Yanumet (Janumet)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceMetformin + SitagliptinMetformin + Sitagliptin
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    Merck Sharp and Doum B.V.     Netherlands
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    Merck Sharp and Doum B.V.     Netherlands
    • Dosage form: & nbspfilm coated tablets
    Composition:One film-coated tablet contains:
    Dosage of 500 mg + 50 mg:
    Active substances: sitagliptin phosphate monohydrate 64.25 mg (equivalent to 50 mg of sitagliptin) and metformin hydrochloride 500 mg. Excipients: microcrystalline cellulose 59.30 mg; Povidone 48.23 mg; sodium stearyl fumarate 13.78 mg, sodium lauryl sulfate 3.445 mg.
    Tablet cover Opadrai® II Pink 85 F 94203 (17.23 mg) contains: polyvinyl alcohol 47.800%, titanium dioxide (E 171) 6,000%, macrogol 3350 23.500%, talc 22.590%, iron oxide black (E 172) 0.005 %, iron oxide red (E 172) 0.105%.
    Dosage of 850 mg + 50 mg:
    Active substances: sitagliptin phosphate monohydrate 64.25 mg (equivalent to 50 mg of sitagliptin) and metformin hydrochloride 850 mg. Excipients: microcrystalline cellulose 96.64 mg; povidone 78.19 mg; sodium stearyl fumarate 22.34 mg; sodium lauryl sulfate 5.590 mg.
    Tablet cover Opadrai® II Pink, 85 F 94182 (27; 93 mg) contains: polyvinyl alcohol 49.950%, titanium dioxide (E 171) 6,000%, macrogol 3350 25.210%, talc 18.470%, iron oxide black (E 172) 0.020 %, iron oxide red (E 172) 0.350%.
    Dosage of 1000 mg + 50 mg:
    Active substances: sitagliptin phosphate monohydrate 64.25 mg (equivalent to 50 mg of sitagliptin) and metformin hydrochloride 1000 mg. Excipients: microcrystalline cellulose 112.3 mg, povidone 91.00 mg, sodium stearyl fumarate 26.00 mg, sodium lauryl sulfate 6,500 mg.
    Opadine® II Red, 85 F 15464 (32.50 mg) contains: polyvinyl alcohol 48.300%, titanium dioxide (E 171) 6,000%, macrogol 3350 24.380%, talc 17.870%, iron oxide black (E 172) 0.150 %, iron oxide red (E 172) 3,300%.
    Description:Tablets 500 mg + 50 mg:
    Oval biconvex tablets covered with a film coating, light pink color with engraving "575" on one side of the tablet.
    View at a break: from white to almost white.
    Tablets 850 mg + 50 mg:
    Oval biconvex tablets covered with a film shell, pink with engraving "515" on one side of the tablet.
    View at a break: from white to almost white.
    Tablets 1000 mg + 50 mg:
    Oval biconvex tablets covered with a film shell, reddish-brown with engraving "577" on one side of the tablet.
    View at a break: from white to almost white.
    Pharmacotherapeutic group:A hypoglycemic agent for oral administration combined (dipeptidyl peptidase-4-inhibitor + biguanide)
    ATX: & nbsp

    A.10.B.D   Combination of biguanides and sulfonylurea derivatives

    A.10.B.D.07   Metformin and sitagliptin

    Pharmacodynamics:The drug Yanumet 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.
    Sitagliptin is active in oral administration, a highly selective inhibitor of DPP-4, 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. 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). Incretiny are part of the internal physiological system of regulation of glucose homeostasis. With a normal or elevated blood glucose concentration, GLP-1 and HIP promote an increase in the synthesis and secretion of insulin by beta-cells of the pancreas.GLP-1 also suppresses the secretion of glucagon by the alpha cells of the pancreas, thereby reducing the synthesis of glucose in the liver. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives that stimulate the release of insulin and 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. Being a highly selective and effective inhibitor of the enzyme DSh1-4, sitagliptin in therapeutic concentrations does not inhibit the activity of related enzymes DPP-8 or DPP-9. Sitagliptin differs in chemical structure and pharmacological effect from GLP-1 analogs, insulin, sulfonylurea derivatives or meglitinides, biguanides, gamma receptor agonists activated with peroxisome proliferator (PPARy), alpha-glycosidase inhibitors and amylin analogs.
    Metformin
    Metformin is a hypoglycemic drug that increases glucose tolerance in patients with type 2 diabetes, reducing basal and postprandial glucose concentrations in the blood. Its pharmacological mechanisms of action differ from the mechanisms of action of oral hypoglycemic drugs of other classes.
    Metformin reduces the synthesis of glucose in the liver, reduces absorption of glucose in the intestine and increases insulin sensitivity by enhancing peripheral uptake and glucose utilization. In contrast to the sulfonylurea derivatives metformin does not cause hypoglycemia in either type 2 diabetes patients, nor in healthy people (with the exception of some circumstances, see "With caution", Metformin) and does not cause hyperinsulinemia. During treatment with metformin, the secretion of insulin does not change, while the fasting insulin concentration and the daily plasma insulin concentration may decrease.
    Oral administration of a single dose of sitagliptin to patients with type 2 diabetes leads to suppression of the activity of the DPP-4 enzyme by 24 h, which is accompanied by a 2-3 fold increase in the concentration of circulating active GLP-1 and HIP, an increase in plasma concentrations of insulin and C-peptide, a decrease in glucagon concentration and plasma glucose concentration on an empty stomach, as well as a decrease in the amplitude of fluctuations in glycemia after a glucose or nutritional load.
    The intake of sitagliptin in a daily dose of 100 mg for 4-6 months significantly improved the function of beta cells of the pancreas in patients with type 2 diabetes,as evidenced by the corresponding changes in such markers as HOMA-β (homeostasis assessment in model-β), proinsulin / insulin ratio, pancreatic beta response from the panel of repeated tests for food tolerance. According to clinical studies of II and III phases, the effectiveness of glycemic control of sitagliptin in a regimen of 50 mg x 2 times a day was comparable to that of 100 mg once daily.
    In a randomized, placebo-controlled, double-blind, double-imitation 4-period, cross-over study, the effect of sitagliptin in combination with metformin, or only sitagliptin, or only metformin, or placebo on plasma concentrations of active and total GLP-1 and glucose after administration food. The weighted mean concentrations of active GLP-1 at 4 hours after ingestion increased approximately 2-fold after taking only sitagliptin or only metformin versus placebo. Combined reception of sitagliptin and metformin prevented the summation of the effect with a 4-fold increase in the concentration of active GLP-1 in comparison with the dynamics in the placebo group.
    The intake of only sitagliptin was accompanied by an increase in the concentration of only active GLP-1 due to inhibition of the DPP-4 enzyme, while the administration of metformin alone was accompanied by a symmetrical increase in the concentration of total and active GLP-1. The data obtained reflect various mechanisms in the basis of increasing the concentration of active GLP-1 after the administration of these two drugs. The results of the study also demonstrated that sitagliptin, but not metformin provides an increase in the concentration of active GLP-1.
    In studies in healthy volunteers, the reception of sitagliptin was not accompanied by a decrease in glucose concentration and did not cause hypoglycemia, which confirms the glucose-dependent nature of insulinotropic action and suppression of glucagon synthesis.
    Effect on blood pressure
    In a randomized, placebo-controlled study involving patients with hypertension, the combined use of antihypertensive drugs (one or more of the list: angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, slow calcium channel blockers, beta-blockers, diuretics) with sitagliptin generally well tolerated by patients. In this category of patients sitagliptin demonstrated a slight hypotensive effect: in a daily dose of 100 mg sitagliptin reduced the average daily outpatient value of systolic blood pressure (BP) by 2 mmHg compared with the placebo group. In patients with normal BP, no hypotensive effect was observed.
    Influence on the electrophysiology of the heart
    In a randomized, placebo-controlled, cross-over study in healthy volunteers, sitagliptin was taken once in a dose of 100 mg or 800 mg (8 times the recommended dose), or a placebo. After receiving the recommended therapeutic dose of any effect of the drug on the duration of the QT interval, both at the time of its maximum plasma concentration and at other points of verification throughout the study, were not observed. After taking 800 mg, the maximum increase in the placebo-adjusted mean change in the duration of the QT interval compared to the baseline value at 3 hours after taking the drug was 8.0 msec. Such a slight increase was assessed as clinically insignificant. After taking 800 mg dose, the maximum plasma concentration of sitagliptin was approximately 11 times higher than the corresponding value after taking a therapeutic dose of 100 mg.
    Pharmacokinetics:The results of the study on the determination of bioequivalence in healthy volunteers demonstrated that the combined tablets Yanumet (metformin + sitagliptin) 500 mg / 50 mg and 1000 mg / 50 mg are bioequivalent to the separate intake of appropriate doses of sitagliptin (JANU�?ЯIA ™) and metformin.
    (Given the proven bioequivalence of tablets with the lowest and highest dose of metformin, tablets with an intermediate dose of metformin (metformin + sitagliptin) 850 mg / 50 mg was also given bioequivalence when combined in a tablet of fixed doses of drugs. Suction
    Sitagliptin
    The absolute bioavailability of sitagliptin is approximately 87%. Reception of sitagliptin simultaneously with fatty food does not affect the pharmacokinetics of the drug.
    Metformin
    The absolute bioavailability of metformin when administered on an empty stomach at a dose of 500 mg is 50-60%. The results of studies of a single dose of metformin tablets at doses of 500 mg to 1500 mg and 850 mg to 2,550 mg indicate a violation of dose-proportionality with an increase in dose, which is more likely due to reduced absorption than accelerated excretion.Simultaneous administration of the drug with food reduces the rate and amount of metformin absorbed, which is confirmed by a decrease in the maximum plasma concentration of Cmax by about 40%, a decrease in the area under the concentration-time curve of AUC by about 25%, and a 35-minute delay in reaching the maximum plasma concentration Tmax after a single dose of metformin at a dose of 850 mg concomitantly with food compared with 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 is not established.
    Distribution
    Sitagliptin
    The average volume of distribution in the equilibrium state after a single IV injection of 100 mg of sitagliptin in healthy volunteers is approximately 198 liters. The fraction of the reversibly binding plasma of sitagliptin is relatively small (38%).
    Metformin
    The volume of metformin distribution following a single oral dose of 850 mg averaged 654 ± 358 liters. Metformin only to a very small extent binds to plasma proteins. Metformin partially and temporarily distributed in erythrocytes. When metformin is used in recommended doses and regimens, plasma concentrations of the equilibrium state (usually <1 μg / ml) are reached after about 24-48 hours. According to the controlled studies, the maximum plasma concentrations of the drug did not exceed 5 μg / ml, even after taking the maximum doses of the drug .
    Metabolism
    Sitagliptin
    Approximately 79% of sitagliptin is excreted unchanged by the kidneys, the metabolic transformation of the drug is minimal.
    After the introduction 14C-labeled sitagliptin into about 16% of the administered radioactivity was excreted as metabolites of sitagliptin. Trace concentrations of six metabolites of sitagliptin were found that did not contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In in vitro studies, cytochrome CYP3A4 and CYP2C8 cytochrome isozymes are identified as the main ones involved in the restricted metabolism of sitagliptin.
    Metformin
    After a single IV injection of healthy metformin volunteers, practically the entire dose administered was excreted unchanged by the kidneys.Metabolic transformations of the drug in the liver and its excretion with bile does not occur. Excretion
    Sitagliptin
    After taking 14C-labeled sitagliptin inside by healthy volunteers, almost all the introduced radioactivity was excreted from the body during the week, including 13% through the intestine and 87% - by the kidneys. The average half-life of sitagliptin for oral administration of 100 mg is approximately 12.4 hours, the renal clearance is approximately 350 ml / min.
    The elimination of sitagliptin is carried out mainly by renal excretion by the mechanism of active tubular secretion. Sitagliptin is the substrate of the transporter of organic human anions of the third type (hОАТ-З), participating in the process of elimination of sitagliptin by the kidneys. The clinical significance of the participation of hOTAT-3 in the transport of sitagliptin is not established. Possible participation of p-glycoprotein in the renal elimination of sitagliptin (as a substrate), however, the inhibitor of p-glycoprotein ciclosporin does not reduce renal clearance of sitagliptin.
    Metformin
    Renal clearance of metformin exceeds the creatinine clearance by 3.5 times, indicating active renal secretion as the main pathway of excretion.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 about 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.
    Pharmacokinetics in selected patient groups
    Patients with type 2 diabetes mellitus
    Sitagliptin
    The pharmacokinetics of sitagliptin in patients with type 2 diabetes is similar to the pharmacokinetics of healthy individuals.
    Metformin
    With preserved renal function, pharmacokinetic parameters after single and repeated metformin administration in patients with type 2 diabetes and healthy individuals are the same, no cumulation of the drug is taken with the therapeutic dose.
    Patients with renal insufficiency
    The drug Yanumet should not be prescribed to patients with renal insufficiency (see "Contraindications").
    Sitagliptin
    In patients with moderate renal insufficiency, an approximately 2-fold increase in plasma AUC of sitagliptin was noted, and in patients with severe and terminal stage (hemodialysis), the increase in AUC was 4-fold compared to control values ​​in healthy individuals.
    Metformin
    In patients with reduced renal function (for creatinine clearance), the half-life of the drug is prolonged, and renal clearance decreases in proportion to a decrease in creatinine clearance.
    Patients with hepatic insufficiency
    Sitagliptin
    In patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), the average values ​​of AUC and Cmax of sitagliptin after a single dose of 100 mg increase by approximately 21% and 13%, respectively, compared to healthy individuals. Such a difference is not clinically significant.
    There are no clinical data on the use of sitagliptin in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale). However, based on the predominantly renal route of excretion, significant changes in the pharmacokinetics of sitagliptin in patients with severe hepatic insufficiency are not predicted.
    Metformin
    Studies of pharmacokinetic parameters of metformin in patients with hepatic insufficiency have not been conducted.
    Floor
    Sitagliptin
    According to the analysis of the pharmacokinetic data of clinical studies of the I and II phases, sex did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin.
    Metformin
    Pharmacokinetic parameters of metformin did not differ significantly in healthy individuals and patients with type 2 diabetes on the basis of gender. According to controlled clinical studies, hypoglycemic effects of metformin in men and women were similar.
    Elderly patients
    Sitagliptin
    According to the population pharmacokinetic analysis of the data of Phase I and II clinical trials, the age of the patients 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 young patients.
    Metformin
    Limited data from controlled pharmacokinetic studies of metformin in healthy elderly individuals suggest that the total plasma clearance of the drug in them is reduced, the half-life is prolonged, and the value of Stach is increased in comparison with young healthy individuals. These data mean that the age-related changes in the pharmacokinetics of the drug are due to a decrease in the excretory function of the kidneys.
    Treatment with the drug Yanumet is not indicated to the elderly at the age of> 80 years,in which the clearance of creatinine indicates that the kidney function is not reduced (see "Special instructions", Metformin).
    Children
    Studies of the drug Yanumet in children were not conducted.
    Race
    Sitagliptin
    According to the analysis of the pharmacokinetic data of phase I and II clinical trials, race did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin, including representatives of Caucasoid and Mongoloid races, representatives of Latin American countries and other ethnic and racial groups.
    Metformin
    Studies on the potential impact of race on the pharmacokinetic parameters of metformin were not conducted. According to controlled studies of metformin in patients with type 2 diabetes, the hypoglycemic effect of the drug was comparable in representatives of the Caucasoid, Negroid races and Latin American countries.
    Body mass index (BMI)
    Sitagliptin
    According to the data of complex and population analysis of pharmacokinetic parameters from clinical studies of I and II phases, BMI had no clinically significant effect on the pharmacokinetic parameters of sitagliptin.
    Indications:Monotherapy
    The drug Yanumet is shown as a starting therapy for patients with type 2 diabetes to improve control of glycemia, if compliance with diet and exercise regimen do not allow adequate control.
    The drug Yanumet is shown as a supplement to the diet and exercise regimen to improve control of glycemia in patients with type 2 diabetes mellitus who did not achieve adequate control against monotherapy with metformin or sitagliptin, or after unsuccessful combination treatment with two drugs.
    Combination Therapy
    The drug Yanumet is indicated for patients with type 2 diabetes to improve glycemic control in combination with sulfonylureas (triple combination: metformin + sitagliptin + derivative of sulfonylureas), when diet and exercise regimen combined with two of these three drugs: metformin, sitagliptin or sulfonylureas do not lead to adequate glycemic control.
    The drug Yanumet is indicated for patients with type 2 diabetes to improve glycemic control in combination with thiazolidinediones (PPARγ receptor agonists,activated by peroxisome proliferator), when diet and exercise regimen combined with two of the three drugs: metformin, sitagliptin or thiazolidinedione do not lead to adequate glycemic control.
    The drug Yanumet is indicated for patients with type 2 diabetes to improve glycemic control in combination with insulin, when diet and exercise in combination with insulin do not lead to adequate glycemic control.
    Contraindications:- known hypersensitivity to sitagliptin, metformin or any of the components of the preparation Yanumet;
    - Type 1 diabetes mellitus;
    - kidney disease or decreased kidney function (at a serum creatinine concentration ≥ 1.5 mg / dL and ≥ 1.4 mg / dL in men and women, respectively, or a decrease in creatinine clearance (<60 mL / min), including cardiovascular collapse (shock), acute myocardial infarction or septicemia;
    - acute conditions that occur with a risk of developing renal dysfunction:
    - dehydration (with diarrhea, vomiting), fever, severe infectious diseases,
    - the state of hypoxia (shock, sepsis, kidney infections, broncho-pulmonary diseases);
    - Acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without coma);
    - clinically pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (including cardiac or respiratory failure, acute myocardial infarction);
    - extensive surgery and trauma, when insulin therapy is indicated (see section "Special instructions");
    - liver failure, a violation of liver function;
    - chronic alcoholism, acute alcohol poisoning;
    - pregnancy, the period of breastfeeding;
    - lactic acidosis (including in the anamnesis);
    - use for at least 48 hours before and within 48 hours after radioisotope or X-ray studies with the introduction of iodine-containing contrast medium (see section "Interaction with other drugs");
    - compliance with the hypocaloric diet (less than 1000 kcal / day);
    - Children under 18 years.
    Carefully:Application in the elderly
    Yanumet
    Since the main way to excrete sitagliptin and metformin are the kidneys, and as the kidney excretory function decreases with age, precautions for prescribing the Yanumet drug increase in proportion to age.Elderly patients undergo a careful dose selection and regular monitoring of kidney function (see "Special instructions", Monitoring of kidney function).
    Sitagliptin
    According to clinical studies, the efficacy and safety of sitagliptin in elderly patients (> 65 years) was comparable to that of young patients (<65 years of age).
    Metformin
    The number of elderly patients among participants in controlled studies of metformin was insufficient to make a formal judgment about the age-related differences in the efficacy and safety of the drug, although no such differences were reported from the available data. Because the metformin is excreted mainly by the kidneys, and with their impaired function, the probability of adverse reactions increases, the drug should be given only to patients with confirmed normal renal function (see "Contraindications").
    Pregnancy and lactation:Yanumet
    Adequately controlled studies of the drug Yanumet or its components in pregnant women are not conducted, therefore, there are no data on the safety of its use in pregnant women. The drug Yanumet, like other oral hypoglycemic drugs, is not recommended for use during pregnancy.
    There was no experimental study of the combined preparation Yanumet to assess its effect on reproductive function. Only available data are available from studies of sitagliptin and metformin.
    Sitagliptin
    Sitagliptin did not demonstrate teratogenicity during organogenesis with oral administration to rats at daily doses up to 250 mg / kg or rabbits at doses up to 125 mg / kg (which exposes the plasma exposure of the drug in humans to 32 and 22 times, respectively, after taking the recommended daily therapeutic dose 100 mg). A slight increase in the frequency of malformation of the ribs in offspring (absence, hypoplasia, curvature) was observed with oral administration of the drug at daily doses of 1000 mg / kg (which exceeds the exposure in humans by approximately 100 times after taking the recommended daily dose of 100 mg). A slight decrease in body weight in both sexes in the offspring of rats during breastfeeding and a decrease in the rate of weight gain after the end of breastfeeding in males when administered orally to pregnant females at a daily dose of 1000 mg / kg. Nevertheless, the data of experimental reproductive studies do not always correlate directly with the effect of the drug on human reproductive function.
    Metformin
    Metformin did not demonstrate teratogenicity when administered orally to rats at daily doses up to 600 mg / kg. This exposes the plasma exposure of the drug in humans 2 and 6 times (in rats and rabbits, respectively) after receiving the maximum recommended daily therapeutic dose of 2000 mg. Values ​​of the plasma concentration of the drug in the fetus indicate partial placental transfer.
    Experimental studies to determine the secretion of components of the combined drug Yanumet in breast milk were not performed. According to studies on individual drugs, both sitagliptin, and metformin are secreted into the breast milk of rats. There is no data on the secretion of sitagliptin in human milk. Therefore, the drug Yanumet should not be prescribed during lactation.
    Dosing and Administration:General information:
    The dosage regimen of the drug Janumet should be selected individually, based on current therapy, efficacy and tolerability, but not exceeding the maximum recommended daily dose of sitagliptin 100 mg.
    The drug Yanumet is usually prescribed twice a day with meals, with a gradual increase in dose, in order to minimize possible side effects from the gastrointestinal tract (GIT), characteristic of metformin.
    Dosing recommendations:
    The initial dose of the drug Yanumet depends on the current hypoglycemic therapy. The preparation of Yanumet is taken 2 times a day with meals.
    The following dosages are suggested:
    500 mg metformin / 50 mg sitagliptin 850 mg metformin / 50 mg sitagliptin 1000 mg metformin / 50 mg sitagliptin Start therapy:
    Patients with type 2 diabetes mellitus with inadequate glycemic control on the background of compliance with diet and exercise regimen, the recommended starting dose of the drug Yanumet is 500 mg metformin / 50 mg sitagliptin 2 times a day. Subsequently, the dose can be increased to 1000 mg metformin / 50 mg sitagliptin 2 times a day.
    For patients who have not achieved adequate control on monotherapy with metformin:
    The recommended starting dose of the drug Yanumet for patients who do not achieve adequate control on monotherapy with metformin should provide the recommended therapeutic daily dose of sitagliptin 100 mg, i.e. 50 mg sitagliptin 2 times a day plus the current dose of metformin.
    For patients who have not achieved adequate control on monotherapy with sitagliptin:
    The recommended starting dose of the drug Janumet for patients who did not achieve adequate control on monotherapy with sitagliptin,is 500 mg metformin / 50 mg sitagliptin 2 times a day. In the future, the dose may be
    increased to 1000 mg metformin / 50 mg sitagliptin 2 times a day. Patients taking a corrected dose of sitagliptin because of renal failure, treatment with Yanumet is contraindicated (see "Contraindications").
    For patients taking a combination of drugs sitagliptin and metformin:
    When switching from a combined treatment with sitagliptin and metformin, the starting dose of the preparation Yanumet can be equivalent to the doses of separately taken sitagliptin and metformin.
    For patients taking two of these three hypoglycemic drugs - sitagliptin, metformin or derivatives of sulfonylureas:
    The starting dose of the drug Yanumet should provide the recommended therapeutic daily dose of sitagliptin 100 mg, i.e. 50 mg of sitagliptin 2 times a day. The starting dose of metformin is determined based on the level of glycemic control and the current (if the patient takes this drug) dose of metformin. An increase in the dose of metformin should be gradual in order to minimize the associated side effects from the gastrointestinal tract.Patients taking a sulfonylureas derivative will be rational to reduce the current dose to reduce the risk of sulfonyl-induced hypoglycemia (see "Special instructions").
    For patients taking two of these three hypoglycemic drugs - sitagliptin, metformin or PPARγ-receptor agonists (thiazolidinediones):
    The starting dose of the preparation Yanumet should correspond to the daily dose of sitagliptin 100 mg, i.e. 50 mg of sitagliptin 2 times a day and the previously taken dose of metformin. If it is necessary to increase the dose of metformin, gradual titration of the drug is recommended to avoid gastrointestinal side effects.
    For patients taking two of these three hypoglycemic drugs - sitagliptin, metformin or insulin:
    The starting dose of the preparation Yanumet should correspond to the daily dose of sitagliptin 100 mg, i.e. 50 mg of sitagliptin 2 times a day and the previously taken dose of metformin. If it is necessary to increase the dose of metformin, gradual titration of the drug is recommended to avoid gastro-intestinal side effects.Patients may need to reduce the dose of insulin to prevent the risk of hypoglycemia (see "Special instructions"). Special studies to assess the safety and effectiveness of the transition from treatment with other hypoglycemic drugs for treatment with the combined drug Yanumet was not carried out. Any changes in the treatment of type 2 diabetes should be conducted with caution and under the control of appropriate parameters, taking into account possible changes in glycemic control.
    Use in children
    The safety of the drug Janumet in children and adolescents under the age of 18 years has not been studied.
    Side effects:In placebo-controlled trials, combined treatment with sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes mellitus. The incidence of side effects with combined treatment with sitagliptin and metformin was comparable to that of metformin in combination with placebo.
    Combined treatment with sitaglitin and metformin
    Start therapy
    In a 24-week placebo-controlled factorial study of initial combination therapy with sitagliptin and metformin (sitagliptin 50 mg +metformin 500 mg or 1000 mg x 2 times a day) in the combination therapy group as compared to the monotherapy groups
    metformin (500 mg or 1000 mg x 2 times per day), sitagliptin (100 mg once daily) or placebo, the following drug-related adverse events observed at a frequency of ≥ 1% in the combination treatment group and more often than in the group placebo: diarrhea (sitagliptin + metformin - 3,5%, metformin - 3,3%, sitagliptin - 0.0%, placebo -1.1%), nausea (1.6%, 2.5%, 0.0% and 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 therapy with metformin
    In a 24-week, placebo-controlled study, with the addition of sitagliptia at a dose of 100 mg / day to current metformin treatment, the only adverse drug-related response observed at a rate of ≥1% in the sitagliptin treatment group and more often than in the placebo group, was nausea (sitagliptin + metformin - 1.1%, placebo + metformin - 0,4%).
    Gynoglycemia and undesirable reactions from the digestive tract
    In placebo-controlled trials of combined treatment with sitagliptin and metformin, the developmental frequencyhypoglycemia (regardless of cause-effect relationship) in the combination therapy groups was comparable to the frequency in the metformin treatment groups in combination with placebo (1.3-1.6% and 2.1%, respectively). The frequency of monitored adverse reactions from the gastrointestinal tract (irrespective of the cause-effect relationship) in the groups of combined treatment with sitagliptin and metformin was comparable with the frequency in the monotherapy with metformin: diarrhea (sitagliptin +metformin - 7,5%, metformin - 7.7%), nausea (4.8%, 5.5%), vomiting (2.1%, 0.5%), abdominal pain (3.0%, 3.8%).
    In all studies, adverse reactions in the form of hypoglycemia were recorded based on all reports of clinically expressed symptoms of hypoglycemia; additional measurement of blood glucose concentration was not required.
    Combined treatment with sitagliptin, metformin and sulfonylurea derivative
    In a 24-week, placebo-controlled study using sitagliptin at a dose of 100 mg / day against the background of the current combined treatment with glimepiride at a dose of ≥4 mg / day and metformin at a dose of ≥1500 mg / day, the following adverse drug reactions observed with the drug frequency ≥1% in the treatment group with sitagliptin and more often than in the placebo group: hypoglycemia (sitagliptin - 13,8%, placebo - 0,9%), constipation (1,7% and 0,0%).
    Combined treatment with sitagliptin, metformin and PPARγ agonist
    According to a placebo-controlled study using sitagliptin at a dose of 100 mg / day against the background of the current combined treatment with rosiglitazone and metformin at week 18, the following drug-related adverse events observed with a frequency of ≥1% in the treatment group with sitagliptin and, more often, than in the group with placebo: headache (sitagliptin - 2.4%, placebo - 0.0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2% 0.0 %), vomiting (1.2%, 0.0%). At the 54th week of the combined treatment, the following adverse drug reactions were observed with a frequency of ≥1% in the treatment group with sitagliptin and more often than in the placebo group: headache (sitagliptin -2.4%, placebo - 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%).
    Combined treatment with sitagliptin, metformin and insulin
    In a 24-week, placebo-controlled study using sitagliptin at a dose of 100 mg / day against the background of the current
    combined treatment with metformin at a dose of ≥1500 mg / day and a constant dose of insulin, the only undesirable reaction associated with taking the drug and observed at a rate of ≥1% in the treatment group with sitagliptin and more often than in the placebo group was hypoglycemiasitagliptin - 10.9%, placebo - 5.2%). In another 24-week study in which patients received sitagliptin as an additional therapy for insulin therapy (with or without metformin), the only adverse reaction observed at a rate of ≥1% in the sitagliptin and metformin treatment group, and more often than in the placebo and metformin group, was vomiting (sitagliptin and metformin -1.1%, placebo and metformin - 0,4%). Pancreatitis
    In a generalized analysis of 19 double-blind randomized clinical trials of the use of sitagliptin (100 mg / day) or the appropriate control drug (active or placebo), the incidence of acute pancreatitis was 0.1 cases per 100 patient-years of treatment in each group (see Table 1). section "Special instructions.").
    Clinically significant deviations in vital signs or ECG (including the duration of the QTc interval) were not observed with combined therapy with sitagliptin and metformin.
    Undesirable reactions due to the use of sitagliptin
    Patients did not experience any undesirable reactions due to the use of sitagliptin, whose frequency was ≥ 1%.
    Undesirable reactions caused by the use of metformin
    Unwanted reactions observed in the metformin group in> 5% of patients and more often than in the placebo group include diarrhea, nausea / vomiting, flatulence, asthenia, dyspepsia, abdominal discomfort and headache.
    Post-market observations
    In the course of post-marketing monitoring of the use of the drug Janumet or sitagliptin, included in its composition, in the monotherapy and / or combined therapy with other hypoglycemic agents, additional undesirable phenomena were identified. Since these data were obtained voluntarily from a population of undetermined size, it is impossible to determine the frequency and cause-and-effect relationship of these undesirable events with therapy. These include: hypersensitivity reactions, including anaphylaxis; angioedema; skin rash; hives; cutaneous vasculitis; exfoliative skin diseases,including Stevens-Johnson syndrome; acute pancreatitis, including hemorrhagic and necrotic forms with lethal and without lethal outcome; impairment of kidney function, including acute renal failure (sometimes dialysis is required); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; pain in the limb; back pain: itching.
    Changes in laboratory indicators
    Sitagliptin
    The frequency of laboratory deviations in the treatment groups for sitagliptin and metformin was comparable to that in the placebo and metformin treatment groups. Most, but not all, of the clinical studies reported a slight increase in white blood cell count (approximately 200 / μL compared with placebo, with an average content of 6600 / μL at the beginning of treatment) due to an increase in the number of neutrophils. This change is not considered clinically significant.
    Metformin
    In controlled clinical studies of metformin for 29 weeks, the normal concentration of cyanocobalamin (vitamin B12) decreased to subnormal serum levels in approximately 7% of patients, with no clinical manifestations.This decrease, caused by selective impairment of absorption of vitamin B12 (namely, a violation of the formation of the complex with the internal factor of the Castle, necessary for absorption of vitamin B12), very rarely leads to the development of anemia and is easily corrected by the abolition of metformin or supplemental intake of vitamin B12 (see section "Special instructions., Metformin ").
    Overdose:Sitagliptin
    During clinical studies in healthy volunteers, a single dose of sitagliptin in a dose of up to 800 mg was generally well tolerated. Minimal changes in the QT interval, not considered clinically significant, were noted in one study of sitagliptin at a daily dose of 800 mg (see Pharmacodynamics, Effect on the Electrophysiology of the Heart). A dose of more than 800 mg per day in humans has not been studied.
    In clinical studies of repeated intake of the drug (Phase I), there were no adverse reactions associated with the treatment of sitagliptin with a daily dose of 400 mg for 28 days.
    In case of an overdose, it is necessary to start the standard supporting measures: removal of the non-sucking drug from the digestive tract, monitoring of vital signs, including ECG, and the appointment of symptomatic therapy if necessary.
    Sitagliptin slightly dialyziruetsya: according to clinical studies during the 3-4-hour dialysis session, only 13.5% of the dose was withdrawn. In case of clinical necessity, prolonged hemodialysis is prescribed. There is no data on the efficacy of peritoneal dialysis of sitagliptin.
    Metformin
    There have been cases of metformin overdose, including ingestion in amounts exceeding 50 g (50,000 mg). Hypoglycemia was observed in about 10% of all cases of overdose, but a clear association with an overdose of metformin has not been established. The development of lactic acidosis has accompanied approximately 32% of all cases of metformin overdose (see "Specific guidance", Metformin). Possible emergency hemodialysis (metformin dialyzed at a rate of up to 170 ml / min under conditions of good hemodynamics) for accelerated elimination of excess metformin if it is suspected of overdose.
    Interaction:Sitagliptin and metformin
    Simultaneous administration of multiple doses of sitagliptin (50 mg twice per day) and metformin (1000 mg twice daily) was not accompanied by significant changes in the pharmacokinetic parameters of sitagliptin or metformin in patients with type 2 diabetes.
    Studies of the inter-drug effect on the pharmacokinetic parameters of the preparation of Yanumet were not carried out, however, a sufficient number of similar studies were carried out for each of the components of the preparation, sitagliptin and metformin.
    Sitagliptin
    In studies on interactions with other drugs, sitagliptin had no clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives. Based on these data, sitagliptin does not inhibit CYP isoenzymes of the cytochrome CYP3A4, 2C8 or 2C9 system. The in vitro data indicate that sitagliptin also does not suppress the isoenzymes CYP2D6, 1A2, 2C19 and 2B6 and does not induce CYP3A4.
    According to the population pharmacokinetic analysis of 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: hypocholesterolemic drugs (statins, fibrates, ezetimibe), antiplatelet agents (clopidogrel), antihypertensive drugs (ACE inhibitors, angiotensin II receptor antagonists, beta-adrenoblockers, blockers of "slow" calcium channels, hydrochlorothiazide, analgesics and non-steroidal anti-inflammatory drugs (naproxen, diclofenac, celecoxib), antidepressants (bupropion, fluoxetine, sertraline), antihistamines (cetirizine), proton pump inhibitors (omeprazole, lansoprazole) and drugs for the treatment of erectile dysfunction (sildenafil).
    An increase in AUC (11%), as well as in mean Cmax (18%) of digoxin, was noted when combined with sitagliptin. This increase is not considered clinically significant, but with simultaneous administration of digoxin, it is recommended that the patient be monitored.
    An increase in AUC and Cmax of sitagliptin was observed at 29% and 68%, respectively, with simultaneous single oral ingestion of the drug JANUVIA ™ at a dose of 100 mg and cyclosporine (a potent inhibitor of p-glycoprotein) at a dose of 600 mg. These changes in pharmacokinetic parameters of sitagliptin are not clinically significant.
    Metformin
    Glyburide: in the study of the inter-drug interaction of single dosesmetformin and glyburide in patients with type 2 diabetes mellitus did not observe any changes in pharmacokinetic and pharmacodynamic parameters of metformin. Changes in the values ​​of AUC and Cmax glyburide were highly variable. Insufficient information (single reception) and discrepancy of plasma concentration of glyburide with observed pharmacodynamic effects call into question the clinical significance of this interaction.
    Furosemide: in the study of the inter-drug interaction of single doses of metformin and furosemide in healthy volunteers, a change in the pharmacokinetic parameters of both drugs was observed. Furosemide increased the concentration of Cmax metformin in plasma and whole blood by 22%, the AUC value of metformin in whole blood by 15%, without altering the kidney clearance of the drug. The Cmax and AUC values ​​of furosemide, in turn, decreased by 31% and 12%, respectively, and the half-life decreased by 32%, without significant changes in the furosemide renal clearance. Information on the inter-drug interaction between the two drugs with long-term combined use is not available.
    Nifedipine: in the study of the inter-drug interaction of nifedipine and metformin after a single dose of healthy volunteers, an increase in plasma Cmax and AUC metformin by 20% and 9%, respectively, as well as an increase in the number of renal metformin. Tmax and half-life of metformin did not change. The basis is an increase in the absorption of metformin in the presence of nifedipine. The effect of metformin on the pharmacokinetics of nifedipine is minimal.
    Cationic preparations: cationic preparations (i.e., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin), secreted by tubular secretion, theoretically can interact with metformin, competing for the shared renal tubular transport system. Similar competition was observed with the simultaneous administration of metformin and cimetidine by healthy volunteers in single and multiple dose studies, with a 60% increase in Cmax of metformin in plasma and whole blood and a 40% increase in metformin AUC in plasma and whole blood.In the study of single doses, the half-life of metformin did not change. Metformin did not affect the pharmacokinetics of cimetidine. And although these inter-drug interactions are mainly of theoretical importance (with the exception of cimetidine), careful monitoring of the patient and correction of the dose of Yanumet and / or the above-mentioned cationic preparations excreted by the proximal sections of the renal tubules are recommended in cases of simultaneous administration.
    Others: some drugs have hyperglycemic potential and can interfere with the established control over glycemia. These include thiazide and other diuretics, glucocorticosteroids, phenothiazines, thyroid medications, estrogens, oral contraceptives, phenytoin, a nicotinic acid, sympathomimetics, blockers of "slow" calcium channels and isoniazid. When prescribing these drugs, the patient receiving the preparation Yanumet is recommended to closely monitor the parameters of glycemic control. With the simultaneous administration of healthy volunteers metformin and propranolol or metformin and ibuprofen, no changes in the pharmacokinetic parameters of these drugs were observed.
    Only a small proportion of metformin binds to plasma proteins, therefore, the inter-drug interactions of metformin with drugs that actively bind to plasma proteins (salicylates, sulfonamides, chloramphenicol and probenecid) are unlikely, unlike sulfonylurea derivatives, which also actively bind to plasma proteins.
    Special instructions:Yanumet
    Pancreatitis
    In the postgrade follow-up period, reports were received of the development of acute pancreatitis, including hemorrhagic or necrotic with a legal and non-lethal outcome, in patients taking sitagliptin (see section "Side effect., Post-registration observations"). Since these messages were received voluntarily from a population of undetermined size, it is impossible to reliably estimate the frequency of these messages or to establish a cause-and-effect relationship with the duration of the drug use. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis disappeared after discontinuation of sitagliptin.In case of suspicion of pancreatitis, it is necessary to stop taking the drug Janumet and other potentially dangerous drugs.
    Monitoring of kidney function
    The primary way to excrete metformin and sitagliptin is renal excretion. The risk of metformin accumulation and the development of lactic acidosis increases in proportion to the degree of renal dysfunction, therefore, the preparation of Janumet should not be administered to patients with a serum creatinine concentration above the upper age limit of the norm. In elderly patients, due to the age-related decline in kidney function, one should strive to achieve adequate glycemic control at the minimum dose of the drug Yanumet. In elderly patients, especially those over the age of 80, regular monitoring of renal function is performed.
    Before starting treatment with Yanumet, as well as less than once a year after the start of treatment, using proper tests confirm normal kidney function. With an increased likelihood of developing renal dysfunction, kidney function monitoring is performed more often, and if it is detected, the drug Yanumet is canceled.
    Development of hypoglycemia with simultaneous use with sulfonylureas or insulin derivatives
    As with other hypoglycemic agents, hypoglycemia was observed with the simultaneous use of sitagliptin and metformin in combination with insulin or sulfonylureas (see "Side effect"). To reduce the risk of developing sulfonylated or insulin-induced hypoglycemia, the dose of the sulfonylurea derivative or insulin should be reduced (see the "Method of administration and dose" section), Sitagliptin
    Development of hypoglycemia with simultaneous use with sulfonylureas or insulin derivatives
    In clinical studies of the sitaglipept both in monotherapy and in combination with drugs that do not lead to the development of hypoglycemia (i.e., metformin or PPAR agonistsγ - thiazolidinediones), the incidence of hypoglycemia in the group of patients taking sitagliptin, was close to the frequency in the group of patients taking placebo. As with the use of other hypoglycemic agents, hypoglycemia was observed with the simultaneous use of the sitagliptip in combination with insulin or sulfonylmucleic derivatives (see section "Side effect").To reduce the risk of developing sulfonyl-induced or insulin-induced hypoglycemia, the dose of the sulfonylurea derivative or insulin must be reduced (see the section "Dosing and Administration").
    Reactions of gynesensitivity
    In the course of post-marketing monitoring of the use of the drug Janumet or sitagliptin, which is part of it, monotherapy and / or combined therapy with other hypoglycemic agents revealed hypersensitivity reactions. These reactions included anaphylaxis, angioedema, exfoliative skin diseases, including Stevens-Johnson syndrome. Since these data were obtained voluntarily from a population of undetermined size, it is impossible to determine the frequency and cause-and-effect relationship with the therapy of these unwanted reactions. These reactions occurred during the first 3 months after the initiation of treatment with sitagliptin, some were observed after the first dose of the drug. If susceptibility to the development of a hypersensitivity reaction is suspected, it is necessary to stop taking the drug Yanumet, to evaluate other possible causes of the development of an undesirable phenomenon and to prescribe another hypolipidemictherapy (see the sections "Contraindications" and "Side effects. Post-registration observations").
    Metformin
    Lactic acidosis
    Lactic acidosis is a rare but serious metabolic complication that develops as a result of the accumulation of metformin during treatment with Yanumet. Mortality in lactic acidosis reaches approximately 50%. The development of lactic acidosis can also occur against a background of somatic diseases, in particular, diabetes mellitus or any other pathological condition, accompanied by pronounced hypoperfusion and hypoxemia tissues and organs. Lactoacidosis is characterized by an elevated concentration of lactate in the blood plasma (> 5 mmol / l). a lower pH value of the blood, electrolyte disturbances with an increase in the anion interval, an increase in the lactate / gruboat ratio. If the cause of the development of acidosis is metformin, the value of its concentration in the plasma is usually> 5 μg / ml.
    According to available data, lactic acidosis during treatment with metformin developed very rarely (approximately in 0.03 cases per 1000 patient-years, with a frequency of legal outcomes of approximately 0.015 cases per 1000 patient-years).For 20,000 patient-years of metformin treatment, no cases of lactic acidosis have been reported in clinical trials. Known cases occurred mainly in patients with diabetes mellitus with severe renal insufficiency, including severe kidney pathology and kidney hypoperfusion, often in combination with concomitant multiple somatic / surgical diseases and polypharmacy. Significantly increased risk of lactic acidosis in patients with chronic heart failure, which requires significant drug correction, especially in unstable angina / chronic heart failure in the acute stage, accompanied by pronounced gynoperfusion and gynoxemia. The risk of developing lactic acidosis increases in proportion to the degree of impairment of kidney function and the age of the patient, so adequate monitoring of renal function and the use of a minimal effective dose of metformin can significantly reduce the risk of lactic acidosis. Careful monitoring of renal function is especially necessary in the treatment of elderly patients,and patients over 80 years of age with metformin are initiated only after confirming the adequate function of the kidneys based on the results of creatinine clearance estimates, as these patients are more at risk of developing lactic acidosis. In addition, in any condition accompanied by the development of gynoxemia, dehydration or sepsis, the mstformiform should be immediately withdrawn. Given that if liver function is impaired, excretion of lactate is significantly reduced, should not be prescribed metformin patients with clinical or laboratory signs of liver disease. During treatment with metformin, alcohol intake should be restricted, since alcohol potentiates the effect of metformin on lactate metabolism. In addition, metformin treatment is temporarily discontinued for the period of intravascular retteiocontrast studies and surgical interventions.
    The onset of lactic acidosis is often difficult to detect, and it is accompanied only by nonspecific symptoms, such as malaise, myalgia, respiratory distress syndrome, increased drowsiness, and nonspecific dyspeptic symptoms.With the aggravation of the flow to the aforementioned lactic acidosis symptoms can join hypothermia, hypotension and resistant bradiaritmnya. The doctor and the patient should be aware of the possible significance of such symptoms, and the patient should immediately inform the doctor about their appearance. Treatment with metformin is canceled until the situation becomes clear. This concentration is determined plasma electrolytes, ketones, blood glucose, and (indication) value of blood pH, lactate concentration. Sometimes information about the plasma concentration of metformin can also be useful. After adjusting the patient to the optimal dose of metformin, symptoms from the digestive tract, characteristic at the initial stages of treatment, should disappear. If such symptoms appear, they are most likely a signal of developing lactic acidosis or another serious disease.
    If during treatment with metformin lactate concentration in venous plasma exceeds the upper limit of normal, remaining ns higher than 5 mmoles / l, ego nepatognomonichpo for lactic acidosis and may be caused by conditions such as poorly controlled diabetes or obesity or excessive physical activity, or technical measurement error.
    In any patient with diabetes mellitus and metabolic acidosis in the absence of confirmation of ketoacidosis (ketonuria and ketonemia), there is a risk of developing lactic acidosis.
    Lactoacidosis is a condition requiring emergency care in a medical facility. Treatment with metformin is canceled and immediately necessary measures of maintenance therapy are carried out. Because the metformin dialysis at a rate of up to 170 ml / min in conditions of good hemodynamics, immediate hemodialysis is recommended for rapid correction of acidosis and excretion of accumulated metformin. These measures often lead to the rapid disappearance of all symptoms of lactic acidosis and restore the patient's condition (see "Contraindications").
    Hypoglycaemia
    Under normal conditions, with metformin monotherapy, hypoglycemia does not develop, but its development is possible against a background of fasting, after considerable physical exertion without subsequent compensation of consumed calories, while taking other hypoglycemic drugs (sulfonylurea and insulin derivatives) or alcohol.To a greater extent, elderly, weakened or debilitated patients, alcohol abusers, patients with adrenal or pituitary insufficiency are exposed to hypoglycemia. Hypoglycemia is difficult to recognize in elderly patients and patients taking beta-blockers.
    Concomitant therapy
    Concomitant pharmacotherapy may adversely affect renal function or the distribution of metformin.
    The simultaneous use of drugs that adversely affect the function of the kidneys, hemodynamics, or pa distribution of metformin (such as cationic drugs that are excreted from the body by tubular secretion) should be administered with caution (see section "Interaction with other drugs, Mstformin").
    Radiological studies with intravascular administration of iodine-containing contrast agents (for example, intravenous urogram, intravenous holography, angiography, computed tomography with vitritional injection of contrast agents)
    Intravascular injection of iodine-containing contrast agents was associated with the development of lactic acidosis in patients taking metformin, and can cause acute disruption of kidney function (see section "Contraindications"). Therefore, patients who are scheduled for this study should temporarily stop taking the drug Yanumet 48 hours before and within 48 hours after the study. Renewal of treatment is permissible only after laboratory confirmation of normal kidney function.
    Hypoxic states
    Vascular collapse (shock) of any etiology, acute heart failure, acute myocardial infarction and other conditions, accompanied by the development of hypoxemia. can provoke the development of lactic acidosis and non-prophylactic azotemia. If the listed conditions develop in the patient against the background of treatment with Yanumet, the drug should be stopped immediately.
    Surgical interventions
    The use of the drug Janumet should be discontinued for the duration of any surgical intervention (except for small manipulations that do not require drinking and hunger restrictions) and until the normal diet is resumed, provided laboratory confirmation of normal kidney function is established.
    Alcohol consumption
    Alcohol potentiates the effect of metformin on the metabolism of lactic acid.
    The patient should be warned about the danger of alcohol abuse (single intake of a large number or a constant intake of small doses) for the period of treatment with the drug Yanumet.
    Impaired liver function
    Since there are cases of the development of lactic acidosis in patients with impaired liver function, it is not recommended to prescribe the preparation of Yanumet to patients with clinical or laboratory signs of liver disease.
    Concentration of cyanocobalamin (vitamin B12) in blood plasma
    In controlled studies of metformin for 29 weeks, 7% of patients had a decrease in the initial normal concentration of cyanocobalamin (vitamin B12) in the blood plasma without developing clinical symptoms of deficiency. This decrease may be due to a selective impairment of absorption of vitamin B12 (namely, a violation of the formation of the complex with an internal factor of the Castle, necessary for absorption of vitamin B12), very rarely leads to the development of anemia and is easily corrected by the abolition of metformin or supplemental intake of vitamin B12.
    In the treatment with the drug Yanumet, it is recommended that blood hematologic parameters be checked annually, and any deviations that occur should be studied and corrected.Patients who are prone to 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.
    Change in the clinical status of patients with adequately controlled type 2 diabetes mellitus
    If there are laboratory abnormalities or clinical symptoms of the disease (in particular any state that can not be clearly identified) in a patient with a previously adequately controlled type 2 diabetes mellitus, the first treatment should be immediately ketoacidosis or lactic acidosis. Assessment of the patient's condition should include blood tests for electrolytes and ketones, blood glucose concentration, and (but indications) blood pH, plasma concentrations of lactate, pyruvate and metformin. With the development of acidosis of any etiology, you should immediately stop taking the drug Yanumet and take appropriate measures to correct acidosis.
    Loss of glycemic control
    In situations of physiological stress (hyperthermia, trauma, infection or surgery) in a patient with a previously stable glycemic control, a temporary loss of glycemic control is possible.In such periods, temporary replacement of Yanumet with insulinotherapy is permissible, and after resolving an acute situation the patient can resume the previous treatment.
    Effect on the ability to drive transp. cf. and fur:There have been no studies to study the effect of the drug Yanumet on the ability to drive vehicles and work with mechanisms. However, the cases of dizziness and drowsiness noted when taking sitagliptin should be considered.
    In addition, patients should be aware of the risk of hypoglycemia with concomitant use of the drug Yanumet with sulfonylureas or insulin.
    Form release / dosage:Film coated tablets 500 mg + 50 mg, 850 mg + 50 mg, 1000 mg + 50 mg.
    Packaging:For 14 tablets in a blister of PVC / PE / PVDC / foil aluminum. For 1, 2, 4, 6 or 7 blisters together with instructions for use in a pack of cardboard.
    Storage conditions:Store at a temperature not exceeding 25 ° C.
    Keep out of the reach of children.
    Shelf life:Dosage 500 mg + 50 mg
    3 years.
    Dosages of 850 mg + 50 mg, 1000 mg + 50 mg
    2 years.
    Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-000046
    Date of registration:22.11.2010 / 23.11.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands
    Manufacturer: & nbsp
    Information update date: & nbsp2016-09-25
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