin and metformin in combination with insulin or sulfonylurea derivatives. To reduce the risk of hypoglycemia induced by sulfonylurea derivatives or insulin, it is possible to reduce the dose of the sulfonylurea derivative or insulin.

Sitagliptin

Development of hypoglycemia when used concomitantly with sulfonylurea derivatives or insulin

In clinical studies of sitagliptin, both in monotherapy and in combination with drugs that do not lead to hypoglycemia (i.e., metformin or PPARγ agonists – thiazolidinediones), the incidence of hypoglycemia in patients taking Sitagliptin was similar to the incidence in patients taking placebo. As with the use of other hypoglycemic agents, hypoglycemia has been observed with the concomitant use of sitagliptin in combination with insulin or sulfonylurea derivatives. To reduce the risk of hypoglycemia induced by sulfonylurea derivatives or insulin, it is possible to reduce the dose of the sulfonylurea derivative or insulin.

Hypersensitivity reactions

During post-marketing monitoring of the use of sitagliptin, which is part of the drug, reports of serious hypersensitivity reactions have been received. These reactions included anaphylaxis, angioedema, exfoliative skin conditions, including Stevens-Johnson syndrome. Since these data were obtained voluntarily from a population of uncertain size, it is generally not possible to reliably determine the frequency and causal relationship of these adverse reactions with therapy. These reactions occurred within the first 3 months after starting sitagliptin therapy, some were observed after the first dose of the drug. If a hypersensitivity reaction is suspected, the drug should be discontinued, other possible causes of the adverse reaction should be assessed, and alternative hypoglycemic therapy should be prescribed.

Metformin

Lactic acidosis

Lactic acidosis is a rare but serious metabolic complication that can develop due to the accumulation of metformin during treatment with the drug, and in case of its occurrence, mortality reaches approximately 50%. The development of lactic acidosis can also occur against the background of some pathophysiological diseases, in particular, diabetes mellitus or any other pathological condition accompanied by severe hypoperfusion and hypoxemia of tissues and organs. Lactic acidosis is characterized by an increased blood lactate concentration (>5 mmol/l), decreased blood pH, electrolyte disturbances with an increasing anion gap, and an increased lactate/pyruvate ratio. If the cause of lactic acidosis is Metformin, its plasma concentration is usually >5 μg/ml.

According to available data, the incidence of lactic acidosis during metformin therapy is very low (approximately 0.03 cases per 1000 patient-years, with a mortality rate of about 0.015 cases per 1000 patient-years). Over 20,000 patient-years of metformin therapy in clinical trials, not a single case of lactic acidosis was registered. Known cases were identified mainly in diabetic patients with severe renal failure, including severe renal pathology and renal hypoperfusion, often in combination with concomitant multiple medical/surgical diseases and polypharmacy. The risk of developing lactic acidosis is significantly increased in patients with congestive heart failure requiring drug correction, especially in unstable or acute congestive heart failure with a risk of hypoperfusion and hypoxemia. The risk of developing lactic acidosis increases in proportion to the degree of renal impairment and the patient’s age, so regular monitoring of renal function in patients taking Metformin, as well as the use of the minimum effective dose of metformin, significantly help reduce the risk of lactic acidosis. In particular, careful monitoring of renal function is necessary when treating elderly patients, and patients over 80 years of age should start metformin therapy only after confirming adequate renal function based on CrCl assessment, as these patients are more susceptible to the risk of lactic acidosis. In addition, in any condition accompanied by the development of hypoxemia, dehydration, or sepsis, metformin should be discontinued immediately. Since lactate elimination is significantly reduced in impaired liver function, metformin should generally be avoided in patients with clinical or laboratory signs of liver disease. The patient should be warned that during metformin therapy, alcohol intake (single or constant) should be limited, as ethanol potentiates the effect of metformin on lactate metabolism. In addition, metformin therapy should be temporarily discontinued during intravascular radiocontrast studies and surgical interventions.

The onset of lactic acidosis is often difficult to detect and is accompanied only by nonspecific symptoms, such as malaise, myalgia, respiratory distress syndrome, increased drowsiness, and nonspecific abdominal symptoms. As lactic acidosis worsens, hypothermia, arterial hypotension, and resistant bradyarrhythmia may be added to the above symptoms. The physician and patient should be aware of the seriousness of these symptoms, and the patient should immediately inform the physician of their appearance. Metformin therapy should be discontinued until the situation is clarified. It is recommended to determine plasma concentrations of electrolytes, ketones, blood glucose, and (if indicated) blood pH, lactate concentration, and metformin concentration in the blood. In the initial stages of treatment, the appearance of gastrointestinal symptoms is associated with metformin intake, while after the patient’s condition has stabilized on any dose of metformin, the appearance of gastrointestinal symptoms is unlikely. The late appearance of such symptoms may indicate developing lactic acidosis or another serious illness.

If, during metformin treatment, the fasting lactate concentration in venous blood plasma exceeds the upper limit of normal, but does not exceed 5 mmol/l, this is not pathognomonic for developing lactic acidosis and may be due to conditions such as poorly controlled diabetes or obesity, or excessive physical exertion, or a technical measurement error.

Any patient with diabetes and metabolic acidosis in the absence of ketoacidosis symptoms (ketonuria and ketonemia) is at risk of developing lactic acidosis. Lactic acidosis is a condition requiring emergency care in a medical facility. In a patient with lactic acidosis taking Metformin, therapy with the drug should be discontinued immediately and necessary supportive care measures should be carried out without delay. Since Metformin is dialyzed at a rate of up to 170 ml/min under conditions of good hemodynamics, immediate hemodialysis is recommended to correct acidosis and remove accumulated metformin. These measures often lead to the rapid disappearance of all symptoms of lactic acidosis and restoration of the patient’s condition.

Hypoglycemia

Under normal conditions, hypoglycemia does not develop during monotherapy with metformin; however, its development is possible during fasting, after significant physical exertion without subsequent compensation of expended calories, or with the simultaneous use of other hypoglycemic drugs (such as sulfonylurea derivatives and insulin) or alcohol. Elderly, debilitated, or emaciated patients, patients with adrenal or pituitary insufficiency, or patients who abuse alcohol are particularly at risk of developing hypoglycemia. Hypoglycemia is difficult to recognize in elderly patients and in patients taking beta-blockers.

Concomitant Therapy

Concomitant pharmacotherapy that may lead to significant hemodynamic changes or affect renal function and the distribution of metformin, for example, cationic drugs eliminated by renal tubular secretion, should be prescribed with caution.

Radiological Studies with Intravascular Administration of Iodinated Contrast Agents (e.g., intravenous urogram, intravenous cholangiography, angiography, CT with intravenous contrast administration)

Intravascular administration of iodinated contrast agents can cause acute renal impairment and is associated with the development of lactic acidosis in patients taking Metformin. Therefore, patients scheduled for such a study should temporarily discontinue the drug at least 48 hours before and for 48 hours after the study. Therapy may be resumed only after normal renal function is confirmed.

Hypoxic Conditions

Vascular collapse (shock) of any etiology, acute congestive heart failure, acute myocardial infarction, and other conditions accompanied by the development of hypoxemia are associated with the development of lactic acidosis and can cause prerenal azotemia. If these conditions develop in a patient during therapy with the Metformin+Sitagliptin combination, the drug should be discontinued immediately.

Surgical Interventions

The use of the drug should be discontinued for the duration of any surgical intervention (except for minor procedures that do not require restrictions on fluid intake and fasting) and until the usual diet is resumed, provided that normal renal function is confirmed.

Alcohol Consumption

Ethanol potentiates the effect of metformin on lactate metabolism. The patient should be warned about the danger of alcohol abuse (single or repeated consumption) during treatment with the drug.

Impaired Liver Function

Since cases of lactic acidosis have been reported in patients with impaired liver function, the use of the drug is not recommended for patients with clinical or laboratory signs of liver disease.

Plasma Cyanocobalamin (Vitamin B₁₂) Concentration

In controlled clinical trials of metformin lasting 29 weeks, a decrease in the normal concentration of cyanocobalamin (vitamin B₁₂) in the blood serum to subnormal values without clinical manifestations was observed in approximately 7% of patients. This decrease, possibly due to selective impairment of vitamin B₁₂ absorption (namely, impaired formation of the complex with intrinsic factor, the so-called complex intrinsic factor necessary for vitamin B₁₂ absorption), is very rarely accompanied by the development of anemia and is easily corrected by discontinuing metformin or by additional intake of vitamin B₁₂. During therapy with the drug, it is recommended to perform annual checks of hematological parameters, and any abnormalities that arise should be adequately investigated and corrected. In patients predisposed to developing vitamin B₁₂ deficiency (due to reduced intake or absorption of vitamin B₁₂ or calcium), it is recommended to determine the plasma concentration of vitamin B₁₂ at intervals of 2-3 years.

Change in Clinical Status in Patients with Previously Well-Controlled Type 2 Diabetes

If laboratory abnormalities or clinical symptoms of the disease (especially any condition that cannot be clearly identified) appear in a patient with previously well-controlled type 2 diabetes during therapy with the drug, it is necessary to immediately verify the absence of signs of ketoacidosis or lactic acidosis. The patient’s assessment should include tests of plasma electrolytes and ketones, blood glucose concentration, and (if indicated) blood pH, lactate, pyruvate, and metformin concentrations. If acidosis of any etiology develops, the drug should be discontinued immediately and appropriate measures to correct the acidosis should be taken.

Deterioration of Glycemic Control

In situations of physiological stress (hyperthermia, trauma, infection, or surgery), a patient with previously satisfactory glycemic control may experience temporary loss of glycemic control. During such periods, temporary replacement of the drug with insulin therapy is acceptable, and after the acute situation resolves, the patient can resume previous treatment.

Effect on Ability to Drive and Operate Machinery

No studies have been conducted on the effect of the drug on the ability to drive vehicles and operate machinery. Nevertheless, cases of dizziness and drowsiness reported during the use of sitagliptin should be taken into account. In addition, patients should be aware of the risk of hypoglycemia when using the drug concomitantly with sulfonylurea derivatives or insulin.

Drug Interactions

Concomitant multiple administration of metformin (1000 mg twice daily) and sitagliptin (50 mg twice daily) in patients with type 2 diabetes was not accompanied by significant changes in the pharmacokinetic parameters of sitagliptin or metformin.

Studies of the effect of drug-drug interaction on the pharmacokinetic parameters of the drug have not been conducted, but there are a sufficient number of such studies for each of the drug’s components.

Sitagliptin

According to drug interaction studies, Sitagliptin did not have a clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives. Based on these data, it can be assumed that Sitagliptin does not inhibit the cytochrome P450 isoenzymes CYP3A4, 2C8, or 2C9. In vitro data indicate that Sitagliptin also does not suppress the isoenzymes CYP2D6, 1A2, 2C19, or 2B6 and does not induce the CYP3A4 isoenzyme.

According to a population pharmacokinetic analysis in patients with type 2 diabetes, concomitant therapy did not have a clinically significant effect on the pharmacokinetics of sitagliptin. The study evaluated a number of drugs most commonly used by patients with type 2 diabetes, including lipid-lowering drugs (e.g., statins, fibrates, ezetimibe), antiplatelet agents (e.g., clopidogrel), antihypertensive drugs (e.g., ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and NSAIDs (e.g., naproxen, diclofenac, celecoxib), antidepressants (e.g., bupropion, fluoxetine, sertraline), antihistamines (e.g., cetirizine), proton pump inhibitors (e.g., omeprazole, lansoprazole) and drugs for the treatment of erectile dysfunction (e.g., sildenafil).

A slight increase in the AUC value (by 11%), as well as the mean C_max value (by 18%) of digoxin was observed when co-administered with sitagliptin. This increase was not considered clinically significant. Monitoring of the patient is recommended when digoxin and sitagliptin are used concomitantly.

An increase in the AUC and C_max values of sitagliptin by approximately 29% and 68%, respectively, was observed with the simultaneous single oral administration of sitagliptin 100 mg and cyclosporine (a strong P-glycoprotein inhibitor) 600 mg. These changes in the pharmacokinetic parameters of sitagliptin were not considered clinically significant.

Metformin

Glibenclamide in a single-dose drug interaction study of metformin and glibenclamide in patients with type 2 diabetes, no changes in the pharmacokinetic and pharmacodynamic parameters of metformin were observed. The decrease in glibenclamide AUC and C_max values was highly variable.

Insufficient information (single dose) and the discrepancy between blood concentrations of glibenclamide and the observed pharmacodynamic effects call into question the clinical significance of this interaction.

Furosemide in a drug interaction study with single doses of metformin and furosemide in healthy volunteers, changes in the pharmacokinetic parameters of both drugs were observed. Furosemide increased the C_max of metformin in plasma and whole blood by 22%, and the AUC of metformin in whole blood by 15%, without a significant change in the renal clearance of metformin. When metformin and furosemide were taken concomitantly, the C_max and AUC of furosemide decreased by 31% and 12%, respectively, compared to taking furosemide alone, and T_1/2 decreased by 32% without a significant change in the renal clearance of furosemide. There is no information on the drug interaction between metformin and furosemide with long-term concomitant use.

Nifedipine a drug interaction study of nifedipine and metformin with single doses in healthy volunteers revealed an increase in the C_max and AUC of metformin in plasma by 20% and 9%, respectively, as well as an increase in the amount of metformin excreted by the kidneys. The T_max and T_1/2 of metformin did not change. Nifedipine increases the absorption of metformin. The effect of metformin on the pharmacokinetics of nifedipine is minimal.

Cationic Drugs cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin), which are eliminated by tubular secretion, could theoretically interact with metformin because they are excreted via a common renal tubular transport system. Such an interaction between metformin and cimetidine was observed with the simultaneous oral administration of metformin and cimetidine in healthy volunteers in single and multiple dose interaction studies, where the C_max and AUC of metformin in plasma and whole blood increased by 60% and 40%, respectively. In the single-dose study, the T_1/2 of metformin did not change. Metformin did not affect the pharmacokinetics of cimetidine. And although the indicated drug interaction is of theoretical significance (except for cimetidine), careful monitoring of the patient and adjustment of the dose of the drug and/or the aforementioned cationic drugs excreted by the proximal renal tubules is recommended in cases of their simultaneous use.

Others some drugs have hyperglycemic potential and may reduce glycemic control. These include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid preparations, estrogens, oral contraceptive drugs, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When these drugs are prescribed to a patient receiving the Metformin + Sitagliptin combination, careful monitoring of glycemic control parameters is recommended.

In interaction studies involving healthy volunteers, no changes in the pharmacokinetic parameters of these drugs were observed with the simultaneous administration of single doses of metformin and propranolol or metformin and ibuprofen.

Metformin is minimally bound to plasma proteins; therefore, a drug interaction between metformin and drugs that are highly bound to plasma proteins (salicylates, sulfonamides, chloramphenicol, and probenecid) is unlikely compared to sulfonylurea derivatives, which are also highly bound to plasma proteins.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.