Vilmitriks^® MET (Tablets) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

Manufactured By

R-Pharm Novoselki LLC (Russia)

ATC Code

A10BD08 (Metformin and Vildagliptin)

Active Substances

Metformin (Rec.INN registered by WHO)

Vildagliptin (Rec.INN registered by WHO)

Dosage Forms

	Vilmitriks® MET	Film-coated tablets 50 mg+500 mg
		Film-coated tablets 50 mg+850 mg
		Film-coated tablets 50 mg+1000 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

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

Pharmacological Action

Combined hypoglycemic agent for oral administration.

Vildagliptin, a representative of the class of pancreatic islet stimulators, selectively inhibits the enzyme DPP-4, improving glycemic control. Inhibition of DPP-4 activity leads to an increase in both basal and postprandial endogenous levels of incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

Use of vildagliptin in patients with type 2 diabetes leads to rapid and complete inhibition of DPP-4 activity, which is observed for 24 hours.

By increasing the concentration of GLP-1 and GIP, Vildagliptin causes an increase in the sensitivity of pancreatic β-cells to glucose, leading to improved glucose-dependent insulin secretion. Use of vildagliptin at doses of 50 mg and 100 mg per day in patients with type 2 diabetes caused a significant improvement in β-cell function parameters.

The degree of improvement in β-cell function depends on the degree of their initial damage; thus, in individuals without diabetes (with normal blood plasma glucose concentration), Vildagliptin does not stimulate insulin secretion and does not reduce glucose concentration. By increasing the concentration of endogenous GLP-1, Vildagliptin increases the sensitivity of α-cells to glucose, leading to improved glucose-dependent regulation of glucagon secretion. The reduction in elevated postprandial glucagon concentration, in turn, leads to a decrease in insulin resistance.

The increase in the insulin/glucagon ratio against the background of hyperglycemia, due to increased concentrations of incretin hormones, causes a decrease in hepatic glucose production both during and after meals, leading to a decrease in blood plasma glucose concentration.

Furthermore, a decrease in postprandial blood lipid concentrations was observed during vildagliptin use, which is not related to the improvement in pancreatic islet cell function mediated by vildagliptin’s effect on incretin hormone activity.

It is known that an increase in GLP-1 concentration can lead to delayed gastric emptying; however, such an effect is not observed during vildagliptin use.

Metformin reduces hepatic glucose production, decreases glucose absorption in the intestine, and reduces insulin resistance by enhancing glucose uptake and utilization by peripheral tissues. Metformin induces intracellular glycogen synthesis by acting on glycogen synthase and enhances glucose transport by some membrane glucose transporter proteins (GLUT-1 and GLUT-4). It improves glucose tolerance in patients with type 2 diabetes by reducing blood plasma glucose concentration both before and after meals. Unlike sulfonylurea derivatives, Metformin does not cause hypoglycemia in patients with type 2 diabetes or in healthy individuals (except in special cases). Metformin does not lead to the development of hyperinsulinemia. When metformin is used, insulin secretion does not change, while fasting and daily plasma insulin concentrations may decrease.

The combination of these components allows for more effective control of blood glucose concentration in patients with type 2 diabetes over 24 hours.

Pharmacokinetics

Food intake does not affect the extent and rate of absorption of vildagliptin as part of this fixed-dose combination. The C_max and AUC values of metformin as part of the fixed combination decreased by 26% and 7%, respectively, when taken simultaneously with food. Furthermore, food intake slowed the absorption of metformin, leading to an increase in the time to reach C_max (T_max, from 2 to 4 hours). Similar changes in C_max and AUC with food intake were also noted when metformin was used separately, although in the latter case the changes were less significant. The effect of food on the pharmacokinetics of vildagliptin and metformin as part of this combination did not differ from that when both drugs were taken separately.

When taken orally on an empty stomach, Vildagliptin is rapidly absorbed, and its C_max is reached 1.75 hours after administration. When taken simultaneously with food, the absorption rate of vildagliptin decreases slightly: a 19% decrease in C_max and an increase in the time to reach it to 2.5 hours are observed. However, food intake does not affect the extent of absorption and AUC. Vildagliptin is rapidly absorbed, and its absolute bioavailability after oral administration is 85%. C_max and AUC in the therapeutic dose range increase approximately proportionally to the dose. The degree of binding of vildagliptin to plasma proteins is low (9.3%). The drug is evenly distributed between plasma and erythrocytes. The distribution of vildagliptin is presumably extravascular; after IV administration, V_ss is 71 L. In the human body, 69% of the vildagliptin dose is metabolized. The main metabolite, LAY151 (57% of the dose), is pharmacologically inactive and is a product of hydrolysis of the cyano component. About 4% of the dose undergoes amide hydrolysis. In in vivo studies in animals with DPP-4 deficiency, a partial positive influence of this enzyme on the hydrolysis of vildagliptin was noted. After oral administration of radiolabeled vildagliptin, about 85% of the dose is excreted by the kidneys and 15% through the intestine; renal excretion of unchanged vildagliptin is 23%. With IV administration in healthy volunteers, the mean T_1/2 reaches 2 hours, the total plasma clearance and renal clearance of vildagliptin are 41 L/h and 13 L/h, respectively. T_1/2 after oral administration is about 3 hours, regardless of the dose.

Vildagliptin is rapidly absorbed; absolute bioavailability after oral administration is 85%. C_max and AUC of vildagliptin increase approximately proportionally to the dose when used in the therapeutic dose range.

In patients with mild, moderate, or severe renal impairment, the AUC of vildagliptin increased compared to healthy volunteers by 1.4, 1.7, and 2 times, respectively. The AUC of the metabolite LAY151 increased by 1.6, 3.2, and 7.3 times, and the metabolite BQS867 by 1.4, 2.7, and 7.3 times in patients with mild, moderate, and severe renal impairment, respectively. Limited data in patients with end-stage chronic kidney disease (CKD) indicate that the parameters in this group are similar to those in patients with severe renal impairment. The concentration of the LAY151 metabolite in patients with end-stage CKD increased 2-3 times compared to the concentration in patients with severe renal impairment. The removal of vildagliptin by hemodialysis is limited (3% during a procedure lasting more than 3-4 hours, 4 hours after a single dose).

The absolute bioavailability of metformin after oral administration of a 500 mg dose on an empty stomach was 50-60%. C_max is reached 2.5 hours after administration. When the single dose of the drug was increased from 500 mg to 1500 mg, and from 850 mg to 2250 mg orally, an absence of dose dependence of pharmacokinetic parameters was noted. This effect is due not so much to a change in the elimination of metformin as to a slowdown in its absorption. With food intake, the extent and rate of metformin absorption also decreased somewhat. Thus, with a single dose of the drug at 850 mg with food, a decrease in C_max by approximately 40%, AUC by 25%, and an increase in T_max by 35 minutes were observed. The clinical significance of these facts has not been established.

After a single oral dose of 850 mg, the apparent V_d of metformin is 654±358 L. Metformin is practically not bound to plasma proteins, while sulfonylurea derivatives are more than 90% bound to them. Metformin penetrates into erythrocytes (this process is likely enhanced over time). When metformin is used according to the standard regimen (standard dose and frequency of administration), C_ss in blood plasma is reached within 24-48 hours and, as a rule, does not exceed 1 µg/ml. In controlled clinical studies, the C_max of metformin in blood plasma did not exceed 5 µg/ml (even at maximum doses).

After a single IV administration of metformin to healthy volunteers, it is excreted by the kidneys unchanged. The drug is not metabolized in the liver (no metabolites have been identified in humans) and is not excreted in bile.

Since the renal clearance of metformin is approximately 3.5 times greater than the GFR, the main route of elimination of the drug is tubular secretion. After oral administration, about 90% of the absorbed dose is excreted by the kidneys within the first 24 hours; the T_1/2 from blood is about 6.2 hours. The T_1/2 of metformin from whole blood is about 17.6 hours, indicating the accumulation of a significant portion of the drug in erythrocytes.

In patients with impaired renal function (assessed by GFR), the T_1/2 of metformin from plasma and whole blood increases, and its renal clearance decreases in proportion to the decrease in GFR.

According to limited data from pharmacokinetic studies in healthy volunteers aged ≥65 years, a decrease in the total plasma clearance of metformin and an increase in T_1/2 and C_max were observed compared to younger volunteers. These features of metformin pharmacokinetics in individuals over 65 years of age are likely primarily associated with changes in renal function; therefore, in patients over 80 years of age, the use of this combination is possible only with normal GFR.

Indications

Type 2 diabetes mellitus (in combination with diet therapy and physical exercise): for insufficient effectiveness of monotherapy with vildagliptin or metformin; in patients previously receiving combination therapy with vildagliptin and metformin as separate drugs; in combination with sulfonylurea derivatives (triple combination therapy) in patients previously treated with sulfonylurea derivatives and metformin without achieving adequate glycemic control; in triple combination therapy with insulin in patients previously receiving insulin therapy at a stable dose and Metformin without achieving adequate glycemic control; as initial therapy in patients with type 2 diabetes mellitus with insufficient effectiveness of diet therapy, physical exercise, and the need to improve glycemic control.

ICD codes

Dosage Regimen

For oral administration. The dosage regimen is selected individually depending on the effectiveness and tolerability of therapy. When using this combination, the recommended maximum daily dose of vildagliptin of 100 mg should not be exceeded.

The recommended initial dose should be selected taking into account the duration of diabetes and the level of glycemia, the patient’s condition, and the treatment regimens with vildagliptin and/or metformin previously used in the patient.

Before starting therapy with metformin-containing drugs, GFR should be determined; this parameter should then be monitored at least annually. In patients at risk of worsening pre-existing renal impairment, as well as in elderly patients, renal function should be monitored more frequently, for example, every 3-6 months.

The maximum daily dose of metformin should be divided into 2 or 3 doses. In patients with GFR <60 ml/min, factors contributing to an increased risk of lactic acidosis should be assessed before starting therapy with metformin-containing drugs. In patients with GFR <30 ml/min, the use of this combination is contraindicated due to the presence of metformin in the drug.

The dose is calculated depending on GFR.

Since impaired renal function is often observed in patients over 65 years of age, the dose of the combination components in these patients should be adjusted based on renal function parameters. When used in patients over 65 years of age, renal function must be regularly monitored.

Adverse Reactions

Nervous system disorders: common – headache, dizziness, tremor. When vildagliptin was used in combination with metformin at various doses, hypoglycemia was observed in 0.9% of cases (compared to 0.4% in the placebo group in combination with metformin).

Gastrointestinal disorders common – nausea, gastroesophageal reflux, dysgeusia; uncommon – diarrhea, flatulence; very rare – hepatitis.

Metabolism and nutrition disorders very common – decreased appetite; common – hypoglycemia; very rare – lactic acidosis.

Infections and infestations very rare – upper respiratory tract infections, nasopharyngitis.

General disorders and administration site conditions common – chills.

Skin and subcutaneous tissue disorders common – hyperhidrosis; very rare – skin reactions (in particular, erythema, pruritus, urticaria).

Musculoskeletal and connective tissue disorders common – arthralgia.

Vascular disorders uncommon – peripheral edema.

Contraindications

Type 1 diabetes mellitus; renal failure or severe renal impairment with GFR <30 ml/min; acute conditions with a risk of renal impairment: dehydration (with diarrhea, vomiting), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, kidney infections, bronchopulmonary diseases); acute and chronic heart failure, acute myocardial infarction, acute cardiovascular failure (shock), respiratory failure; liver dysfunction; acute or chronic metabolic acidosis (including diabetic ketoacidosis with or without coma); lactic acidosis (including history); should not be used 48 hours before surgical operations, radioisotope, radiological studies with the administration of contrast agents and for 48 hours after their performance; chronic alcoholism, acute alcohol poisoning; adherence to a low-calorie diet (less than 1000 kcal/day); pregnancy, lactation (breastfeeding); children under 18 years of age; hypersensitivity to vildagliptin or metformin.

With caution

Drugs containing Metformin are recommended to be used with caution in patients over 60 years of age when performing heavy physical work, due to an increased risk of developing lactic acidosis in them.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Should not be used in patients with liver diseases or abnormalities in biochemical parameters of liver function.

Use in Renal Impairment

Contraindicated in renal failure or severe renal impairment with glomerular filtration rate (GFR) <30 ml/min.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety of use have not been established).

Geriatric Use

Drugs containing Metformin are recommended to be used with caution in patients over 60 years of age when performing heavy physical work, due to an increased risk of developing lactic acidosis in them.

Special Precautions

In patients receiving insulin treatment, this combination cannot replace insulin therapy.

It is recommended to regularly determine biochemical parameters of liver function during treatment with the drug. If an increase in aminotransferase activity is detected, a repeat test should be performed to confirm the result, and then biochemical parameters of liver function should be regularly determined until they normalize. If an increase in AST or ALT activity 3 or more times above the ULN is confirmed by a repeat test, treatment is recommended to be discontinued.

Lactic acidosis is a very rare but serious metabolic complication, most often occurring with a sharp deterioration in renal function, as well as with cardiorespiratory syndromes, sepsis. With a sharp deterioration in renal function, metformin accumulates in the body, which contributes to an increased risk of lactic acidosis.

In case of dehydration (for example, associated with severe diarrhea or vomiting, fever, or reduced fluid intake), a patient taking metformin-containing drugs should immediately stop taking the aforementioned drugs and seek medical help.

In patients taking drugs containing Metformin, therapy with drugs that can sharply worsen renal function (for example, antihypertensive drugs, diuretics, NSAIDs) should be started with caution. Other risk factors include: alcohol abuse, liver dysfunction, inadequately controlled diabetes, ketoacidosis, prolonged fasting, conditions associated with hypoxia, as well as simultaneous use of drugs that can cause lactic acidosis. If lactic acidosis is suspected, therapy with metformin-containing drugs should be discontinued, and the patient should be hospitalized immediately.

It has been established that Metformin causes an asymptomatic decrease in serum vitamin B₁₂ concentration in approximately 7% of cases. Such a decrease very rarely leads to the development of anemia. After discontinuation of metformin and/or replacement therapy with vitamin B₁₂, the serum vitamin B₁₂ concentration quickly normalizes. In patients receiving metformin-containing drugs, complete blood count parameters should be monitored at least once a year. If deviations of hematological parameters from the norm are detected, the etiology of such disorders should be clarified and appropriate treatment should be administered.

Some patients (for example, patients with insufficient intake or impaired absorption of vitamin B₁₂ or calcium) have a predisposition to decreased serum vitamin B₁₂ concentration. In such patients, determining the serum vitamin B₁₂ concentration at least once every 2-3 years may have diagnostic value.

Cardiovascular collapse (shock), acute heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia are associated with lactic acidosis and may also contribute to prerenal azotemia. If the above conditions occur, the use of metformin-containing drugs should be discontinued immediately.

During surgical interventions with general, spinal, or epidural anesthesia (except for minor operations not associated with restriction of food and fluid intake), the use of metformin-containing drugs should be discontinued. Resumption of administration is possible no earlier than 48 hours after the intervention or after the restoration of oral food intake, following laboratory confirmation of stabilized renal function.

As a rule, hypoglycemia is not observed in patients receiving therapy with this combination alone; however, it may occur against the background of a low-calorie diet (when intense physical exertion is not compensated by caloric intake) or against the background of alcohol consumption. The development of hypoglycemia is most likely in elderly, debilitated, or emaciated patients, as well as against the background of hypopituitarism, adrenal insufficiency, or alcohol intoxication. In elderly patients and in persons receiving beta-blockers, the diagnosis of hypoglycemia may be difficult.

During stress (fever, trauma, infection, surgery, etc.) developing in patients receiving hypoglycemic agents according to a standard regimen, a sharp decrease in their effectiveness for some time is possible. In this case, temporary discontinuation of this combination drug and insulin therapy may be necessary. Resumption of treatment is possible after the acute period has ended.

Effect on the Ability to Drive Vehicles and Operate Machinery

If dizziness develops while using drugs containing this combination, one should refrain from driving vehicles and operating machinery.

Drug Interactions

Furosemide increases the C_max and AUC of metformin but does not affect its renal clearance. Metformin decreases the C_max and AUC of furosemide and also does not affect its renal clearance.

Nifedipine increases the absorption, C_max, and AUC of metformin; in addition, it increases its renal excretion. Metformin has virtually no effect on the pharmacokinetic parameters of nifedipine.

Glibenclamide does not affect the pharmacokinetic/pharmacodynamic parameters of metformin. Metformin, in general, reduces the C_max and AUC of glibenclamide, but the magnitude of the effect varies greatly. For this reason, the clinical significance of such an interaction remains unclear.

Iodinated X-ray Contrast Agents administration of metformin-containing drugs should be temporarily discontinued before the procedure or for the duration of the procedure; administration should be resumed no earlier than 48 hours after the procedure, after receiving laboratory confirmation of stabilized renal function.

Organic Cations, for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin, and others, excreted by the kidneys through tubular secretion, can theoretically interact with metformin due to competition for common renal tubular transport systems. Thus, cimetidine increases both the plasma concentration of metformin and its AUC by 60% and 40%, respectively.

Other Drugs. Some drugs may adversely affect renal function, thereby increasing the risk of lactic acidosis, for example, NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, ACE inhibitors, diuretics, especially “loop” diuretics. In patients receiving therapy with metformin-containing drugs at the start, as well as during simultaneous use of the above agents, renal function should be carefully monitored.

Some drugs can cause hyperglycemia and contribute to a decrease in the effectiveness of hypoglycemic agents. Such drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormone preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are used concomitantly or, conversely, upon their discontinuation, it is recommended to carefully assess the effectiveness of glycemic control and adjust the dose of metformin.

Concomitant use of danazol is not recommended to avoid its hyperglycemic effect. If treatment with danazol is necessary and after its discontinuation, dose adjustment of metformin under blood glucose control is required.

Chlorpromazine when used in high doses (100 mg/day) increases glycemia by reducing insulin release. When treating with antipsychotics and after their discontinuation, dose adjustment of the combination components under blood glucose control is required.

Injectable beta₂-sympathomimetics increase glycemia due to stimulation of β₂-adrenergic receptors. In this case, glycemic control is necessary. If necessary, insulin administration is recommended.

When metformin is used concomitantly with sulfonylurea derivatives, insulin, acarbose, salicylates, an enhancement of the hypoglycemic effect is possible.

Since the use of metformin in patients with acute alcohol intoxication increases the risk of lactic acidosis (especially during fasting, exhaustion, or hepatic insufficiency).

Storage Conditions

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

Dispensing Status

Rx Only

Important Safety Information

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