Velmetia - instructions for use, dose, side effects, contraindications

Active substanceMetformin + SitagliptinMetformin + Sitagliptin

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Velmetia®

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Berlin-Chemie, AG Germany

Yanumet

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Merck Sharp and Doum B.V. Netherlands

Yanumet® Long

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Merck Sharp and Doum B.V. Netherlands

Dosage form: & nbspfilm coated tablets

Composition:

One film-coated tablet contains:

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: cellulose microcrystalline 96.64 mg, povidone K-29/32 78.19 mg, sodium stearyl fumarate 22.34 mg, sodium lauryl sulfate 5.585 mg; tablet shell Opadrai® II pink, 85F94182 (27.93 mg) contains: polyvinyl alcohol 49.950%, titanium dioxide (E 171) 6,000%, macrogol 3350 (polyethylene glycol) 25.210%, talc 18.470%, ferric 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: cellulose microcrystalline 112.3 mg, povidone K-29/32 91.00 mg, sodium stearyl fumarate 26.00 mg, sodium lauryl sulfate 6,500 mg. Casing of the tablet Opadry® II red, 85F15464 (32.50 mg) contains: polyvinyl alcohol 48.300%, titanium dioxide (E 171) 6,000%, macrogol 3350 (polyethylene glycol) 24.380%, talc 17.870%, ferric oxide black (E 172) 0.150% iron oxide red (E 172) 3,300%.

Description:

Tablets 850 mg + 50 mg:

Oval biconvex tablets covered with a film shell, pink with engraving "515" on one side of the tablet.

Tablets 1000 mg + 50 mg:

Oval, biconvex tablets covered with a film coat, reddish-brown in color with an engraving "577" on one side of the tablet.

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 Velmetia® is a combination of two hypoglycemic drugs with a complementary mechanism of action designed to improve glycemic control in patients with type 2 diabetes mellitus: 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. 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 highly selective and efficient inhibitor of the enzyme DPP-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 the analogs of GLP-1, insulin,derivatives of sulfonylurea or meglitinides, biguanides, gamma receptor agonists, peroxisome proliferator activated (PPARy), alpha-glycosidase inhibitors and amylin analogs.

Metformin

Metformin is a hypoglycemic drug that increases glucose tolerance in patients with type 2 diabetes mellitus, 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 patients with type 2 diabetes, nor in healthy people (with the exception of certain circumstances, see the section "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 in patients with type 2 diabetes 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, increased plasma concentrations of insulin and C-peptide, 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 mellitus, as evidenced by the corresponding changes in such markers as HOMA-β (estimation of homeostasis in the β model) the ratio of proinsulin / insulin, the evaluation of the response of beta cells of the pancreas according to the panel of repeated tests for food tolerance. According to the clinical studies of II and III phases, the effectiveness of glycemic control of sitagliptin in the 50 mg x 2-times-a-day regime was comparable with the efficacy of the 100 mg regimen once a day.

In a study in healthy volunteers, the effects of sitagliptin in combination with metformin, or only sitagliptin, or only metformin, or placebo on change in plasma concentrations of active and total GLP-1 and glucose after food intake. The weighted average concentrations of active GLP-1 after 4 h after food intake increased approximately 2 times after taking only sitagliptin or only metformin versus placebo. Combined reception of sitagliptin and metformin provided summation of the effect with a 4-fold increase in the concentration active GLP-1 compared with the dynamics in the placebo group. Admission only Sitagliptin was accompanied by an increase in the concentration of only active GLP-1 due to inhibition of the enzyme DPP-4, 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 the various mechanisms underlying the increase concentration of active GLP-1 after taking these two drugs. results The studies also demonstrated that sitagliptin, and 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 study involving patients with hypertension, the combined use of antihypertensive drugs (one or more of the list: inhibitors angiotensin converting enzyme (ACE), angiotensin II receptor antagonists, slow calcium channel blockers, beta-blockers, diuretics) with sitagliptin were 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 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 taking the recommended therapeutic dose of any drug effect on the duration of the interval QT as at the moment 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 interval QT in comparison with the initial value 3 hours after the administration of 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 bioequivalence study in healthy volunteers demonstrated that combination tablets metformin + sitagliptin 500 mg + 50 mg and 1000 mg + 50 mg bioequivalent to the separate intake of appropriate doses of sitagliptin and metformin.

In view of 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, provided that the combination of fixed doses of the drug is combined in the tablet.

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 reception of the drug with food reduces the speed and amount of absorbed metformin, which is confirmed by a decrease in the value of the maximum plasma concentration FROM_m_Oh by about 40%, a decrease in the area under the "concentration-time" curve AUC by about 25%, and also by a 35-minute delay in reaching the maximum plasma concentration T_m_Oh after a single dose of metformin at a dose of 850 mg at the same time with food as compared to the values of the corresponding parameters after taking a similar dose drug on an empty stomach. Clinical significance of decreasing the values of pharmacokinetic parameters is not set.

Distribution

Sitagliptin

The average volume of distribution in the equilibrium state after a single IV injection 100 mg of sitagliptin in healthy volunteers is about 198 l. 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 using metformin 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 inside about 16% of the administered radioactivity excreted as metabolites of sitagliptin.Traces of 6 metabolites of sitagliptin were detected. Not making any contribution to the plasma DPP-4 inhibitory activity of sitagliptin. In studies in vitro isoenzymes of the cytochrome system CYP3A4 and CYP2C8 are identified as the main enzymes 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 of the introduced radioactivity was removed from the body during weeks, 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 a substrate of the transporter of organic human anions of the third type (hOAT-3), involved in the process of elimination of sitagliptin by the kidneys. Clinical significance of participation hOAT-3 in the transport of sitagliptin is not established. Possible participation of P-glycoprotein in the renal elimination of sitagliptin (as a substrate), but the P-glycoprotein inhibitor 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 mellitus is similar to pharmacokinetics in 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 therapeutic doses.

Patients with renal insufficiency

The drug Velmetia® should not be given to patients with renal insufficiency (see the section "Contraindications"),

Sitagliptin

In patients with moderate renal insufficiency, a 2-fold increase in plasma AUC sitagliptin, and in patients with severe and terminal stage (on hemodialysis) increase in the value AUC was 4-fold compared with the 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), mean values AUC and C_m_Oh sitagliptin after a single admission of 100 mg increase by approximately 21% and 13%, respectively, compared with 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 mellitus on the basis of sex. 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 pharmacokinetic parameters of sitagliptin. The concentration of sitagliptin y 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 allow us to conclude that the total plasma clearance of the drug in them decreases, the half-life is prolonged, and the value of C_m_Oh increases 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 Velmetia® is not indicated for elderly patients ≥80 years of age, except for those in whom creatinine clearance indicates that renal function has not been reduced (see section "Special instructions., Metformin").

Children

Studies of metformin + sitagliptin in children have not been 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 mellitus, the hypoglycemic effect of the drug was comparable in representatives of 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

Velmetia® is indicated as a starting therapy for patients with type 2 diabetes to improve control of glycemia, if compliance with the diet and exercise regimen does not allow adequate control.

Velmetia® is indicated as an adjunct to the diet and exercise regimen to improve control of glycemia in patients with type 2 diabetes mellitus who have not achieved adequate control with monotherapy with metformin or sitagliptin, or after unsuccessful combination treatment with two drugs.

Combination Therapy

The Velmetia® preparation is indicated in 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 Velmetia® preparation is indicated in patients with type 2 diabetes to improve glycemic control in combination with thiazolidinediones (agonists PPARyreceptors activated by the peroxisome proliferator), when diet and exercise regimen combined with two of the three of these drugs: metformin, sitagliptin or thiazolidinedione do not lead to adequate glycemic control.

The Velmetia® preparation is indicated for patients with type 2 diabetes to improve glycemic control in combination with insulin, when diet and exercise regimen in combination with insulin do not lead to adequate glycemic control.

Contraindications:

- Known hypersensitivity to sitagliptin, metformin or any of the components of the Velmety® preparation.

- Type 1 diabetes mellitus.

- Kidney disease or decreased kidney function (with serum creatinine ≥1.5 mg / dl and ≥1.4 mg / dl in men and women, respectively, or a decrease in creatinine clearance (<60 mL / min), including due to 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,

- states of 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, which 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").

- Hepatic failure, a violation of the liver.

- 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 carrying out radioisotope or X-ray studies with the introduction of iodine-containing contrast medium (see section "Interaction with other drugs").

- Compliance with a hypocaloric diet (less than 1000 kcal / day).

- Children under 18 years.

Carefully:

Application the elderly

Velmetia®

Since the main way to excrete sitagliptin and metformin are the kidneys and as the kidney excretory function decreases with age, the precautions for prescribing the Velmety® drug increase in proportion to the age. Elderly patients receive a careful dose selection and regular monitoring of kidney function (see section "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 controlledmetformin studies were insufficient to make a formal conclusion about the age-related differences in the efficacy and safety of the drug, although no such differences were observed 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 prescribed only to patients with confirmed normal renal function (see "Contraindications").

Pregnancy and lactation:

Velmetia®

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

There was no experimental study of the combined preparation Velmetia ® 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 when administered orally to rats at daily doses up to 250 mg / kg orrabbits in doses up to 125 mg / kg (which exceeds the plasma exposure of the drug in humans 32 and 22 times, respectively, after taking the recommended daily therapeutic dose of 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). There was a slight decrease in body weight in both sexes of 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 exceeds 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 penetration of components of the combined preparation Velmetia ® in breast milk were not performed. According to studies on individual drugs as sitagliptin, and metformin penetrate the breast milk of rats. There is no data on the penetration of sitagliptin into human milk. Therefore, Velmetia® should not be given during breastfeeding.

Dosing and Administration:

general information

Dosage regimen of Velmetia® should be selected individually, based on current therapy, efficacy and tolerability, but not exceeding the maximum recommended daily dose of 100 mg of sitagliptin.

VELMETHYA® is usually given twice daily with meals, with a gradual increase in dose to minimize possible gastrointestinal side effects (gastrointestinal) associated with metformin.

Dosing recommendations

The initial dose of Velmetia ® depends on the current hypoglycemic therapy.The drug Velmetia® is taken 2 times a day with meals.

The following dosages are suggested:

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 recommended starting dose 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 Velmetia® for patients who do not achieve adequate control with metformin monotherapy 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 did not achieve adequate control on monotherapy with sitagliptin

The recommended starting dose for patients who do not achieve adequate control with sitagliptin monotherapy is 500 mg metformin + 50 mg sitagliptin * 2 times a day.In the future, the dose can be increased to 1000 mg of metformin + 50 mg of sitagliptin 2 times a day. Patients taking a corrected dose of sitagliptin because of renal failure, treatment with Velmetia® is contraindicated (see section "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 Velmetia ® may be equivalent to the doses taken for the isolation of sitagliptin and metformin.

For patients taking two of the three listed hypoglycemic preparations - sitagliptin, metformin or sulfonylureas

The starting dose of Velmetia® 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 the sulfonylurea derivative will be rational to reduce the current dose to reduce the risk of sulfonyl-induced hypoglycemia (see section "Specific guidance").

For patients taking two of the listed three hypoglycemic drugs - sitagliptin, metformin or agonists PPARy-peChains (thiazolidinediones)

The starting dose of Velmetia® should correspond to a 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, it is recommended gradual titration of the drug to avoid gastrointestinal side effects. effects.

For patients, taking two of the three hypoglycemic drugs listed - sitagliptin, metformin or insulin

The starting dose of Velmetia® should correspond to the daily dose sitagliptin 100 mg, i.e. 50 mg of sitagliptin 2 times a day and the previously taken dose of metformin. When The need to increase the dose of metformin is recommended gradual titration of the drug to avoid gastrointestinal side effects. effects.Patients may need to reduce the dose of insulin to prevent the risk of hypoglycemia (see section "Special instructions").

Special studies to assess the safety and efficacy of the transition from treatment with other hypoglycemic drugs for treatment with a combination drug Velmetia was not performed. 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 Velmetia® in children and adolescents under the age of 18 has not been studied.

* - when initiating start therapy, it should be noted that the preparation Velmetia® in a dose of 500 mg metformin + 50 mg sitagliptin in the Russian Federation is not registered.

Side effects:

In studies, 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 sitagliptin and metformin

Start therapy

In a 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 monotherapy with metformin (500 mg or 1000 mg x 2 times a day), sitagliptin (100 mg once daily) or placebo, the following adverse drug reactions were observed, observed at a frequency of ≥ 1% in the combination treatment group and more often than in the placebo group: diarrheasitagliptin + 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 the study, with the addition of 100 mg / day of sitagliptin to current metformin treatment, the only adverse drug-related response observed at a rate of ≥ 1% in the treatment group with sitagliptin and more often than in the placebo group was nauseasitagliptin + metformin - 1.1%, placebo + metformin - 0,4%).

Hypoglycemia and unwanted reactions from the digestive tract

In studies of combined treatmentsitagliptin and metformin, the incidence of hypoglycemia (regardless of cause and effect) in the combination therapy groups was comparable to that 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 (regardless of 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 100 mg / day sitagliptin study, 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 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: hypoglycemia (sitagliptin - 13.8%, placebo - 0.9%), constipation (1.7% and 0,0%).

Combined treatment with sitagliptin, metformin and agonist FPARy

According to a 100 mg / day study of sitagliptin, 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 were more frequent 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 week 54 of the combined treatment, the following adverse drug reactions were observed, observed at 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 infection (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 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 the drug and was observed with a frequency of ≥1% in the treatment group with sitagliptin and more often than in the placebo group, there was hypoglycemia (sitagliptin-10.9%, placebo-5.2%). In another study in which patients received sitagliptin as an additional therapy for insulin therapy (e or without metformin), the only undesirable response 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 the use of sitagliptin (100 mg / day) or the appropriate control drug (active or placebo), the incidence of unconfirmed acute pancreatitis was 0.1 cases per 100 patient-years of treatment in each group. See also a study of cardiovascular safety assessment of sitagliptin (TECOS) below (see section "Special instructions. Pancreatitis"). Clinically significant deviations in vital signs or ECG (including the duration of the interval QTc) on the background of combined therapy with sitagliptin and metformin were not observed.

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 of> 5% of patients and more often than in the placebo group, are diarrhea, nausea / vomiting, flatulence, asthenia, dyspepsia, abdominal discomfort and headache.

A study evaluating the cardiovascular safety of sitagliptin (TECOS)

In a study evaluating the cardiovascular safety of sitagliptin (TECOS) included 7332 patients who took the drug sitagliptin, and 7339 patients taking placebo in the general population of patients who received treatment. The test drug (sitagliptin or placebo) was added to standard therapy according to existing national standards for target level selection HbA₁_C and control of cardiovascular risk factors. The study included a total of 2004 patients aged 75 years and older. The overall incidence of serious adverse events in patients taking the drug sitagliptin. was the same as in patients taking placebo. Evaluation of previously identified complications associated with diabetes mellitus revealed a comparable incidence of adverse events between groups, including infections (18.4% in patients taking the drug sitagliptin, and 17.7% in patients taking placebo) and renal dysfunction (1.4% in patients taking the drug sitagliptin, and 1.5% in patients taking placebo). The profile of adverse events in patients aged 75 years and older was generally similar to that of the general population.

In the population of patients who were prescribed treatment ("intention-to-treat"), Among those who initially received insulin therapy and / or sulfonylureas, the incidence of episodes of severe hypoglycemia was 2.7% in patients taking the drug sitagliptin, and 2.5% in patients taking placebo. Among patients who did not initially receive insulin and / or sulfonylureas, the incidence of episodes of severe hypoglycemia was 1.0% in patients taking the drug sitagliptin. and 0.7% in patients taking placebo.The incidence of confirmed cases of pancreatitis was 0.3% in patients taking the drug sitagliptin, and 0.2% in patients taking placebo. The incidence of confirmed cases of malignant neoplasms was 3.7% in patients taking the drug sitagliptin, and 4.0% in patients taking placebo.

Post-market observations

In the course of post-registration monitoring of the application of the combination metformin + sitagliptin or sitagliptin, included in its composition, in monotherapy and / or in combination 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; backache; itching; pemphigoid.

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 studies of metformin, a decrease in the normal concentration of cyanocobalamin (vitamin B₁₂) to subnormal serum levels in approximately 7% of patients without clinical manifestations. Such a decrease, caused by 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 (see section "Special instructions., Metformin").

Overdose:

Sitagliptin

During clinical trials in healthy volunteers, a single dose Sitagliptin in a dose of up to 800 mg was generally well tolerated. Minimal changes interval QT, not considered clinically significant, were noted in one of the studies of sitagliptin in a daily dose of 800 mg (see the section "Pharmacodynamics: Effects 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 weakly dialyziruetsya: according to clinical studies during the 3 to 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 administration in amounts exceeding 50 g (50,000 mg). Hypoglycemia was observed in about 10% of all cases of overdose, but a clear connection with an overdose of metformin was not established. The development of lactic acidosis was accompanied by approximately 32% of all cases of metformin overdose (see section "Special instructions., 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 daily) and metformin (1000 mg twice daily) was not accompanied by significant changes in pharmacokinetic parameters of sitagliptin or metformin in patients with type 2 diabetes mellitus.

Studies of the inter-drug effect on the pharmacokinetic parameters of the Velmetia® preparation have not been carried out, however, a sufficient number of similar studies have been 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 isoenzymes CYP cytochrome systems CYP3A4, 2C8 or 2C9. Data in vitro evidence that sitagliptin also does not suppress isoenzymes CYP2D6, 1A2, 2C19 and 2B6 and does not induce CYP3A4.

According to the population pharmacokinetic analysis of 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 by patients with type 2 diabetes, including hypocholesterolemic drugs (statins, fibrates, ezetimibe), antiplatelet agents (clopidogrel), antihypertensive drugs (ACE inhibitors, angiotensin receptor antagonists II, 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 was noted AUC (11%), as well as the average C_m_Oh (18%) digoxin 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 was noted AUC and C_m_Oh sitagliptin by 29% and 68%, respectively, with simultaneous single oral intake of sitagliptin 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 doses metformin and glyburide in patients with type 2 diabetes mellitus did not observe any changes in pharmacokinetic and pharmacodynamic parameters of metformin.

Changes in Values AUC and C_m_Oh 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 C_m_Oh metformin in plasma and whole blood by 22%, the value of AUC metformin in whole blood by 15%, without changing the kidney clearance of the drug. Values C_max and AUC furosemide, in turn, decreased by 31% and 12%, respectively, and the half-life decreased by 32% without significant changes in renal clearance of furosemide. Information on the inter-drug interaction between the two drugs with long-term combined use is not available.

Nifedipine: when investigating the inter-drug interaction of nifedipine and metformin after a single intake of drugs by healthy volunteers, an increase in plasma C_m_Oh and AUC metformin by 20% and 9%, respectively, as well as an increase in the number of renal metformin. T_m_Oh and the 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-dose and multiple-dose studies, with a 60% increase in the concentration of C_m_Ohmetformin in plasma and whole blood and a 40% increase in the value AUC metformin 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 dose adjustment of Velmetin® and / or the above cationic drugs excreted by the proximal tubule kidneys in cases of their simultaneous administration is recommended.

Others: some drugs have hyperglycemic potential and may 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 medications, the patient receiving the Velmetia® preparation 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:

Velmetia®

Pancreatitis

There have been reports of the development of acute pancreatitis, including hemorrhagic or necrotic with a lethal and non-lethal outcome, in patients taking sitagliptin (see section "Side effect"). 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 Velmetia ® 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 impaired renal function,therefore the preparation Velmetia® 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 a minimum dose of Velmetia ®. In elderly patients, especially those over the age of 80, conduct regular monitoring of kidney function.

Before starting treatment with metformin + sitagliptin, and at least once a year after the start of treatment with the help of proper tests confirm normal kidney function. With an increased likelihood of developing renal dysfunction, kidney function monitoring is performed more often, and when it is detected, Velmetia® is canceled.

Development of hypoglycemia with simultaneous use with derivatives sulfonylureas or insulin

As with other hypoglycemic agents, hypoglycemia was observed with the simultaneous use of sitagliptin and metformin in combination with insulin or sulfonylurea derivatives (see "Side effect" section). To reduce the risk of developing sulfonyl-induced or insulin-induced hypoglycemia, the dose of a sulfonylureas or insulin derivative should be reduced (see Fig.See section "Dosing and Administration").

Sitagliptin

Development of hypoglycemia with simultaneous use with derivatives sulfonylureas or insulin

In clinical studies of sitagliptin both in monotherapy and in combination with drugs that do not lead to the development of hypoglycemia (that is, metformin or agonists PPARy- 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 other hypoglycemic agents, hypoglycemia was observed with the simultaneous use of sitagliptin in combination with insulin or sulfonylurea derivatives (see "Side effect" section). To reduce the risk of developing sulfonyl-induced or insulin-induced hypoglycemia, the dose of the sulfonylurea or insulin derivative should be reduced (see the section "Dosing and Administration").

Hypersensitivity reactions

In the course of post-registration monitoring of the application of the combination metformin + sitagliptin or sitagliptin included in its composition, in monotherapy and / or in combination therapy with other hypoglycemic agents, hypersensitivity reactions have been identified.These reactions included anaphylaxis, angioedema, exfoliative skin diseases, including Stevens-Johnson syndrome. Since these data were obtained voluntarily from the population of an indefinite size, frequency and cause-and-effect relationship with therapy; these undesirable reactions can not be determined. 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 hypersensitivity reaction is suspected, it is necessary to stop taking Velmetia ®, assess other possible causes of undesirable development and prescribe other lipid-lowering therapy (see the sections "Contraindications" and "Side effects. Post-acquisition surveillance").

Metformin

Lactic acidosis

Lactic acidosis is a rare but serious metabolic complication that develops as a result of metformin accumulation during treatment with metformin + sitagliptin. Mortality in lactic acidosis reaches approximately 50%. The development of lactic acidosis can also occur against a background of some somatic diseases, in particular,diabetes mellitus or any other pathological condition, accompanied by pronounced hypoperfusion and hypoxemia of tissues and organs. Lactic acidosis is characterized by an elevated concentration of lactate in the blood plasma (> 5 mmol / l), a lower blood pH, electrolyte disturbances with an increase in the anion interval, an increase in the lactate / pyruvate 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 in the treatment with metformin developed very rarely (in about 0.03 cases per 1000 patient-years, with a death rate of about 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 have occurred mainly in patients with diabetes mellitus with severe renal failure, including severe renal pathology and kidney hypopersy, often in combination with concomitant multiple somatic / surgical diseases and polypharmacy.The risk of lactic acidosis in patients with chronic cardiac insufficiency requiring a significant drug correction is significantly increased, especially in unstable angina / chronic heart failure in the acute stage, accompanied by severe hypoperfusion and hypoxemia. 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, as well as the use the lowest effective dose of metformin helps to significantly reduce the risk of developing lactic acidosis. Careful monitoring of renal function is particularly necessary in the treatment of elderly patients, and patients older than 80 years of age with metformin are initiated only after confirming adequate renal function based on creatinine clearance estimates, as these patients are more at risk of developing lactic acidosis. In addition, in any condition accompanied by the development of hypoxemia, dehydration or sepsis, metformin must be immediately canceled. Given that if the liver function is impaired, lactate removal is significantly reduced,should not be appointed 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 stopped for the period of intravascular radiopaque 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 course of lactic acidosis, hypothermia, arterial hypotension and resistant bradyarrhythmia can join the above symptoms. 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. Determine the plasma concentrations of electrolytes, ketones, blood glucose, as well as (according to indications) the pH of the blood, the concentration of lactate.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 the concentration of lactate in the plasma of venous blood exceeds the upper limit of the norm, not exceeding 5 mmol / l, against the background of metformin therapy, it is not pathological for lactic acidosis and can be caused by 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 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

In normal conditions, monotherapy with metformin does not develop hypoglycemia, but its development is possible against 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.Simultaneous use of drugs that adversely affect the function of the kidneys, hemodynamics, or the distribution of metformin (such as cationic drugs that are excreted by the tubular secretion) should be administered with caution (see section "Interaction with other drugs., Metformin").

Radiological studies with intravascular injection of iodine-containing contrast agents (for example,, intravenous urogram, intravenous cholangiography, angiography, computed tomography with intravenous 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 impaired renal function (see section "Contraindications"). Therefore, which are scheduled for such a study, should temporarily stop taking preparation Velmetia® 48 hours before and within 48 hours after the test. Renewal treatment is permissible only after laboratory confirmation of normal function kidney.

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 a preferential azotemia. If the listed conditions develop in the patient on the background of treatment with metformin + sitagliptin, the drug should be stopped immediately.

Surgical interventions

The use of Velmetia® should be discontinued for the duration of any surgical intervention (with the exception of 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 dangers of alcohol abuse (single intake of a large number or constant intake of small doses) for the period of treatment with metformin + sitagliptin.

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 drug Velmetia® to patients with clinical or laboratory signs of liver disease.

Concentration of cyanocobalamin (vitamin B₁₂) in the blood plasma

In studies of metformin, 7% of patients observed a decrease in the initially normal concentration of cyanocobalamin (vitamin B₁₂) in the blood plasma without the development of clinical symptoms of deficiency. Such a decrease, perhaps, is 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 of metformin + sitagliptin It is recommended that hematological blood parameters, and any deviations that occur should be studied and corrected.

Patients who are predisposed to developing vitamin B deficiency₁₂ (due to reduced intake or absorption of vitamin B₁₂ or calcium) it is recommended to determine the plasma concentration of vitamin B₁₂ with 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, metformin + sitagliptin should first of all be treated immediately with 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 Velmetin® 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 Velmetia® with insulin therapy is permissible, and after resolution of acute situation the patient can resume previous treatment.

A study to assess the cardiovascular safety of sitagliptin (TECOS)

In a study evaluating the cardiovascular safety of sitagliptin (TECOS) patients took the drug sitagliptin or placebo, which were added to standard therapy according to existing national standards for the determination of target levels HbA_1C and control of cardiovascular risk factors. At the end of the average follow-up period of 3 years, in patients with type 2 diabetes mellitus sitagliptin in addition to standard treatment did not increase the risk of serious cardiovascular adverse events or the risk of hospitalization due to heart failure, compared with standard treatment without additional drug intake sitagliptin.

Effect on the ability to drive transp. cf. and fur:

There have been no studies to study the effect of Velmetia® 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 Velmetia® with sulfonylureas or insulin.

Form release / dosage:

Film coated tablets 850 mg + 50 mg, 1000 mg + 50 mg.

Packaging:

For 14 tablets in a blister of PVC / PE / PVDC film and aluminum foil. For 4 blisters are placed in a cardboard box together with instructions for use.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004547

Date of registration:20.11.2017

Expiration Date:20.11.2022

The owner of the registration certificate:Berlin-Chemie, AGBerlin-Chemie, AG Germany

Manufacturer: & nbsp

BERLIN-PHARMA, CJSC Russia

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp14.12.2017

Illustrated instructions

Instructions

Velmetia® (Velmetia®)