Janumet Long Prolonged pills 1000mg+50mg, 56pcs

Composition

In one tablet: Active ingredients: 1000 mg of metformin;50 mg of sitagliptin phosphate monohydrate. Inactive excipients: Microcrystalline cellulose; Povidone; Sodium Stearyl fumarate;Sodium Lauryl Sulfate. Opadry II shell in pink 85 F 94203: Polyvinyl alcohol; Titanium dioxide (e171); Macrogol; Talc;Iron oxide black (e172); Iron oxide red (e172).

Pharmacological action

The drug is a combination of two hypoglycemic drugs with a complementary mechanism of action, designed to improve glycemic control in patients with type 2 diabetes: sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), 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, reducing basal and postprandial blood glucose concentrations. Its pharmacological mechanisms of action differ from those of oral hypoglycemic drugs of other classes. Metformin reduces glucose synthesis in the liver, 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 people (except in certain circumstances) and does not cause hyperinsulinemia. During treatment with metformin, insulin secretion does not change, while the fasting insulin concentration and the daily value of the plasma insulin concentration may decrease. Sitagliptin Sitagliptin is an orally active, highly selective DPP-4 enzyme inhibitor intended for the treatment of type 2 diabetes mellitus. The pharmacological effects of a class of DPP-4 inhibitors are mediated by incretin activation. 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 internal physiological system for regulating glucose homeostasis. At normal or elevated blood glucose concentrations, GLP-1 and GIP promote increased insulin synthesis and secretion by pancreatic beta cells. GLP-1 also inhibits the secretion of glucagon by pancreatic alpha cells, thus reducing glucose synthesis in the liver. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives, which stimulate the release of insulin even at low blood glucose concentrations, which is fraught with the development of sulfonyl-induced hypoglycemia not only in patients with type 2 diabetes, but also in healthy individuals. Sitagliptin in therapeutic concentrations does not inhibit the activity of related enzymes DPP-8 or DPP-9. Sitagliptin differs in chemical structure and pharmacological action from analogues of GLP-1, insulin, sulfonylureas or meglitinides, biguanides, agonists of gamma-receptors activated by the peroxisome proliferator (PPARy), alpha-glucosidase inhibitors and amylin analogues. Pharmacodynamics peroral use of a single dose of sitagliptin in patients with type 2 diabetes mellitus leads to suppression of the activity of the DPP-4 enzyme for 24 hours, which is accompanied by a 2-3-fold increase in the concentration of circulating active GLP-1 and GIP, an increase in the plasma concentration of insulin and C-peptide, a decrease in the concentration of glucagon and fasting plasma glucose, as well as a decrease in the amplitude of glycemic fluctuations after glucose or food loading. Taking sitagliptin at a daily dose of 100 mg for 4-6 months significantly improved the function of pancreatic beta cells in patients with type 2 diabetes mellitus, as evidenced by corresponding changes in such markers as HOMA-β (assessment of homeostasis in the-β model), the proinsulin/insulin ratio, and assessment of the response of pancreatic beta cells according to the panel of repeated food tolerance tests. According to the data of phase II and III clinical trials, the effectiveness of glycemic control of sitagliptin at a dose of 50 mg 2 times / day was comparable to the effectiveness of sitagliptin at a dose of 100 mg 1 time/day. A randomized, placebo-controlled, double-blind, four-period, two-day cross-sectional study in adult healthy volunteers examined the effect of a 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 meals. The weighted average value of the increasing concentration of the active hormone GLP-1 within 4 hours after a meal increased approximately 2-fold after taking sitagliptin alone or metformin alone compared to placebo. Concomitant use of sitagliptin and metformin combined the effect with approximately a 4-fold increase in the concentration of the active hormone GLP-1 compared to placebo. Sitagliptin alone was associated with an increase in the concentration of the active GLP-1 hormone alone due to inhibition of the DPP-4 enzyme, while metformin alone was associated with a symmetrical increase in the concentration of the active and total GLP-1 hormone. The data obtained correspond to different mechanisms of action of sitagliptin and metformin, which are responsible for increasing the concentration of the active hormone GLP-1. The results of this study also showed that it is sitagliptin, and not metformin, that increases the concentration of the active hormone GIP. In studies involving healthy volunteers, sitagliptin intake was not associated with 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. In a randomized, placebo-controlled, cross-sectional study in hypertensive patients, concomitant use of antihypertensive medications (one or more of the following: ACE inhibitors, angiotensin II receptor antagonists, slow calcium channel blockers, beta-blockers, diuretics) with sitagligpin was generally well tolerated by patients. In this category of patients, sitagliptin showed a slight antihypertensive effect: at a dose of 100 mg/day, sitagliptin reduced the average daily outpatient systolic blood pressure by approximately 2 mm Hg compared to the placebo group. Such changes were not observed in patients with normal blood pressure. Effects on cardiac electrophysiology In a randomized, placebo-controlled, cross-sectional study, healthy volunteers took sitagliptin orally once at 100 mg,800 mg (8 times the recommended dose), and placebo. After taking the recommended dose (100 mg), there was no effect of the drug on the duration of the QTc interval, either at the time of its maximum plasma concentration, or at other time points of assessment throughout the study. After taking 800 mg, the maximum increase in the placebo-adjusted mean change in QTc interval duration 3 hours after taking the drug compared to the initial value was 8.0 ms. Such a small increase was assessed as clinically insignificant. After taking 800 mg, the Cmax value of sitagliptin in blood plasma was approximately 11 times higher than the corresponding value after taking a dose of 100 mg. In patients with type 2 diabetes mellitus, when using sitagliptin at a dose of 100 mg / day or 200 mg/day, there were no significant changes in the duration of the QTc interval (based on electrocardiographic studies obtained at the time of the expected Cmax of sitagliptin in blood plasma). Pharmacokineticsresults of a study to determine bioequivalence in healthy volunteers showed that the combined tablets metformin+sitagliptin 500 mg+50 mg and 1000 mg+50 mg are bioequivalent to separate use of sitagliptin and metformin in the appropriate doses. Taking into account the proven bioequivalence of tablets with the lowest and highest dose of metformin, tablets with an intermediate dose of metformin (metformin+sitagliptin) of 850 mg+50 mg were also assigned bioequivalence, provided that fixed doses of drugs were combined in the tablet. Metforminabsolute bioavailability of metformin when taken on an empty stomach at a dose of 500 mg is 50-60%. The results of studies of a single dose of metformin tablets in doses from 500 mg to 1500 mg and from 850 mg to 2550 mg indicate a violation of dose proportionality with increasing dose, which is more likely due to reduced absorption than accelerated elimination. Concomitant use of the drug with food reduces the rate and amount of absorbed metformin, which is confirmed by a decrease in the plasma Cmax value by about 40%, a decrease in the AUC value by about 25%, as well as a 35-minute delay in reaching Cmax after a single dose of metformin at a dose of 850 mg simultaneously with food compared to the values of the corresponding parameters after taking a similar dose of the drug on an empty stomach. The clinical significance of reducing the values of pharmacokinetic parameters has not been established. The Vd of metformin after a single oral dose of 850 mg averaged 654±358 L. Metformin binds to plasma proteins only to a very small extent. Metformin is partially and temporarily distributed in red blood cells. When using metformin at the recommended doses, plasma concentrations of the equilibrium state (usually According to controlled studies, Cmax in the drug’s plasma did not exceed 5 mcg/ml even after taking the drug in maximum doses. After a single intravenous injection of metformin to healthy volunteers, almost all of the administered dose was excreted unchanged by the kidneys.Metabolic transformations of the drug in the liver and its excretion with bile do not occur. The renal clearance of metformin exceeds CC 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 the blood this value is extended to 17.6 hours, indicating the possible participation of red blood cells as a potential distribution compartment. Sitagliptinabsolute bioavailability of sitagliptin is approximately 87%. Taking sitagliptin concomitantly with fatty foods does not affect the pharmacokinetics of the drug. The average steady-state Vd after a single intravenous use of 100 mg of sitagliptin in healthy volunteers is approximately 198 l. The fraction of reversibly binding plasma protein sitagliptin is relatively small (38%). Approximately 79% of sitagliptin is excreted unchanged by the kidneys, and the metabolic transformation of the drug is minimal. After ingestion of 14C-labeled sitagliptin, approximately 16% of the administered radioactivity was excreted as sitagliptin metabolites. Trace concentrations of 6 sitagliptin metabolites were detected, which did not contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies have identified cytochrome CYP3A4 and CYP2C8 isoenzymes as the main enzymes involved in limited sitagliptin metabolism. After ingestion of 14C-labeled sitagliptin by healthy volunteers, almost all the radioactivity administered was eliminated from the body within a week, including 13% – through the intestines and 87% – by the kidneys; the average T 1/2 of sitagliptin when taken orally at a dose of 100 mg is approximately 12.4 hours, and the renal clearance is approximately 350 ml / min. Sitagliptin is excreted primarily by renal excretion through the mechanism of active tubular secretion. Sitagliptin is a substrate of the third type of human organic anion transporter (hOAT-3), which is involved in the process of elimination of sitagliptin by the kidneys. 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), but the P-glycoprotein inhibitor cyclosporine does not reduce the renal clearance of sitagliptin. Pharmacokinetics in selected patient groups The pharmacokinetics of sitagliptin in patients with type 2 diabetes mellitus are similar to those in healthy individuals. With preserved renal function, the pharmacokinetic parameters after single and repeated doses of metformin in patients with type 2 diabetes mellitus and healthy individuals are the same, no accumulation of the drug occurs when taking therapeutic doses. The drug should not be prescribed to patients with renal insufficiency. In patients with moderate renal insufficiency, an approximately 2-fold increase in the plasma AUC of sitagliptin was observed, and in patients with severe and end-stage (on hemodialysis), an increase in the AUC value was 4-fold compared to the control values in healthy volunteers. In patients with reduced renal function (according to creatinine clearance) T 1/2 of the drug is prolonged, and renal clearance decreases in proportion to the decrease in creatinine clearance. In patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the mean AUC and Cmax values of sitagliptin after a single 100 mg dose increase by approximately 21% and 13%, respectively, compared with healthy individuals. This difference is not clinically significant. There are no clinical data on the use of sitagliptin in patients with severe hepatic insufficiency (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 insufficiency are not predicted. According to the analysis of pharmacokinetic data from phase I and II clinical trials, 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 trials, the hypoglycemic effects of metformin in men and women were similar. According to a population pharmacokinetic analysis of data from phase I and II clinical trials, the age of patients did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin. The sitagliptin concentration in elderly patients (65-80 years) was approximately 19% higher than in young patients. Limited data from controlled pharmacokinetic studies of metformin in healthy elderly volunteers suggest that the total plasma clearance of the drug decreases, T 1/2 lengthens, and the Cmax value increases in comparison with young healthy individuals. These data indicate that age-related changes in the pharmacokinetics of the drug are due to a decrease in excretory function of the kidneys. Treatment with the drug is not indicated for the elderly aged >80 years, with the exception of those 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 representatives of the Caucasian and Mongoloid races, representatives of Latin American countries and other ethnic and racial groups. According to controlled studies of metformin in patients with type 2 diabetes, the hypoglycemic effect of the drug was comparable in representatives of the Caucasian, Negroid races and Latin American countries. According to complex and population-based 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. Long-release pillsresults of a study with healthy volunteers showed that the combined drug (metformin and sitagliptin) in the form of long-release tablets in dosages of 500 mg+50 mg and 1000 mg+100 mg is bioequivalent to the combination of monopreparations of sitagliptin and metformin with prolonged release in the corresponding dosages. Bioequivalence was also demonstrated between taking 2 long-release tablets at a dosage of 500 mg+50 mg and 1 long-release tablet at a dosage of 1000 mg+100 mg. In a cross-sectional study involving healthy volunteers, the AUC and Cmax values of sitagliptin and the AUC values of metformin after taking 1 tablet with a prolonged release at a dosage of 500 mg+50 mg and after taking 1 tablet with a standard release at a dosage of 500 mg+50 mg were similar. After taking 1 tablet with a prolonged release at a dosage of 500 mg+50 mg, the average Cmax of metformin decreased by 30%, and the median time to reach maximum concentration (Tmax) increased by 4 hours compared to the corresponding values after taking 1 tablet with a standard release at a dosage of 500 mg+50 mg, which is consistent with the expected mechanism of prolonged release of metformin. When healthy adult volunteers took 2 long-release tablets at a dosage of 1000 mg+50 mg 1 time/day in the evening with food for 7 days, the Css of sitagliptin and metformin in the blood was achieved on days 4 and 5, respectively. The median Tmax of sitagliptin and metformin at steady state after use was about 3 hours and 8 hours, respectively, while the median Tmax of 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 long-release tablets simultaneously with a high-fat breakfast, the AUC value of sitagliptin did not change. The mean Cmax value decreased by 17%, although the median Tmax value did not change compared to the same parameters when taking the drug on an empty stomach. After taking the drug in the form of long-release tablets with a high-fat breakfast, the AUC value of metformin increased by 62%, the Cmax value of metformin decreased by 9%, and the median Tmax value of metformin increased by 2 hours compared to similar parameters when taking the drug on an empty stomach. Taking a sustained-release metformin monopreparation concomitantly with a low-fat and high-fat diet increased the systemic exposure to metformin (measured by AUC) 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 Tmax value of metformin by about 3 hours, while the Cmax value did not change.

Indications

Monotherapy

• As a starting therapy for patients with type 2 diabetes mellitus to improve glycemic control, if compliance with the diet and exercise regimen does not allow for adequate control;
• As an adjunct to diet and exercise regimen to improve glycemic control in patients with type 2 diabetes mellitus who did not achieve adequate control on the background of metformin or sitagliptin monotherapy, or after unsuccessful combined treatment with two drugs.

Combination therapy

• 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 regimen in combination with two of these three drugs (metformin, sitagliptin or sulfonylurea derivatives) do not lead to adequate glycemic control;
• In combination with thiazolidinediones (PPARy-receptor agonists activated by the peroxisome proliferator), when diet and exercise regimen 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 regimen in combination with insulin do not lead to adequate glycemic control.

Contraindications

• Diabetes type 1 diabetes;

• kidney Disease or reduced kidney function (at the concentration of serum creatinine >1.5 mg/DL and >1.4 mg/DL in men and women, respectively, or reducing KK (<60 ml/min), including due to cardiovascular collapse (shock), acute myocardial infarction or septicemia;

• Acute conditions with a risk of developing impaired renal function, such as dehydration (with diarrhea, vomiting), fever, severe infectious diseases, hypoxia (shock, sepsis, kidney infections, bronchopulmonary diseases);

• Acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without coma);

• Clinically expressed manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (including heart or respiratory failure, acute myocardial infarction);

• Extensive surgical operations and injuries, when insulin therapy is indicated;

• Liver failure, impaired liver function; chronic alcoholism, acute alcohol poisoning; pregnancy, lactation;

• Lactic acidosis (including in the anamnesis);

• Use for at least 48 hours before and 48 hours after conducting radioisotope or X-ray studies with the introduction of an iodine-containing contrast agent;

• Compliance with a hypocaloric diet (less than 1000 kcal / day);

• Children and adolescents under 18 years of age; hypersensitivity to sitagliptin, metformin or any of the components of the drug.

With caution:

Since the main route of elimination of sitagliptin and metformin is the kidneys, and since the excretory function of the kidneys decreases with age, caution should be exercised when prescribing the drug to elderly patients. It is necessary to carefully select the dose and regularly monitor renal function in order 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 was comparable with the efficacy and safety in young (under 65 years) patients.

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

Side effects

In studies, combined treatment with sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes mellitus. The frequency of side effects associated with sitagliptin and metformin combined treatment was comparable to that of metformin in combination with placebo.

Combined treatment with sitagliptin and metformin

Starting therapy. In a 24-week placebo-controlled factorial start-up study in a group of patients taking sitagliptin 50 mg twice daily in combination with metformin 500 mg or 1000 mg twice daily, the following drug-related adverse reactions were observed with a frequency of ≥1% and more often compared to the monotherapy groups with metformin 500 mg or 1000 mg twice daily or sitagliptin 100 mg once daily, or placebo: diarrhea – 3.5% (3.3%.0.0%.1.1% – in the metformin, sitagliptin, and placebo monotherapy 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%).

Adding sitagliptin to current metformin therapy. In a 24-week placebo-controlled study, sitagliptin was added to metformin therapy: 464 patients received metformin plus sitagliptin 100 mg once daily, and 237 patients received placebo and metformin. The only drug-related adverse reaction in the sitagliptin and metformin treatment group that occurred with a frequency of ≥1% and exceeded that in the placebo group was nausea (1.1% in the metformin-sitagliptin combination group,0.4% in the placebo-metformin group).

Hypoglycemia and adverse reactions from the gastrointestinal tract. In placebo-controlled studies of sitagliptin and metformin combination therapy, the incidence of hypoglycemia (regardless of causation) in patients receiving a combination of sitagliptin and metformin was comparable to that in the group of patients taking metformin in combination with placebo. In the initial sitagliptin-metformin study, the incidence of hypoglycemia was 1.6% in the metformin-sitagliptin combination group and 0.8% in the metformin group. In the study of metformin therapy with sitagliptin, the incidence of hypoglycemia was 1.3% in the metformin-sitagliptin combination group and 2.1% in the metformin therapy group. In the sitagliptin-metformin start – up study, the frequency of monitored gastrointestinal adverse reactions (regardless of causation) in patients treated with a combination of sitagliptin and metformin was comparable to the frequency in the group of patients taking metformin with placebo: diarrhea (7.5% in the sitagliptin – metformin combination therapy group,7.7% in the metformin group), nausea (4.8%,5.5%), vomiting (2.1%,0.5%), abdominal pain (3.0%,3.8%). In the metformin-plus – sitagliptin study, the incidence of traceable gastrointestinal adverse reactions (regardless of causation) in patients treated with a combination of sitagliptin and metformin was comparable to that in patients treated with placebo: diarrhea (2.4% in the sitagliptin – plus-metformin combination group,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. No additional measurement of blood glucose concentration was required.

Combined treatment with sitagliptin, Metformin and sulfonylureas

In the 24-week placebo-controlled study of adding sitagliptin in a daily dose of 100 mg to the current combination therapy with glimepiride in a daily dose of ≥4 mg and Metformin daily dose of ≥1500 mg were associated with medication adverse reactions with a frequency ≥1% in the sitagliptin treatment group and more frequently than in the placebo group: hypoglycemia (13.8% in the sitagliptin group and 0.9% of the placebo group), constipation (1.7% and 0.0%).

Combination therapy with sitagliptin, metformin and PPARy agonist

In a placebo-controlled study, when sitagliptin was added at a daily dose of 100 mg to the current combination therapy with rosiglitazone and metformin at week 18 of treatment, the following drug-related adverse reactions were observed with a frequency of ≥1% in the sitagliptin treatment group and more often 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 week 54 of therapy, the following drug-related adverse reactions were observed with a frequency of ≥1% in the sitagliptin treatment group and more often 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 the 24-week placebo-controlled study of adding sitagliptin in a daily dose of 100 mg to the current combination therapy with Metformin in a daily dose of ≥1500 mg and insulin in a constant dose of the only adverse reaction related to the administration of drugs and observed with a frequency of ≥1% in the treatment group with sitagliptin and more frequently than in the placebo group, were hypoglycemia (10.9% in the sitagliptin group,5.2% in the placebo group). In another 24-week study in which patients received sitagliptin as adjunctive therapy during the period of intensive insulin therapy (with or without metformin), the only drug-related adverse reaction observed with a frequency of ≥1% in the sitagliptin and metformin treatment group and more often than in the placebo and metformin group was vomiting (1.1% in the sitagliptin and metformin treatment group,0.4% in the placebo and metformin group).

Pancreatitis

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

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

Adverse reactions due to sitagliptin use

Patients did not experience adverse reactions due to sitagliptin use, the frequency of which was ≥1%.

Metformin-related adverse reactions

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

Effects on the cardiovascular system (TECOS Safety Study)

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

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

Post-registration observations

During post-marketing monitoring of the use of the metformin + sitagliptin combination or sitagliptin included in its composition, in monotherapy and/or in combination therapy with other hypoglycemic agents, additional adverse reactions were detected. Since these data were obtained voluntarily from a population of indeterminate size, it is usually impossible 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 diseases, including Stevens-Johnson syndrome, acute pancreatitis, including hemorrhagic and necrotic forms with or without fatal outcome, deterioration 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 incidence of laboratory abnormalities in the sitagliptin and metformin treatment groups was comparable to that in the placebo and metformin treatment groups. In most, but not all, clinical trials, there was a slight increase in white blood cell count (approximately 200/µl compared to placebo, the average content at the beginning of treatment is approximately 6600/µl), due to an increase in the number of neutrophils. 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. Such a decrease, probably due to selective malabsorption of vitamin B12 (namely, a violation of the formation of a complex with the internal Castle factor, the so-called complex internal complex necessary for the absorption of vitamin B12), is very rarely accompanied by the development of anemia and is easily corrected by the withdrawal of metformin or an additional intake of vitamin B12.

Interaction

Simultaneous multiple use of metformin (1000 mg 2 times / day) and sitagliptin (50 mg 2 times / day) in patients with type 2 diabetes mellitus was not accompanied by significant changes in the pharmacokinetic parameters of sitagliptin or metformin. Studies of the effect of inter-drug interaction on the pharmacokinetic parameters of the drug have not been conducted, but there are a sufficient number of similar studies for each of the components of the drug. Sitagliptin According to a study on interaction with other drugs, 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 SUR isoenzymes of the cytochrome CYP3A4,2C8 or 2C9 system. In vitro data indicate that sitagliptin also does not inhibit the CYP2D6,1A2,2C19 or 2B6 isoenzymes and does not induce the CYP3A4 isoenzyme. According to a population pharmacokinetic analysis in patients with type 2 diabetes mellitus, concomitant therapy did not have a clinically significant effect on the pharmacokinetics of sitagliptin. The study evaluated a number of drugs most commonly used in 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, slow calcium channel blockers, hydrochlorothiazide), analgesics, and NSAIDs antihistamines (e. g., cetirizine), proton pump inhibitors (e. g., omeprazole, lansoprazole), and drugs for the treatment of erectile dysfunction (e. g., sildenafil). There was a slight increase in the AUC value (by 11%), as well as the average Cmax value (by 18%) of digoxin when co-administered with sitagliptin. This increase was not considered clinically significant. With the simultaneous use of digoxin and sitagliptin, monitoring of the patient is recommended. The AUC and Cmax values of sitagliptin increased by approximately 29% and 68%, respectively, with simultaneous single oral use of sitagliptin at a dose of 100 mg and cyclosporine (a strong P-glycoprotein inhibitor) at a dose of 600 mg. These changes in the pharmacokinetic parameters of sitagliptin were not considered clinically significant. Metforminglibenclamide: No changes in the pharmacokinetic and pharmacodynamic parameters of metformin were observed in the drug-drug interaction study of single doses of metformin and glibenclamide in patients with type 2 diabetes mellitus. The decrease in the AUC and Cmax values of glibenclamide was highly variable. Insufficient information (single dose) and the discrepancy between the blood concentrations of glibenclamide and the observed pharmacodynamic effects call into question the clinical significance of this interaction. Furosemide: In a drug-to-drug interaction study, single doses of metformin and furosemide in healthy volunteers showed changes in the pharmacokinetic parameters of both drugs. Furosemide increased the Cmax of metformin in plasma and whole blood by 22%, and the AUC of metformin in whole blood by 15% without significantly changing the renal clearance of metformin. When metformin and furosemide were co-administered, the Cmax and AUC values of furosemide decreased by 31% and 12%, respectively, compared to furosemide alone, and T 1/2 decreased by 32% without a significant change in the renal clearance of furosemide. There is no information about the drug-drug interaction of metformin and furosemide during long-term concomitant use. Nifedipine: a single-dose study of the drug-drug interaction between nifedipine and metformin in healthy volunteers showed an increase in the C Max and AUC values of metformin in plasma by 20% and 9%, respectively, as well as an increase in the amount of metformin excreted by the kidneys. The Tmax and T 1/2 values 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 (for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin) secreted by tubular secretion can theoretically interact with metformin, since they are excreted through the common renal tubular transport system.A similar interaction between metformin and cimetidine was observed with simultaneous oral use of metformin and cimetidine in healthy volunteers in single-and multiple-dose interaction studies in which the Cmax and AUC values 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. Although these drug-drug interactions are of theoretical significance (with the exception of cimetidine), careful monitoring of the patient and dose adjustment of the drug and/or the above-mentioned cationic drugs excreted by the proximal renal tubules are recommended in cases of their simultaneous use. Others: Some medications have hyperglycemic potential and may reduce glycemic control. These include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid medications, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, slow calcium channel blockers, and isoniazid. When prescribing these drugs to a patient receiving a combination of metformin + sitagliptin, careful monitoring of the parameters of glycemic control is recommended. In interaction studies with healthy volunteers, no changes in the pharmacokinetic parameters of these drugs were observed when single doses of metformin and propranolol or metformin and ibuprofen were administered simultaneously. Metformin is slightly bound to plasma proteins, so the drug-drug interaction of metformin with drugs that actively bind to plasma proteins (salicylates, sulfonamides, chloramphenicol and probenecid) is unlikely in comparison with sulfonylurea derivatives, which also actively bind to plasma proteins.

How to take, course of use and dosage

The dosage regimen of the drug is selected individually, based on the current therapy, effectiveness 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 produced in the following dosages: 850 mg of metformin+50 mg of sitagliptin and 1000 mg of metformin+50 mg of sitagliptin. The drug is taken 2 times a day with meals. The drug in the form of tablets with prolonged release is produced 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 2 tablets simultaneously 1 time/day; 1000 mg+100 mg-1 tablet 1 time/day, with meals, preferably in the evening. To ensure a prolonged release of metformin, the tablet should not be divided, broken, crushed or chewed before ingestion. There are reports of incompletely dissolved tablets being found in the stool. It is not known whether this material contained active ingredients. The patient should be warned about the need to inform the attending physician about cases of repeated detection of tablets in the feces. When receiving such reports, the attending physician should evaluate the adequacy of the patient’s glycemic control. Long-release, film-coated tablets. The dose of the drug should be increased gradually to reduce the adverse reactions from the gastrointestinal tract caused by 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 a diet and exercise regimen, the recommended starting dose is 500 mg of metformin+50 mg of sitagliptin 2 times / day. Subsequently, the dose can be increased to 1000 mg of metformin+50 mg of sitagliptin 2 times / day. The starting dose of the drug in the form of long-release tablets should be equivalent to 1000 mg of metformin and 100 mg of sitagliptin. In patients taking the drug at the above dose and who have not achieved adequate glycemic control, it is possible to gradually increase the dose of the drug up to the maximum recommended daily dose of metformin 2000 mg (in order to reduce the number of adverse reactions from the gastrointestinal tract caused by the action of metformin). In patients who do not achieve 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 of metformin+50 mg of sitagliptin 2 times / day. In the future, the dose can be increased to 1000 mg of metformin+50 mg of sitagliptin 2 times / day. The recommended starting dose of the drug in the form of long-release tablets should be equivalent to 1000 mg of metformin and 100 mg of sitagliptin. The metformin dose may be modified to achieve adequate glycemic control. It should be borne in mind that to reduce the number of adverse reactions from the gastrointestinal tract caused by the action of metformin, the dose of metformin should be increased gradually. Patients with renal insufficiency who are taking the adjusted dose of sitagliptin in monotherapy due to this disease, treatment with the drug is contraindicated. In patients taking a combination of sitagliptin and metformin, 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. In patients taking two of these three hypoglycemic medications (sitagliptin, metformin, or sulfonylureas), 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 adverse reactions from the gastrointestinal tract caused by the action of metformin, the dose of metformin should be increased gradually. Patients taking or starting to take a sulfonylurea derivative may need to reduce the dose of the sulfonylurea derivative to reduce the risk of developing sulfonyl-induced hypoglycemia. In patients taking two of these three hypoglycemic drugs (sitagliptin, metformin, or PPARy-receptor agonists (thiazolidinediones), the initial dose of the drug should correspond to the 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 adverse reactions from the gastrointestinal tract caused by the action of metformin, the dose should be increased gradually. In patients taking two of these three hypoglycemic medications (sitagliptin, metformin, or insulin), the initial dose of the drug should correspond to the 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 adverse reactions from the gastrointestinal tract caused by the action of metformin, the dose of metformin should be increased gradually. Patients receiving or beginning to receive insulin therapy may need to reduce the dose of insulin to reduce the risk of developing insulin-induced hypoglycemia. No specific studies have been conducted to evaluate the safety and efficacy of this drug in patients who were previously treated with other oral hypoglycemic agents and switched to combination therapy. Any changes in the treatment of type 2 diabetes should be carried out with caution and under the control of appropriate parameters, taking into account possible changes in glycemic control. The drug should not be used in patients with renal insufficiency or renal dysfunction, for example, if the serum creatinine concentration is >1.5 mg / dl (in men) and >1.4 mg/dl (in women), respectively, or with a decrease in creatinine clearance. The use of the drug in patients with severe hepatic insufficiency 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.

Special instructions

Pancreatitis Acute pancreatitis, including hemorrhagic or necrotic pancreatitis with or without fatal outcome, has been reported in patients taking sitagliptin. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis disappeared after discontinuation of sitagliptin. If pancreatitis is suspected, you should stop taking the drug and other potentially dangerous medications. Renal function monitoring Metformin and sitagliptin are mainly excreted by the kidneys. The risk of metformin accumulation and lactic acidosis increases in proportion to the degree of impaired renal function, 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, a minimum dose of the drug should be used to achieve adequate glycemic control. Renal function should be regularly monitored in elderly patients, especially those aged ≥80 years. Before starting therapy with the drug, as well as at least once a year after the start of treatment, normal renal function should be confirmed with appropriate tests.In patients at risk of developing renal dysfunction, monitoring of renal function should be carried out more often, and if symptoms of renal dysfunction are detected, the drug should be discontinued. The development of hypoglycemia when used concomitantly with sulfonylurea derivatives or insulin, as in the case of taking other hypoglycemic agents, hypoglycemia was observed with the simultaneous use of sitagliptin and metformin in combination with insulin or sulfonylurea derivatives. To reduce the risk of hypoglycemia induced by taking a sulfonylurea or insulin derivative, it is possible to reduce the dose of a sulfonylurea or insulin derivative. 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 PPARy – thiazolidinediones agonists), the incidence of hypoglycemia in patients taking sitagliptin was close to that in patients taking placebo. As with other hypoglycemic agents, hypoglycemia was observed when sitagliptin was co-administered in combination with insulin or sulfonylureas. To reduce the risk of hypoglycemia induced by taking sulfonylurea or insulin derivatives, it is possible to reduce the dose of a sulfonylurea or insulin derivative. Hypersensitivity reactsin the course of post-marketing monitoring of the use of sitagliptin, which is part of the drug, serious hypersensitivity reactions were reported. These reactions included anaphylaxis, angioedema, and exfoliative skin disorders, including Stevens-Johnson syndrome. Since these data are obtained voluntarily from a population of indeterminate size, it is usually impossible 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 taking the first dose of the drug. If a hypersensitivity reaction is suspected, you should stop taking the drug, evaluate other possible causes of the adverse reaction, and prescribe another hypoglycemic therapy. 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, the mortality rate reaches approximately 50%. The development of lactic acidosis can also occur against the background of certain 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 concentration of lactate in the blood (>5 mmol / l), a reduced blood pH, electrolyte disturbances with an increase in the anion interval, and an increase in the lactate/pyruvate ratio. If metformin is the cause of lactic acidosis, its plasma concentration is usually >5 micrograms / ml. According to available data, the incidence of lactic acidosis with metformin therapy is very low (approximately 0.03 cases per 1000 patient-years, with a fatal rate of about 0.015 cases per 1000 patient-years). During the 20,000 patient-years of metformin therapy, no cases of lactic acidosis have been reported in clinical trials. Known cases have been identified primarily in patients with diabetes mellitus with severe renal insufficiency, including severe renal pathology and renal hypoperfusion, often in combination with concomitant multiple somatic/surgical diseases and polypragmasia. The risk of lactic acidosis is significantly increased in patients with congestive heart failure requiring medical 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 impaired renal function 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, can significantly reduce the risk of developing lactic acidosis. In particular, careful monitoring of renal function is necessary in the treatment of elderly patients, and in patients over 80 years of age, metformin therapy should be initiated only after confirmation of adequate renal function by the results of creatinine clearance assessment, since these patients are more at risk of developing lactic acidosis. In addition, metformin should be discontinued immediately for any condition associated with hypoxemia, dehydration, or sepsis. Since lactate excretion is significantly reduced in patients with impaired liver function, metformin should generally be avoided in patients with clinical or laboratory signs of liver disease. The patient should be warned to limit alcohol intake (single or continuous) during metformin therapy, as ethanol potentiates the effect of metformin on lactate metabolism. In addition, metformin therapy should be temporarily discontinued for the duration of intravascular radiopaque studies and surgical interventions. The onset of lactic acidosis is often difficult to detect, and it is accompanied only by non-specific symptoms, such as malaise, myalgia, respiratory distress syndrome, increased drowsiness, and non-specific abdominal symptoms. As lactic acidosis worsens, hypothermia, hypotension, and resistant bradyarrhythmia may also occur. The doctor and patient should be aware of the severity of these symptoms, and the patient should immediately inform the doctor if they occur. Metformin therapy should be discontinued until the situation is clarified. It is recommended to determine the plasma concentrations of electrolytes, ketones, blood glucose, as well as (if indicated) the pH value of the blood, the concentration of lactate, the concentration of metformin in the blood. At the initial stages of treatment, the appearance of gastrointestinal symptoms is associated with taking metformin, while after the patient’s condition stabilizes at any dose of metformin, the appearance of gastrointestinal symptoms is unlikely. The late appearance of such symptoms may indicate a developing lactic acidosis or other serious illness. If the fasting lactate concentration in venous blood plasma during metformin treatment exceeds the ULN, remaining no higher than 5 mmol / l, this is not pathognomonic for developing lactic acidosis and may be due to conditions such as poorly controlled diabetes mellitus or obesity, or excessive physical exertion, or technical measurement error. Any patient with diabetes mellitus and metabolic acidosis in the absence of symptoms of ketoacidosis (ketonuria and ketonemia) is at risk of developing lactic acidosis. Lactic acidosis is a condition that requires emergency care in a medical facility. In a patient with lactic acidosis who is taking metformin, therapy with the drug should be stopped immediately and the necessary maintenance therapy measures should be taken immediately. Since metformin is dialyzed at a rate of up to 170 ml / min under good hemodynamic conditions, 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 the restoration of the patient’s condition. Hypoglycemia Under normal conditions, hypoglycemia does not develop with metformin monotherapy, but it may develop against the background of fasting, after significant physical activity without subsequent compensation for calories consumed, or with the simultaneous use of other hypoglycemic drugs (such as sulfonylureas and insulin derivatives) 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 detect in elderly patients and patients taking beta-blockers. Concomitant therapyexisting pharmacotherapy that may lead to severe hemodynamic changes or affect renal function and metformin distribution, such as cationic drugs that are eliminated from the body by renal tubular secretion, should be prescribed with caution. Radiological studies with intravascular administration of iodine-containing contrast agents (for example, intravenous urogram, intravenous cholangiography, angiography, CT with intravenous administration of contrast agents)Intravascular administration of iodine-containing contrast agents can cause acute renal failure and is associated with lactic acidosis in patients taking metformin. Therefore, patients who are scheduled for such a study should temporarily stop taking the drug at least 48 hours before and within 48 hours after the study. Resumption of therapy is allowed only after confirmation of normal renal function. Hypoxic statesvascular 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 pre-renal azotemia. If these conditions develop in a patient during therapy with a combination of metformin+sitagliptin, the drug should be discontinued immediately. Surgical interventionsthe use of the drug should be discontinued for the duration of any surgical intervention (with the exception of minor manipulations that do not require restrictions on drinking and hunger) and up to the resumption of normal food intake, 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 risk of alcohol abuse (single or multiple use) during treatment with the drug. Impaired liver function Since lactic acidosis has been reported in patients with impaired liver function, it is not recommended to use the drug in 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 serum to subnormal values without clinical manifestations was observed in approximately 7% of patients. Such a decrease, possibly due to selective malabsorption of vitamin B12 (namely, a violation of the formation of a complex with the internal Castle factor, the so-called complex internal complex necessary for the absorption of vitamin B12), is very rarely accompanied by the development of anemia and is easily corrected by the withdrawal of metformin or an additional intake of vitamin B12. When using the drug, it is recommended to check the hematological parameters of the blood annually, and any deviations that occur should be adequately studied and corrected. Patients predisposed to developing vitamin B12 deficiency (due to reduced intake or absorption of vitamin B12 or calcium) are recommended to determine the plasma concentration of vitamin B12 at intervals of 2-3 years. Changes in clinical status in patients with previously adequately controlled type 2 diabetes mellitus If laboratory abnormalities or clinical symptoms of the disease (in particular, any condition that cannot be clearly identified) occur in a patient with previously adequately controlled type 2 diabetes mellitus during drug therapy, you should immediately make sure that there are no signs of ketoacidosis or lactic acidosis. Assessment of the patient’s condition should include blood plasma tests for 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 stopped immediately and appropriate measures should be taken to correct the acidosis. Deterioration of glycemic controli N situations of physiological stress (hyperthermia, trauma, infection, or surgery), a patient with previously satisfactory glycemic control may temporarily lose glycemic control. During such periods, it is permissible to temporarily replace the drug with insulin therapy, and after the acute situation is resolved, the patient can resume the previous treatment. Effects on the ability to drive vehicles and mechanisms No studies have been conducted to study the effect of the drug on the ability to drive vehicles and work with mechanisms. However, cases of dizziness and drowsiness that have been reported with sitagliptin should be considered. In addition, patients should be aware of the risk of hypoglycemia when the drug is co-administered with sulfonylureas or insulin.

Form of production

Long-release, film-coated tablets.

Active ingredient

Metformin, Sitagliptin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Type 2 Diabetes