Galvinea-m: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GHALVINIA-M (GALVINIA-M)

Composition:

Active substances: vildagliptin, metformin hydrochloride;

One film-coated tablet contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride, equivalent to 660 mg of metformin;

One film-coated tablet contains 50 mg of vildagliptin and 1000 mg of metformin hydrochloride, equivalent to 780 mg of metformin;

Excipients: copovidone K-28, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating containing: Opadry II Yellow 57U220039 (for tablets 50 mg / 850 mg), Opadry II Yellow 57U220040 (for tablets 50 mg / 1000 mg): hypromellose-2910 (E 464), polydextrose (E 1200), titanium dioxide (E 171), talc (E 553b), iron oxide yellow (E 172), maltodextrin/dextrin, MCT/capryl and caprin.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics:

Tablets 50 mg / 850 mg: yellow oval film-coated tablet with beveled edges, engraved with "50" on one side and "850" on the other, length — 21.6 ± 0.2 mm, width — 8.6 ± 0.2 mm, thickness — 7.4 ± 0.4 mm;

Tablets 50 mg / 1000 mg: dark yellow oval film-coated tablet with beveled edges, engraved with "50" on one side and "1000" on the other, length — 22.0 ± 0.2 mm, width — 9.0 ± 0.2 mm, thickness — 8.1 ± 0.4 mm.

Pharmacotherapeutic group. Antidiabetic agents. Combination of oral hypoglycemic agents. ATC code A10BD08.

Pharmacological Properties

Pharmacodynamics

Galvus-M is a combination of two antihyperglycemic agents with different mechanisms of action that improve glycemic control in patients with type 2 diabetes: vildagliptin, a member of the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and metformin hydrochloride, a member of the biguanide class.

Vildagliptin, a representative of the class of agents enhancing pancreatic islet function, is a potent and selective inhibitor of DPP-4. Metformin acts primarily by decreasing endogenous glucose production in the liver.

Vildagliptin

Vildagliptin acts primarily by inhibiting DPP-4, an enzyme responsible for the degradation of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 activity by vildagliptin leads to a rapid and complete increase in endogenous levels of the incretin hormones GLP-1 and GIP after food intake and in the fasting state.

By increasing endogenous levels of these incretin hormones, vildagliptin enhances beta-cell sensitivity to glucose, thereby improving glucose-dependent insulin secretion. Treatment of patients with type 2 diabetes with vildagliptin at doses of 50 to 100 mg per day significantly improved markers of beta-cell function, including HOMA-β (homeostatic model assessment of beta-cell function), proinsulin-to-insulin ratio, and beta-cell sensitivity indices during repeated meal tolerance tests. In non-diabetic individuals (with normal glucose levels), vildagliptin did not stimulate insulin secretion or lower glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin enhances alpha-cell sensitivity to glucose, thereby increasing glucose-responsive glucagon secretion. The enhanced increase in the insulin/glucagon ratio during hyperglycemia, driven by elevated incretin hormone levels, leads to reduced hepatic glucose production in both fasting and postprandial states, resulting in decreased glucose levels.

The known effect of elevated GLP-1 levels on delayed gastric emptying is not observed with vildagliptin treatment.

Metformin

Metformin is an oral antidiabetic agent of the biguanide class whose hypoglycemic effect is primarily based on overcoming insulin resistance in the liver and muscles. In the presence of insulin, it reduces both basal and postprandial plasma glucose levels. Metformin does not stimulate insulin secretion and therefore does not cause hypoglycemia when used as monotherapy.

Metformin may reduce glucose levels through three mechanisms:

Hepatic glucose production largely contributes to fasting hyperglycemia. Metformin reduces insulin resistance-driven hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, thereby counteracting the hyperglycemic effect of glucagon. Through this mechanism, metformin reduces fasting hyperglycemia.
Impaired peripheral glucose uptake and utilization primarily contribute to postprandial hyperglycemia. Metformin increases cellular sensitivity to insulin by stimulating tyrosine kinase activity of insulin receptors, thereby promoting cellular glucose uptake. Metformin enhances the transport capacity of all cellular membrane glucose transporters (GLUT). This effect of metformin is particularly evident under hyperglycemic conditions. Intracellular glycogen synthesis is increased by stimulation of the key enzyme glycogen synthase. Through this mechanism, metformin reduces postprandial hyperglycemia.
Metformin reduces glucose absorption in the gastrointestinal tract, thereby reducing postprandial glucose load.

In humans, independent of its effects on glycemia, metformin hydrochloride has favorable effects on lipid metabolism. This has been demonstrated for therapeutic doses in controlled, medium- or long-term clinical trials: metformin hydrochloride reduces levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides.

Additionally, in some studies, metformin has been shown to increase high-density lipoprotein cholesterol levels. Metformin also exhibits fibrinolytic properties.

The prospective randomized UKPDS (UK Prospective Diabetes Study) established long-term benefits of intensive glycemic control in type 2 diabetes. Analysis of outcomes in overweight patients who received metformin after inadequate response to diet alone showed:

A significant reduction in absolute risk of any diabetes-related complications in the metformin group (29.8 events per 1000 patient-years) compared to the diet-only group (43.3 events per 1000 patient-years), p = 0.0023, and compared to combined groups receiving sulfonylurea or insulin as monotherapy (40.1 events per 1000 patient-years), p = 0.0034;
A significant reduction in absolute risk of diabetes-related mortality: metformin — 7.5 events per 1000 patient-years, diet-only — 12.7 events per 1000 patient-years, p = 0.017;
A significant reduction in absolute risk of all-cause mortality: metformin — 13.5 events per 1000 patient-years compared to diet-only — 20.6 events per 1000 patient-years (p = 0.011) and compared to combined groups receiving sulfonylurea or insulin as monotherapy — 18.9 events per 1000 patient-years (p = 0.021);
A significant reduction in absolute risk of myocardial infarction: metformin — 11 events per 1000 patient-years, diet-only — 18 events per 1000 patient-years (p = 0.01).

Pharmacokinetics

Vildagliptin / Metformin Hydrochloride

Absorption

In a bioequivalence study, the combination product vildagliptin/metformin tablets at different strengths (50 mg / 850 mg and 50 mg / 1000 mg) were compared with the combination of separate vildagliptin and metformin hydrochloride tablets at corresponding doses. Food intake did not affect the extent or rate of absorption of vildagliptin — the active ingredient in the vildagliptin/metformin combination. The maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of metformin hydrochloride were reduced by 26% and 7%, respectively, when the vildagliptin/metformin 50 mg / 1000 mg formulation was taken with food, and the time to peak concentration (Tmax) was delayed (from 2.0 to 4.0 hours).

The pharmacokinetic properties of the individual active substances are described below.

Vildagliptin

After oral administration on an empty stomach, vildagliptin is rapidly absorbed, with peak plasma concentrations observed at 1.7 hours. Food intake slightly delays the time to peak plasma concentrations to 2.5 hours but does not alter total exposure (AUC). Administration of vildagliptin with food resulted in a 19% reduction in Cmax compared to fasting conditions. However, the magnitude of these changes is not clinically significant; therefore, vildagliptin can be taken with or without food. Absolute bioavailability is 85%.

Metformin Hydrochloride

After oral administration, Cmax of metformin is reached at approximately 2.5 hours. Absorption is believed to occur primarily in the upper gastrointestinal tract. Absolute bioavailability of metformin hydrochloride (850 mg tablets) administered fasting is approximately 50–60% in healthy volunteers. Single oral doses of 500–2500 mg result in less than proportional increases in Cmax, likely due to a saturable mechanism. At usual dosing and administration regimens, steady-state plasma concentrations are achieved within 24–48 hours and typically remain below 1 µg/mL. In controlled clinical trials, Cmax did not exceed 4 µg/mL even with maximum doses.

Food intake reduces the extent and slightly delays the absorption of metformin hydrochloride, as evidenced by approximately 40% lower mean Cmax, 25% lower AUC, and a 35-minute increase in Tmax. The clinical significance of this reduction is unknown.

Distribution

Vildagliptin

Plasma protein binding of vildagliptin is low (9.3%), and vildagliptin distributes equally between plasma and erythrocytes. The mean volume of distribution at steady state (Vss) after intravenous administration is 71 L, indicating extravascular distribution.

Metformin Hydrochloride

Plasma protein binding of metformin is negligible. Metformin penetrates into erythrocytes. Maximum concentration in blood is lower than maximum concentration in plasma and is reached at approximately the same time. Erythrocytes likely serve as a secondary distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 liters.

Metabolism

Vildagliptin

Metabolism is the main elimination pathway of vildagliptin in humans (69% of dose). The major metabolite LAY151 is pharmacologically inactive and results from hydrolysis of the cyano fragment (57% of dose), followed by hydrolysis of the amide fragment (4% of dose). Vildagliptin is not metabolized by cytochrome P450 enzymes.

Metformin Hydrochloride

Metformin is excreted unchanged in urine. Metabolites have not been identified in humans.

Elimination

Vildagliptin

85% of the dose is excreted in urine and 15% in feces. After oral administration, 23% of the dose is excreted in urine as unchanged vildagliptin. The elimination half-life after oral administration is approximately 3 hours.

Metformin Hydrochloride

Metformin is excreted unchanged in urine. Renal clearance is > 400 mL/min, approximately 3.5 times greater than creatinine clearance. Therefore, the drug is primarily eliminated via active tubular secretion. The terminal elimination half-life after oral administration is approximately 6.5 hours. When measured in whole blood, the elimination half-life is approximately 17.6 hours. In patients with normal renal function, metformin does not accumulate at standard doses (1500–2000 mg).

Vildagliptin

Linearity/Non-linearity

Cmax and AUC of vildagliptin increased almost proportionally with dose across the entire therapeutic dose range.

Gender

No differences in vildagliptin pharmacokinetic parameters were observed between healthy male and female volunteers.

Age

Plasma concentrations are increased in patients over 70 years of age; however, these changes are not considered clinically significant.

Hepatic Impairment

Exposure to vildagliptin (100 mg) was not increased after a single 100 mg dose in patients with mild and moderate hepatic impairment. In patients with severe hepatic impairment, exposure was increased by 22% (68% upper limit of confidence interval).

Renal Impairment

In pharmacokinetic studies, AUC of vildagliptin increased on average by 1.4, 1.7, and 2 times in patients with mild (creatinine clearance [CrCl] 50–<80 mL/min), moderate (CrCl 30–<50 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively, compared to healthy volunteers. AUC of metabolite LAY151 increased by 1.6, 3.2, and 7.3 times, and metabolite BQS867 by 1.4, 2.7, and 7.3 times in patients with mild, moderate, and severe renal impairment, respectively. Some data in patients with end-stage chronic renal disease (CRD) indicate similar pharmacokinetic parameters to those in patients with severe renal impairment. LAY151 AUC in patients with CRD was 6.8 times higher than in patients with normal renal function. Elimination of vildagliptin by hemodialysis is limited (3% after a single dose within 4 hours, with procedure duration exceeding 3–4 hours).

Effect of metformin: in patients with impaired renal function, renal clearance decreases proportionally to creatinine clearance, prolonging elimination half-life and increasing the risk of accumulation.

Ethnic Groups

Limited data indicate no effect of ethnicity on vildagliptin pharmacokinetics.

Clinical characteristics.

Indications.

The medicinal product Galvignia-M is indicated as an adjunct to diet and physical exercise to improve glycemic control in adult patients with type 2 diabetes mellitus:

in whom glycemic control with metformin hydrochloride alone is inadequate;
who are already receiving treatment with a combination of vildagliptin and metformin hydrochloride as separate tablets;
in combination with other medicinal products used in the treatment of type 2 diabetes, including insulin, when they do not provide adequate glycemic control (available data on various combinations are provided in the sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use").

Contraindications.

Hypersensitivity to vildagliptin or metformin hydrochloride or to any of the other components of the medicinal product;
any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis);
diabetic precoma;
renal failure or impaired renal function (creatinine clearance < 30 mL/min) (see section "Special precautions for use");
acute conditions which may alter renal function, such as dehydration, severe infection, shock, or intravascular administration of iodinated contrast agents;
acute or chronic conditions that may lead to tissue hypoxia, such as cardiac or respiratory failure, recent myocardial infarction, shock;
hepatic impairment (see sections "Special precautions for use", "Method of administration", "Adverse reactions");
acute alcohol intoxication, alcoholism;
breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Formal drug interaction studies with the combination product vildagliptin/metformin have not been conducted. The information below refers to interactions of the individual active substances vildagliptin and metformin separately.

Vildagliptin

Since vildagliptin is not a substrate of cytochrome P450 (CYP) enzymes and does not inhibit or induce CYP450 enzymes, clinically relevant pharmacokinetic interactions between vildagliptin and substrates, inhibitors, or inducers of these enzymes are unlikely.

Clinical studies conducted with the oral antidiabetic agents pioglitazone, metformin, and glyburide in combination with vildagliptin did not reveal clinically significant pharmacokinetic interactions in the target population.

Drug interaction studies with digoxin (a P-glycoprotein substrate) and warfarin (a CYP2C9 substrate) in healthy volunteers did not show clinically significant pharmacokinetic interactions when coadministered with vildagliptin.

Drug interaction studies in healthy volunteers have been conducted with amlodipine, ramipril, valsartan, and simvastatin. No clinically significant pharmacokinetic interactions were observed after coadministration with vildagliptin. However, this has not been established in the target population.

Combination with ACE inhibitors

In patients taking angiotensin-converting enzyme (ACE) inhibitors concomitantly, the risk of angioedema may be increased (see section "Adverse reactions").

As with other oral antidiabetic medicinal products, the hypoglycemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid hormones, and sympathomimetics.

Metformin hydrochloride

Alcohol. In patients taking metformin, acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly following fasting or inadequate nutrition, or in the presence of hepatic impairment.

Iodinated contrast agents. Administration of metformin must be discontinued before or during contrast imaging procedures and should not be restarted for at least 48 hours afterward, provided that renal function has been re-evaluated and found to be stable (see sections "Dosage and administration", "Special precautions for use").

Combinations requiring caution in use

Some medicinal products may adversely affect renal function, thereby increasing the risk of lactic acidosis, e.g., NSAIDs, including selective cyclooxygenase (COX)-2 inhibitors, ACE inhibitors, angiotensin II receptor antagonists, and diuretics, particularly loop diuretics. Careful monitoring of renal function is required when such agents are prescribed or used concomitantly with metformin.

Glucocorticoids, beta-2 agonists, and diuretics have intrinsic hyperglycemic activity. Patients should be informed and monitored more frequently for blood glucose levels, especially at the beginning of treatment. Dose adjustment of Galvignia-M may be necessary during concomitant therapy and upon its discontinuation.

Angiotensin-converting enzyme (ACE) inhibitors may lower blood glucose levels. The dose of the antihyperglycemic medicinal product may need to be adjusted during therapy with such agents and upon their withdrawal.

Concomitant use of medicinal products that affect the common renal tubular transport systems involved in the renal elimination of metformin (e.g., inhibitors of organic cation transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors, such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase systemic exposure to metformin.

Special precautions for use.

Galvus-M does not replace insulin in insulin-dependent patients. The medicinal product should not be used in patients with type 1 diabetes.

Lactic acidosis

Lactic acidosis is an extremely rare (3 cases per 100,000 patient-years), but serious metabolic complication associated with high mortality, which may occur in the setting of acute worsening of renal function, cardiopulmonary diseases, or sepsis. It may result from metformin accumulation. Cases of lactic acidosis in patients taking metformin have occurred primarily in diabetic patients with marked renal insufficiency. In patients with hepatic impairment, lactate clearance may be reduced. The incidence of lactic acidosis can and should be reduced by eliminating other concomitant risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency, and any condition associated with hypoxia (see also sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients with established or suspected mitochondrial disorders

Metformin is not recommended in patients with established mitochondrial disorders such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) and mitochondrial inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, which may lead to worsening of the disease course.

If signs and symptoms suggestive of MELAS or MIDD occur after metformin administration, treatment with metformin should be immediately discontinued and prompt diagnostic evaluation initiated.

In case of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), metformin should be temporarily discontinued and medical advice sought.

Medicinal products that may abruptly impair renal function (such as antihypertensives, diuretics, and NSAIDs) should be initiated with caution in patients receiving metformin.

Patients and/or caregivers should be informed about the risk of developing lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia progressing to coma. In case of suspicion of such symptoms, the patient should discontinue metformin and seek immediate medical attention. Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated plasma lactate levels (> 5 mmol/L), and increased anion gap and lactate/pyruvate ratio.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued before or during imaging procedures and not restarted for at least 48 hours thereafter, provided renal function has been re-evaluated and confirmed to be stable (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Renal function impairment

eGFR should be assessed before initiating treatment and regularly thereafter (see section "Dosage and administration").

Metformin is contraindicated in patients with eGFR < 30 mL/min and should be temporarily discontinued in conditions affecting renal function (see section "Contraindications").

Concomitant medicinal products that may affect renal function, cause significant hemodynamic changes, or inhibit renal transport and increase systemic exposure to metformin should be used with caution (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic function impairment

Vildagliptin should not be used for treatment of patients with hepatic impairment, including patients in whom alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceed the upper limit of normal (ULN) by more than 3 times before treatment initiation.

Monitoring of liver enzymes

Rare cases of hepatic dysfunction (including hepatitis) have been reported during vildagliptin use. In these cases, patients usually did not exhibit symptoms or clinical complications, and liver function tests (LFTs) returned to normal after discontinuation of treatment. Prior to initiating Galvus-M, LFTs should be performed to establish baseline values in patients. LFTs should be monitored every 3 months during the first year of treatment and periodically thereafter. Patients who develop elevated transaminase levels require re-evaluation of liver function to confirm changes, followed by frequent LFT monitoring until values return to normal. If AST and ALT levels remain elevated above ULN by more than 3 times, discontinuation of Galvus-M is recommended. Patients who develop jaundice or other signs indicating hepatic dysfunction require discontinuation of Galvus-M treatment.

After discontinuation of Galvus-M and normalization of LFTs, re-initiation of treatment with this medicinal product is not recommended.

Heart failure

A clinical study of vildagliptin in patients with heart failure of NYHA functional class I–III showed that treatment with vildagliptin was not associated with changes in left ventricular ejection fraction or worsening of existing congestive heart failure compared to placebo.

There is no clinical experience with vildagliptin in patients with heart failure of NYHA functional class III–IV; therefore, it should not be used in these patients.

Metformin is contraindicated in patients with heart failure; therefore, the medicinal product Galvus-M is also contraindicated in these patients.

Skin disorders

In preclinical toxicological studies with vildagliptin, skin lesions including blistering and ulceration on the extremities of animals were reported. Although no increased incidence of skin lesions was observed during clinical trials, experience regarding skin complications in diabetic patients has been limited. Additionally, post-marketing reports of bullous and exfoliative skin lesions have been received. Therefore, during routine follow-up of diabetic patients, monitoring for skin disorders such as blistering or ulceration is recommended.

Pancreatitis

Adverse reactions in the form of acute pancreatitis have been reported during post-marketing surveillance. Patients should be informed about the characteristic symptom of acute pancreatitis—persistent severe abdominal pain.

Pancreatitis symptoms resolved after discontinuation of vildagliptin treatment. In case of suspected pancreatitis, vildagliptin and other potentially causative agents should be discontinued.

Hypoglycemia

Hypoglycemia usually does not occur in patients receiving Galvus-M, but may occur if caloric intake is inadequate, physical exertion is not compensated by additional caloric intake, or with alcohol consumption. Elderly, debilitated, or malnourished patients, as well as those with adrenal or pituitary insufficiency or alcohol intoxication, are prone to hypoglycemia. Hypoglycemia may be difficult to recognize in elderly patients and those taking beta-blockers.

Sulfonylurea derivatives are known to cause hypoglycemia. Patients receiving Galvus-M in combination with sulfonylureas are at risk of hypoglycemia. To reduce the risk of hypoglycemia, it is advisable to use the lowest effective dose of sulfonylurea.

Surgical procedures

Since Galvus-M contains metformin, treatment with this product should be discontinued 48 hours prior to elective surgical procedures involving general, spinal, or epidural anesthesia and should not be resumed earlier than 48 hours after the procedure (provided normal renal function and oral intake of food).

Radiological examinations

Intravascular administration of iodine-containing contrast agents during radiological procedures may lead to acute renal function impairment. Therefore, due to metformin content, Galvus-M should be discontinued before or during such procedures and restarted no earlier than 48 hours after the procedure and only if renal function is confirmed to be normal.

Hypoxic conditions

Cardiovascular insufficiency (shock), acute heart failure, acute myocardial infarction, and other conditions characterized by hypoxia are associated with lactic acidosis, which may lead to prerenal azotemia. In such conditions, therapy with Galvus-M should be immediately discontinued.

Alcohol effects

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol consumption.

Effect on vitamin B12 levels

Metformin, a component of this medicinal product, reduces vitamin B12 concentration levels in approximately 7% of patients. This reduction may also be associated with anemia. These manifestations resolve rapidly upon discontinuation of treatment. Annual hematological monitoring is recommended in patients receiving Galvus-M.

Changes in clinical status in patients with controlled type 2 diabetes

Patients are usually well controlled when receiving Galvus-M, but the risk of ketoacidosis or lactic acidosis should be considered, and the drug should be immediately discontinued at the first sign of deviation from normal, with appropriate measures taken.

Loss of glucose control

Patients with stabilized glucose levels on any antidiabetic regimen may experience loss of glucose control during stressful conditions such as fever, trauma, infections, or surgical procedures. In such situations, Galvus-M should be temporarily discontinued, glycemic control managed with insulin, and Galvus-M resumed after the patient's condition normalizes.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have demonstrated reproductive toxicity with high doses of vildagliptin. Animal studies with metformin did not show reproductive toxicity. Animal studies conducted with vildagliptin and metformin did not reveal teratogenic effects, but fetotoxic effects were observed at doses toxic to pregnant animals. The potential risk in humans is unknown. Galvus-M should not be used during pregnancy.

Breastfeeding. Animal studies have shown excretion of metformin and vildagliptin into milk. It is unknown whether vildagliptin is excreted in human breast milk, but metformin is known to be excreted in human breast milk in small amounts. Considering the potential risk of neonatal hypoglycemia associated with metformin and the lack of data on vildagliptin effects, Galvus-M should not be used in women during breastfeeding.

Fertility. Studies on the effect of Galvus-M on human fertility have not been conducted.

Ability to affect reaction rate when driving or operating machinery.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Therefore, patients who may experience dizziness should avoid such hazardous activities.

Dosage and Administration

Dosing

Adult patients with normal renal function (GFR [glomerular filtration rate] ≥ 90 mL/min)

The dosage of antihyperglycemic therapy should be individually selected based on the current treatment regimen, efficacy, and tolerability. When using the medicinal product Galvignia-M, the maximum daily dose of vildagliptin (100 mg) should not be exceeded.

Administration

For oral use.

Treatment with the medicinal product Galvignia-M can be initiated at a dose of 50 mg/850 mg or 50 mg/1000 mg twice daily, one tablet in the morning and one in the evening.

For patients whose condition is not adequately controlled on maximum tolerated doses of hydrochloride metformin monotherapy.

The initial dose of the medicinal product Galvignia-M should be: vildagliptin – 50 mg twice daily (total daily dose – 100 mg), metformin – the dose already being taken by the patient.

For patients switching from concomitant administration of vildagliptin and metformin as separate agents.

The initial dose of the medicinal product Galvignia-M should correspond to the previously used doses of vildagliptin and metformin.

For patients whose condition is not adequately controlled on dual combination therapy with metformin and a sulfonylurea.

The recommended dose of the medicinal product Galvignia-M should correspond to a vildagliptin dose of 50 mg twice daily (total daily dose – 100 mg) and a metformin dose according to the dose the patient is already receiving.

When used in combination with a sulfonylurea, consideration should be given to using a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.

For patients whose condition is not adequately controlled on dual combination therapy with insulin and the maximum tolerated dose of metformin:

The safety and efficacy of vildagliptin and metformin as triple oral therapy in combination with a thiazolidinedione have not been established.

Special patient groups

Elderly patients (over 65 years of age)

Since metformin is excreted by the kidneys, and elderly patients tend to have reduced renal function, regular monitoring of kidney function is required during treatment with the medicinal product Galvignia-M (see sections "Special precautions", "Pharmacological properties").

Patients with renal impairment

GFR should be assessed before initiating treatment with medicinal products containing metformin and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in elderly patients, careful monitoring of renal function should be performed as frequently as possible, for example every 3–6 months.

The total maximum daily dose should be divided into 2–3 doses throughout the day. Prior to initiating metformin in patients with GFR ≥ 60 mL/min, factors increasing the risk of lactic acidosis should be considered (see section "Special precautions").

If the required dosage strength of vildagliptin/metformin hydrochloride is not available, the individual components should be used instead of a fixed-dose combination.

eGFR mL/min	Metformin	Valdagliptin
60–89	Maximum daily dose — 3,000 mg. In case of reduced kidney function, dose reduction should be considered.	No dose adjustment required.
45–59	Maximum daily dose — 2,000 mg. Initial dose should not exceed half of the maximum dose.	Maximum daily dose — 50 mg.
30–44	Maximum daily dose — 1,000 mg. Initial dose should not exceed half of the maximum dose.
< 30	Metformin is contraindicated.

Patients with hepatic impairment

Galvignia-M should not be used for the treatment of patients with hepatic impairment, including patients in whom ALT or AST levels exceed the ULN by more than 3 times prior to treatment initiation (see sections "Contraindications", "Special precautions", "Adverse reactions").

Children

Galvignia-M is not recommended for use in children and adolescents (under 18 years of age). Safety and efficacy of the medicinal product in children and adolescents have not been established. Data are lacking.

Overdose

There have been no reports of overdose with this medicinal product.

Vildagliptin

Information regarding vildagliptin overdose is limited.

Symptoms. At a dose of 400 mg, three cases of muscle pain were observed, along with isolated cases of mild transient paraesthesia, fever, edema, and transient increase in lipase levels. At a dose of 600 mg, one patient developed swelling of the feet and hands, marked elevation in creatine phosphokinase (CPK) levels, accompanied by increased AST, C-reactive protein, and myoglobin levels. In three other patients receiving the same dose, bilateral foot swelling occurred, accompanied by paraesthesia in two cases. All symptoms and laboratory abnormalities resolved after discontinuation of the investigational drug.

Treatment. In case of overdose, the medicinal product should be discontinued and symptomatic and supportive therapy should be provided. Vildagliptin is not dialyzable, but its major hydrolytic metabolite can be removed by hemodialysis.

Metformin

Symptoms. Significant metformin overdose (or presence of risk factors for lactic acidosis) may lead to lactic acidosis, which requires emergency medical care and treatment in a medical facility.

Treatment

Hemodialysis is the most effective method for removing metformin from the body. However, vildagliptin is not eliminated by hemodialysis, unlike its major hydrolytic metabolite (LAY 151). Supportive therapy is recommended.

Adverse Reactions

Summary of safety profile

Safety data were obtained from a total of 6,197 patients who received vildagliptin/metformin in randomized, placebo-controlled studies. Of these patients, 3,698 received vildagliptin/metformin and 2,499 received placebo/metformin.

Clinical trials specifically evaluating vildagliptin/metformin hydrochloride have not been conducted. However, bioequivalence of the vildagliptin/metformin hydrochloride combination has been demonstrated compared to co-administered separate vildagliptin and metformin formulations (see section "Pharmacological properties").

Most adverse reactions were mild and transient and did not require discontinuation of treatment.

No association was observed between adverse reactions and age, ethnicity, exposure, or daily dose. Use of vildagliptin is associated with a risk of developing pancreatitis. Cases of lactic acidosis have been reported following metformin use, particularly in patients with renal impairment (see section "Special warnings and precautions for use").

List of adverse reactions

Adverse reactions observed in patients treated with vildagliptin in double-blind studies as monotherapy or as add-on therapy are listed below by system organ class and absolute frequency.

The adverse reactions listed in Table 5 are based on data from the Summary of Product Characteristics for metformin available in the EU. The frequency of adverse reactions is categorized as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from available data). Within each row, adverse reactions are listed in decreasing order of severity.

Table 1. Adverse reactions observed in patients treated with vildagliptin and metformin (as individual components or as fixed-dose combination or in combination with other antidiabetic agents) in clinical trials and in the post-marketing period

Adverse Reactions	Frequency
Infections and infestations
Upper respiratory tract infection	Common
Nasopharyngitis	Common
Metabolism and nutrition disorders
Hypoglycemia	Uncommon
Loss of appetite	Uncommon
Decreased vitamin B12 absorption and lactic acidosis	Very rare*
Nervous system disorders
Dizziness	Common
Headache	Common
Tremor	Common
Metallic taste	Uncommon
Gastrointestinal disorders
Vomiting	Common
Diarrhea	Common
Nausea	Common
Gastroesophageal reflux disease	Common
Flatulence	Common
Constipation	Common
Abdominal pain, including upper abdominal pain	Common
Pancreatitis	Uncommon
Hepatobiliary disorders
Hepatitis	Uncommon
Skin and subcutaneous tissue disorders
Hyperhidrosis	Common
Pruritus	Common
Rash	Common
Dermatitis	Common
Erythema	Uncommon
Urticaria	Un游戏副本 Velaglitazin Liver dysfunction Rare cases of liver function abnormalities (including hepatitis) have been reported during treatment with velaglitazin. In these cases, the abnormalities were generally asymptomatic, without clinical consequences, and liver function returned to normal after discontinuation of treatment. According to data from controlled monotherapy and add-on therapy studies of up to 24 weeks, the incidence of ALT or AST elevation ≥ 3 × ULN (at least at two consecutive measurements or at the last on-treatment visit) was 0.2%, 0.3%, and 0.2% with velaglitazin 50 mg once daily, velaglitazin 50 mg twice daily, and all comparator agents, respectively. These transaminase elevations were generally asymptomatic, did not progress, and were not associated with cholestasis or jaundice. Angioedema Rare cases of angioedema have been reported with velaglitazin use, with a frequency similar to that in the control group. A higher incidence of angioedema was observed when velaglitazin was used in combination with an ACE inhibitor. Most events were mild in severity and resolved without discontinuation of velaglitazin therapy. Hypoglycemia Hypoglycemia was an uncommon event with velaglitazin (0.4%) as monotherapy in comparative controlled monotherapy studies with active comparator or placebo (0.2%). No severe or serious cases of hypoglycemia were reported. When velaglitazin was used as add-on to metformin, hypoglycemia occurred in 1% of patients receiving velaglitazin and in 0.4% of those receiving placebo. When pioglitazone was added, hypoglycemia occurred in 0.6% of patients receiving velaglitazin and in 1.9% of those receiving placebo. When a sulfonylurea was added, hypoglycemia occurred in 1.2% of patients receiving velaglitazin and in 0.6% of those receiving placebo. When sulfonylurea and metformin were added, hypoglycemia occurred in 5.1% of patients receiving velaglitazin and in 1.9% of those receiving placebo. In patients receiving velaglitazin in combination with insulin, the incidence of hypoglycemia was 14% in the velaglitazin group and 16% in the placebo group. Metformin Reduced vitamin B12 absorption Reduced vitamin B12 absorption with decreased serum levels has been observed very rarely in patients treated with metformin over a prolonged period. This etiology should be considered if a patient presents with megaloblastic anemia. Liver function Isolated cases of abnormalities in liver function tests or resolution of hepatitis after discontinuation of metformin have been reported. Gastrointestinal disorders Gastrointestinal adverse reactions occur most frequently at the start of therapy and usually resolve spontaneously in most cases. To prevent them, it is recommended to divide the daily dose of metformin into two doses taken during or after meals. Gradual dose escalation may also improve gastrointestinal tolerability. Reporting suspected adverse reactions Reporting of suspected adverse reactions after drug registration is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua. Shelf life. 2 years. Storage conditions. Store at temperatures not exceeding 30°C in the original packaging to protect from moisture. Keep out of reach of children. Packaging. 10 tablets in a blister, 3 or 6 blisters in a cardboard box. Prescription status. Prescription only. Manufacturers. FARMATEN S.A. FARMATEN INTERNATIONAL S.A. Manufacturer's location and address of business activity. 6, Drervenakion, Pallini Attiki, 15351, Greece Industrial Park in the Prefecture of Sapes Rodopi, Block No. 5, Sapes, 69300, Greece