Instructions for use Glyptar-M film-coated tablets 50/850 mg blister No. 60
Composition
active ingredients: metformin, vildagliptin;
1 film-coated tablet 50 mg/850 mg contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride;
1 film-coated tablet 50 mg/1000 mg contains 50 mg vildagliptin and 1000 mg metformin hydrochloride;
excipients: lactose, hydroxypropylcellulose, microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate;
The coating mixture contains: hypromellose, titanium dioxide (E 171), macrogol/PEG, talc, iron oxide yellow (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties:
Film-coated tablets, 50 mg/850 mg: yellow, oval, film-coated tablets with a score on one side and “VA” on the other side. Tablet length 19.4±0.5 mm;
Film-coated tablets, 50 mg/1000 mg: dark yellow, oval, film-coated tablets with a score between “V” and “B” on one side and a score on the other side. Tablet length 21.1±0.5 mm.
Pharmacotherapeutic group
Antidiabetic drugs. Combination of oral hypoglycemic drugs. ATX code A10B D08.
Pharmacological properties
Pharmacodynamics
Gliptar®-M is a combination of two antihyperglycemic agents with different mechanisms of action that improve glucose control in patients with type 2 diabetes: vildagliptin, a member of the dipeptidyl peptidase-4 (DPP-4) inhibitor family, and metformin hydrochloride, a member of the biguanide class.
Vildagliptin, a member of the islet-enhancing class of agents, is a potent and selective DPP-4 inhibitor. Metformin acts primarily by reducing endogenous hepatic glucose production.
Vildagliptin
Vildagliptin acts primarily by inhibiting DPP-4, an enzyme responsible for the degradation of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). Inhibition of DPP-4 activity by vildagliptin results in a rapid and complete increase in endogenous levels of the incretin hormones GLP-1 and GIP after meals and fasting.
By increasing endogenous levels of these incretin hormones, vildagliptin increases beta-cell sensitivity to glucose, resulting in improved glucose-dependent insulin secretion. Treatment of patients with type 2 diabetes mellitus with vildagliptin at doses of 50 to 100 mg per day significantly improved markers of beta-cell function, including HOMA-β (homeostatic model of beta-cell function assessment), proinsulin to insulin ratio, and measures of beta-cell sensitivity in a multiple meal tolerance test. In non-diabetic subjects (with normal glucose levels), vildagliptin did not stimulate insulin secretion or lower glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin increases the sensitivity of pancreatic alpha cells to glucose, resulting in increased glucose-responsive glucagon secretion. The increased insulin/glucagon ratio during hyperglycemia results in increased incretin hormone levels, which in turn leads to decreased hepatic glucose production in the fasting and postprandial periods, leading to decreased glucose levels.
The known effect of elevated GLP-1 levels with gastric acid retention is not observed with vildagliptin treatment.
Metformin hydrochloride
Metformin is an oral antidiabetic agent of the biguanide class, the hypoglycemic effect of which is based mainly on overcoming insulin resistance in the liver and muscle. In the presence of insulin, it reduces both basal and postprandial plasma glucose levels. Metformin does not stimulate insulin secretion, therefore it does not lead to hypoglycemia in monotherapy.
Metformin may cause glucose lowering through three mechanisms:
- hepatic glucose production is largely responsible for fasting hyperglycemia. Metformin reduces hepatic glucose production, which is activated by insulin resistance, by inhibiting gluconeogenesis and glycogenolysis, thus simultaneously counteracting the hyperglycemic effect of glucagon. By this mechanism, metformin reduces fasting hyperglycemia.
- Impaired peripheral glucose uptake and storage are mainly responsible for postprandial hyperglycemia. Metformin increases the sensitivity of cells to insulin by stimulating the activity of insulin receptor tyrosine kinase, thereby promoting glucose uptake at the cellular level. Metformin increases the permeability of all cell membrane glucose transporters (GLUT). This effect of metformin is particularly pronounced in hyperglycemia. Intracellular glycogen synthesis is increased by stimulating a key enzyme, glycogen synthase. Through this mechanism, metformin reduces postprandial hyperglycemia.
In humans, independently of its effect on glycemia, metformin hydrochloride has a beneficial effect on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, low-density lipoproteins and triglycerides.
In addition, metformin has been shown in some studies to increase high-density lipoprotein levels. Metformin also exhibits fibrinolytic properties.
The UKPDS (British Prospective Diabetes Study) prospective randomized trial established the long-term benefits of intensive blood glucose control in type 2 diabetes. Analysis of the results in overweight patients treated with metformin after insufficient efficacy of diet alone showed:
- a significant reduction in the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) compared with the diet alone group (43.3 events/1000 patient-years), p = 0.0023, compared with the combined groups receiving sulfonylurea and insulin as monotherapy (40.1 events/1000 patient-years), p = 0.0034;
- significant reduction in the absolute risk of diabetes-related deaths: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p = 0.017;
- significant reduction in absolute risk of death: metformin
13.5 events/1000 patient-years compared to diet alone 20.6 events/1000 patient-years (p = 0.011) and compared to combined groups receiving sulfonylurea and insulin as monotherapy 18.9 events/1000 patient-years (p = 0.021);
- significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p = 0.01).
Clinical efficacy and safety
Vildagliptin was administered to patients whose glycaemic control was inadequate on metformin monotherapy, resulting in an additional statistically significant mean reduction in HbA1c compared to placebo after 6 months of treatment (between-group differences of -0.7% to -1.1% for vildagliptin 50 mg and 100 mg, respectively). The proportion of patients achieving a reduction in HbA1c ≥ 0.7% from baseline was statistically significantly higher in both vildagliptin + metformin groups (46% and 60%, respectively) compared to the metformin + placebo group (20%).
In a 24-week study, vildagliptin (50 mg twice daily) was compared with pioglitazone (30 mg once daily) in patients inadequately controlled on metformin (mean daily dose: 2020 mg). The mean reduction from a baseline HbA1c of 8.4% was -0.9% in the vildagliptin+metformin group and -1.0% in the pioglitazone+metformin group. The mean weight gain was +1.9 kg in patients treated with pioglitazone+metformin compared with +0.3 kg in those treated with vildagliptin+metformin.
In a 52-week study, vildagliptin (50 mg twice daily) was compared with gliclazide (mean daily dose: 229.5 mg) in patients inadequately controlled on metformin (initial metformin dose 1928 mg/day). After 1 year, the mean reduction in HbA1c was -0.81% in the vildagliptin + metformin group (mean baseline HbA1c 8.4%) and -0.85% in the gliclazide + metformin group (mean baseline HbA1c 8.5%); non-inferiority was achieved (95% CI -0.11-0.20). Weight gain with vildagliptin was +0.1 kg compared with a weight gain of 1.4 g with gliclazide.
In a 24-week study, the efficacy of a fixed combination of vildagliptin and metformin (with gradual dose titration to 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy was evaluated in treatment-naïve patients. Vildagliptin/metformin 50 mg/1000 mg twice daily reduced HbA1c by -1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by -1.61%, metformin 1000 mg twice daily by -1.36% and vildagliptin 50 mg twice daily by -1.09% from a mean baseline HbA1c of 8.6%.
The reduction in HbA1c observed in patients with baseline levels ≥10.0% was greater.
A 24-week, randomized, double-blind, placebo-controlled study was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or mixed insulin (mean daily dose 41 units) with or without concomitant metformin (N = 276). Vildagliptin in combination with insulin significantly reduced HbA1c compared to placebo. In the overall population, the placebo-adjusted mean reduction from baseline of 8.8% was -0.72%. In the subgroups receiving insulin with or without metformin, the placebo-adjusted mean reduction in HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycemia in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. There was no weight gain in patients receiving vildagliptin (+0.2 kg), while there was a weight loss in patients receiving placebo (-0.7 kg).
A five-year, multicenter, randomized, double-blind study (VERIFY) was conducted in patients with type 2 diabetes to evaluate the efficacy of early combination therapy with vildagliptin and metformin (N = 998) compared with initial metformin monotherapy in standard care followed by the addition of vildagliptin (sequential treatment group) (N = 1003) in patients with newly diagnosed type 2 diabetes.
The combination regimen of vildagliptin 50 mg twice daily and metformin resulted in a statistically and clinically significant relative risk reduction in “time to confirmed initial treatment failure” (HbA1c ≥7%) compared with metformin monotherapy in treatment-naïve patients with type 2 diabetes mellitus, 5-year study duration (HR [95% CI]: 0.51 [0.45, 0.58]; p
In another 24-week study in patients with more severe type 2 diabetes inadequately controlled with insulin (short- and long-acting, mean insulin dose 80 IU/day), the mean reduction in HbA1c with vildagliptin (50 mg twice daily) plus insulin was statistically significantly greater than with placebo plus insulin (0.5% vs. 0.2%). The incidence of hypoglycemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).
Cardiovascular risk
A meta-analysis of independent and prospective cardiovascular events in 37 phase III and IV monotherapy and combination therapy trials of more than 2 years duration (median exposure of 50 weeks for vildagliptin and 49 weeks for comparators) showed that treatment with vildagliptin was not associated with an increased cardiovascular risk compared with comparators. The composite endpoint of adjudicated major adverse cardiovascular events (MACE) including acute myocardial infarction, stroke, or cardiovascular death was similar for vildagliptin compared with comparators and placebo [Mantel–Haenszel hazard ratio (MH RR) 0.82 (95% CI 0.61–1.11)]. MACE occurred in 83 of 9599 (0.86%) patients treated with vildagliptin and in 85 of 7102 (1.20%) patients in the comparator group. Individual case assessment of MACE did not show an increased risk (similar to the MH RR). Confirmed heart failure (HF), defined as HF requiring hospitalization or new HF, was reported in 41 (0.43%) patients treated with vildagliptin and 32 (0.45%) patients treated with comparator, with a MH RR of 1.08 (95% CI 0.68-1.70).
Pharmacokinetics
Absorption
Vildagliptin with metformin
In a bioequivalence study of vildagliptin with metformin, tablets of different strengths (50 mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg) were compared with the combination of individual vildagliptin and metformin hydrochloride at the respective doses. Food intake did not affect the extent and extent of absorption of vildagliptin, the active substance of vildagliptin with metformin. The maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of metformin hydrochloride when vildagliptin with metformin at a dose of 50 mg/1000 mg was taken with food were reduced by 26 and 7%, respectively, and the time to reach (Tmax) was delayed (from 2.0 to 4.0 hours).
The pharmacokinetic properties of the individual active ingredients of the drug are given below. Vildagliptin
Absorption. After oral administration on an empty stomach, vildagliptin is rapidly absorbed, with Cmax observed after 1.7 hours. Simultaneous administration with food slightly delays the time to reach Cmax in blood plasma - up to 2.5 hours, but does not affect the total exposure (AUC). The use of vildagliptin with food leads to a decrease in the maximum concentration Cmax (19%). Despite this, the magnitude of the change is not clinically significant, so vildagliptin can be taken regardless of food intake. Absolute bioavailability is 85%.
Metabolism. Metabolism is the major route of elimination of vildagliptin in humans, accounting for 69% of the administered dose. The major metabolite (LAY151) is pharmacologically inactive and is a hydrolysis product of the cyanide moiety, accounting for 57% of the dose, followed by glucuronide (BQS867) and amide hydrolysis (4% of the dose). Data from an in vitro study in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite LAY151. DPP-4 is partially involved in the hydrolysis of vildagliptin, which was confirmed in an in vivo study in DPP-4-deficient rats.
Vildagliptin is not metabolised by cytochrome P450 enzymes to a detectable extent. Therefore, concomitant administration of medicinal products such as CYP450 inhibitors and/or inducers is not expected to affect the metabolic clearance of vildagliptin. In vitro studies have demonstrated that vildagliptin does not inhibit or induce cytochrome P450 enzymes. Therefore, vildagliptin is unlikely to affect the metabolic clearance of concomitantly administered medicinal products metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination. After oral administration of [14C]-vildagliptin, approximately 85% of the dose is excreted in the urine and 15% in the feces. Renal excretion of unchanged vildagliptin accounts for 23% of the oral dose. After intravenous administration to healthy volunteers, the total plasma and renal clearance of vildagliptin are 41 l/h and 13 l/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.
Linearity/non-linearity: Vildagliptin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increase approximately proportionally with dose over the entire therapeutic dose range.
Certain groups of patients.
Gender: No differences in pharmacokinetics were observed in healthy male and female volunteers of different ages and body mass index (BMI). DPP-4 inhibition by vildagliptin is independent of gender.
Elderly: In healthy subjects (aged 70 years and older), total exposure to vildagliptin (100 mg once daily) was increased by 32% and maximum plasma concentration by 18% compared to younger healthy subjects (aged 18 to 40 years).
These changes, however, are not considered clinically significant. DPP-4 inhibition by vildagliptin is independent of age in the age groups studied.
Hepatic impairment: There were no clinically meaningful changes (maximum 30%) in vildagliptin exposure in patients with mild, moderate, or severe hepatic impairment (AC according to Child-Pugh classification).
Renal impairment: In patients with mild, moderate or severe renal impairment, systemic exposure to vildagliptin was increased (Cmax 8-66%; AUC 32-134%) and total body clearance was reduced compared to subjects with normal renal function.
Race: Limited data suggest that race does not have a significant effect on the pharmacokinetics of vildagliptin.
Metformin
Absorption.
After oral administration of metformin, the time to maximum concentration (Cmax) is approximately 2.5 hours (Tmax). The absolute bioavailability of metformin in the form of 500 mg tablets is approximately 50-60% in healthy volunteers. After oral administration, the fraction that is not absorbed and is excreted in the feces is 20-30%.
After oral administration, the absorption of metformin is saturable and incomplete.
The absorption of metformin is assumed to be non-linear. When metformin is used at recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and are less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/ml even at maximum doses.
When taken with food, the absorption of metformin is reduced and somewhat slowed down.
Following oral administration of 850 mg, a 40% decrease in peak plasma concentration, a 25% decrease in AUC, and a 35-minute increase in time to peak plasma concentration were observed. The clinical significance of these changes is unknown.
Distribution.
Binding to plasma proteins is insignificant. Metformin penetrates into erythrocytes. The mean volume of distribution (Vd) ranges from 63 to 276 liters.
Metabolism.
Metformin is excreted unchanged in the urine. Metabolites have not been identified in humans.
Breeding.
Metformin is eliminated by renal excretion. Renal clearance of metformin is > 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In cases of impaired renal function, renal clearance decreases in proportion to creatinine clearance and therefore the elimination half-life increases, leading to increased metformin plasma levels.
Indication
Gliptar®-M is indicated for the treatment of patients with type 2 diabetes mellitus (as an adjunct to diet and exercise to improve glycemic control):
- in adult patients already receiving a combination of vildagliptin and metformin as separate drugs;
- in combination with other medicines for the treatment of diabetes, including insulin, if they do not provide adequate control of glucose levels (see sections "Special instructions for use", "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamics").
Contraindication
- hypersensitivity to vildagliptin, metformin, or any other components of the drug;
- any type of acute metabolic acidosis (e.g. lactic acidosis, diabetic ketoacidosis);
- diabetic precoma;
- renal failure or impaired renal function (creatinine clearance
- acute conditions that may alter renal function, such as dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see section "Special warnings and precautions for use");
- acute or chronic diseases that can lead to tissue hypoxia, such as heart or respiratory failure, recent myocardial infarction, shock;
- liver dysfunction (see sections "Special instructions for use", "Method of administration and dosage");
- acute alcohol intoxication, alcoholism;
- breastfeeding period (see section "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other types of interactions
Drug interaction studies of vildagliptin with metformin have not been conducted. Below is information on the interactions of the active substances, vildagliptin and metformin separately.
Vildagliptin
Vildagliptin has a low potential for drug interactions with concomitantly administered medicinal products. Since vildagliptin is not a substrate of cytochrome P (CYP) 450 enzymes and does not inhibit or induce CYP 450 enzymes, it is unlikely that vildagliptin will interact with substrates, inhibitors or inducers of these enzymes when administered concomitantly.
Clinical studies have been conducted with oral antidiabetic agents in patients with type 2 diabetes or drugs with a narrow therapeutic window. These studies have not shown clinically significant pharmacokinetic interactions with oral antidiabetic agents (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin.
Use with ACE inhibitors
Patients taking ACE inhibitors concomitantly may be at increased risk of angioedema (see section 4.8).
As with other oral antidiabetic drugs, the hypoglycemic effect of vildagliptin may be reduced when used with other drugs, including thiazides, corticosteroids, thyroid hormones and sympathomimetics.
Metformin
Not recommended combinations
Alcohol: In acute alcohol intoxication, patients taking metformin are at increased risk of developing lactic acidosis, especially after fasting or in the presence of malnutrition or impaired liver function.
Iodinated contrast media: Metformin should be discontinued prior to or at the time of the imaging procedure and not resumed for at least 48 hours thereafter, provided that renal function has been assessed and found to be stable (see sections 4.2 and 4.4).
Combinations requiring caution when used
Some medicinal products may adversely affect renal function, which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When prescribing or using such medicinal products with metformin, careful monitoring of renal function is necessary.
Glucocorticoids, beta-2-agonists and diuretics have intrinsic hyperglycemic activity. The patient should be informed of the need for more frequent monitoring of blood glucose levels, especially at the beginning of treatment. If necessary, the dosage of Gliptar®-M may need to be adjusted during concomitant therapy.
Angiotensin-converting enzyme (ACE) inhibitors may reduce blood glucose levels. If necessary, the dosage of the antihyperglycemic drug should be adjusted during concomitant therapy with other drugs.
Concomitant use of medicinal products that affect common renal tubular transport systems affecting the renal elimination of metformin (e.g. organic cation transporter-2 [OCT2]/MATE transporter [MATE], such as ranolazine, vandetanib, dolutegravir and cimetidine) may increase systemic exposure to metformin.
Application features
General
Gliptar®-M is not a substitute for insulin in insulin-dependent patients. The drug should not be used in patients with type 1 diabetes.
Lactic acidosis
Lactic acidosis, a very rare but serious metabolic complication, most often occurs in the setting of renal impairment, cardiorespiratory disease, or sepsis. Metformin accumulation occurs in acute renal impairment and increases the risk of lactic acidosis.
Medicinal products that may cause acute renal impairment (such as antihypertensives, diuretics and NSAIDs) should be administered with caution to patients receiving metformin. Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).
Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, hypothermia, and may progress to coma. If symptoms of lactic acidosis develop, the patient should discontinue metformin and seek immediate medical attention. Laboratory findings include decreased blood pH (5 mmol/L) and increased anion gap and lactate/pyruvate ratio.
Use of iodinated contrast agents
Intravascular administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. Therefore, due to the metformin content, Gliptar®-M should be discontinued prior to or during such an examination and resumed no earlier than 48 hours after the examination and only if renal function is normal.
X-ray examinations
Intravascular administration of iodinated contrast agents during X-ray examinations may lead to acute renal failure. Therefore, due to the metformin content, Gliptar®-M should be discontinued prior to or during such an examination and resumed no earlier than 48 hours after the examination and only if renal function is normal.
Kidney dysfunction
GFR should be checked before starting treatment and regularly during treatment (see section 4.2). Metformin is contraindicated in patients with GFR
Use with caution with medicinal products that may affect renal function, lead to significant changes in haemodynamics or inhibit renal transport and increase systemic exposure to metformin (see section “Interaction with other medicinal products and other forms of interaction”).
Liver dysfunction
Vildagliptin should not be used to treat patients with impaired liver function, including patients with baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 3 times the upper limit of normal (ULN) (see sections 4.3, 4.8, 4.8).
Monitoring liver enzyme levels
Rare cases of liver dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, patients were usually asymptomatic and did not experience clinical complications, and liver function tests (LFTs) returned to normal after discontinuation of treatment. Before initiating treatment with Gliptar®-M, LFTs should be performed to determine baseline values in patients. LFTs should be monitored every 3 months during treatment for the first year of treatment and periodically thereafter. Patients who develop elevated transaminases should have their liver function re-evaluated to confirm changes in their levels, and LFTs should be performed frequently until the changes return to normal. If AST and ALT levels exceed 3 times the upper limit of normal, it is recommended that Gliptar®-M be discontinued. Patients who develop jaundice or other signs suggestive of liver dysfunction should be discontinued.
After discontinuation of treatment with Gliptar®-M and normalization of FPP, re-treatment with this drug should not be initiated.
Skin disorders
In preclinical toxicology studies with vildagliptin, skin lesions, including blistering and ulceration of the limbs of monkeys, were reported. Although no increase in the incidence of skin lesions was observed in clinical studies, experience with skin complications in patients with diabetes mellitus was limited. In addition, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, monitoring for skin disorders, such as blistering or ulceration, is recommended in the routine care of patients with diabetes mellitus.
Acute pancreatitis
During post-marketing surveillance, adverse reactions of acute pancreatitis have occurred. Patients should be informed about the characteristic symptom of acute pancreatitis - persistent, severe abdominal pain.
Pancreatitis resolved after discontinuation of vildagliptin. Vildagliptin should be discontinued if pancreatitis is suspected; vildagliptin should not be re-administered if acute pancreatitis is confirmed. Use with caution in patients with a history of acute pancreatitis.
Sulfonylureas are known to cause hypoglycemia. Patients receiving Gliptar®-M in combination with a sulfonylurea are at risk of hypoglycemia. To reduce the risk of hypoglycemia, it is advisable to use the lowest possible dose of the sulfonylurea.
Surgical interventions
Since Gliptar®-M contains metformin, treatment with this drug should be discontinued 48 hours before elective surgery with general, spinal or epidural anesthesia and should not be resumed earlier than 48 hours afterwards (provided that renal function and oral intake are normal).
Use during pregnancy or breastfeeding
Pregnancy
Animal studies have shown reproductive toxicity at high doses of vildagliptin. Animal studies have not shown reproductive toxicity with metformin. Animal studies with vildagliptin and metformin have not shown teratogenicity, but have shown fetotoxic effects at doses toxic to pregnant women. The potential risk to humans is unknown. Gliptar®-M should not be used during pregnancy.
Breastfeeding period
Animal studies have shown excretion of metformin and vildagliptin in milk. Metformin is known to pass into human breast milk in small amounts. Given the potential risk of neonatal hypoglycemia associated with metformin and the lack of data on the effects of vildagliptin, Gliptar®-M should not be used in women during breastfeeding.
Fertility
Studies on the effects of vildagliptin with metformin on human fertility have not been conducted.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted on the effect of the drug on the reaction speed when driving vehicles or operating other mechanisms. Therefore, patients who may experience dizziness should avoid driving vehicles or operating mechanisms.
Method of administration and doses
The dosage of antihyperglycemic treatment for the control of type 2 diabetes should be selected individually based on the current therapy regimen, efficacy and tolerability. When using the drug Gliptar®-M, the maximum daily dose of vildagliptin (100 mg) should not be exceeded. Gliptar®-M tablets should be taken twice a day, in the morning and in the evening.
Method of administration and doses
For oral use.
Taking Gliptar®-M with or immediately after food may reduce gastrointestinal symptoms associated with metformin use.
For patients whose condition is not adequately controlled with metformin hydrochloride monotherapy at the patient's maximum tolerated doses.
The initial dose of Gliptar®-M should consist of vildagliptin 50 mg 2 times a day (total daily dose – 100 mg) and metformin at the dose that the patient is already taking.
For patients switching from concomitant treatment with vildagliptin and metformin as separate drugs.
The initial dose of Gliptar®-M should correspond to the doses of vildagliptin and metformin used previously.
For patients whose condition is not adequately controlled with metformin and sulfonylurea drugs.
The initial dose of Gliptar®-M should consist of vildagliptin 50 mg twice daily (total daily dose – 100 mg) and metformin at the dose that the patient is already taking. When used in combination with a sulfonylurea, a lower dose of the sulfonylurea should be considered to reduce the risk of hypoglycemia.
Use in combination with insulin and the maximum tolerated doses of metformin.
The initial dose of Gliptar®-M should consist of vildagliptin 50 mg 2 times a day (total daily dose – 100 mg) and metformin at the dose that the patient is already taking.
The safety and efficacy of vildagliptin and metformin as triple oral therapy in combination with thiazolidinediones have not been established.
Special patient groups
Elderly patients (65 years and older)
Since metformin is excreted by the kidneys, and elderly patients tend to have decreased renal function, they require regular monitoring of renal function while taking Gliptar®-M.
Kidney dysfunction
GFR should be assessed before starting treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal disease
