Glipvilo® met

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLYPVILO® MET

Composition:

Active substances: vildagliptin and metformin hydrochloride;

One film-coated tablet contains vildagliptin 50 mg and metformin hydrochloride 850 mg, or vildagliptin 50 mg and metformin hydrochloride 1000 mg.

Excipients: hydroxypropylcellulose, mannitol, sodium stearyl fumarate, magnesium stearate, hypromellose (E 464), titanium dioxide (E 171), talc, propylene glycol, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg/850 mg: brownish-yellow, oval, biconvex film-coated tablets with engraving V1 on one side.

50 mg/1000 mg: brownish-yellow, oval, biconvex film-coated tablets with engraving V2 on one side.

Pharmacotherapeutic group. Antidiabetic agents. Combined oral hypoglycemic agents. ATC code A10BD08.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Glypivilo® MET is a combination of two antihyperglycemic agents with different mechanisms of action that improve glycemic control in patients with type 2 diabetes: vildagliptin, a representative of the incretin enhancer class, and metformin, a member of the biguanide class.

Vildagliptin belongs to the class of agents that enhance pancreatic islet function and is a potent, selective inhibitor of dipeptidyl peptidase-4 (DPP-4). Metformin acts primarily by reducing endogenous glucose production in the liver.

Pharmacodynamic Effects

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). Administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity, leading to increased endogenous levels of the incretin hormones GLP-1 and GIP in both fasting and postprandial states.

As a result of elevated endogenous levels of these incretin hormones, vildagliptin enhances β-cell sensitivity to glucose, thereby increasing glucose-dependent insulin secretion. Treatment with vildagliptin in patients with type 2 diabetes at doses of 50 mg to 100 mg daily significantly improved markers of β-cell function, including HOMA-β (homeostasis model assessment of β-cell function), proinsulin-to-insulin ratio, and β-cell sensitivity indices during repeated meal tolerance tests. In individuals without diabetes (with normal blood glucose levels), vildagliptin does not stimulate insulin secretion or lower glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin also enhances α-cell sensitivity to glucose, resulting in glucose-dependent glucagon secretion. The significant increase in the insulin-to-glucagon ratio during hyperglycemia, driven by elevated incretin hormone levels, leads to reduced hepatic glucose production in both fasting and postprandial states, thereby lowering glycemia.

The known effect of elevated GLP-1 levels in delaying gastric emptying is not observed during treatment with vildagliptin.

Metformin

Metformin is a biguanide with antihyperglycemic activity that reduces both fasting and postprandial plasma glucose levels without stimulating insulin secretion and without causing hypoglycemia or weight gain.

Metformin may reduce glucose levels through three mechanisms:

• Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;
  • Improvement of insulin sensitivity in muscle, leading to enhanced peripheral glucose uptake and utilization;
  • Reduction of intestinal glucose absorption.

Metformin stimulates endogenous glycogen synthesis by acting on glycogen synthase and increases the transport capacity of specific types of glucose membrane transporters (GLUT-1 and GLUT-4).

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

Pharmacokinetics

Vildagliptin/Metformin

Absorption

In a bioequivalence study, the combination of vildagliptin and metformin at doses of 50 mg/500 mg, 50 mg/850 mg, and 50 mg/1000 mg was compared with the combination of monotherapy tablets of vildagliptin and metformin hydrochloride at corresponding doses. Food intake did not affect the rate or extent of absorption of vildagliptin, the active ingredient in Glypivilo® MET. The maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) of metformin hydrochloride were reduced by 26% and 7%, respectively, when the 50 mg/1000 mg combination product was taken with food, and the time to reach maximum concentration (Tmax) was delayed from 2 hours to 4 hours.

The pharmacokinetic properties of the individual active substances in Glypivilo® MET are described below.

Vildagliptin

Absorption

After oral administration on an empty stomach, vildagliptin is rapidly absorbed, with maximum plasma concentration (Cmax) reached within 1.7 hours. Co-administration with food slightly delays the time to reach Cmax to 2.5 hours but does not affect overall exposure (AUC). Administration of vildagliptin with food reduces Cmax by 19%. However, the magnitude of these changes is not considered clinically significant; therefore, vildagliptin can be taken independently of food intake. Absolute bioavailability is 85%.

Distribution

The plasma protein binding of vildagliptin is low (9.3%). Vildagliptin is evenly distributed between plasma and erythrocytes. The mean volume of distribution at steady state (Vss) after intravenous administration is 71 liters, indicating extravascular distribution.

Biotransformation

Metabolism is the main route of elimination of vildagliptin in humans, accounting for 69% of the administered dose. The primary metabolite (LAY151) is pharmacologically inactive and results from hydrolysis of the cyano group, accounting for 57% of the dose, and amide hydrolysis (4% of the dose). DPP-4 partially contributes to the hydrolysis of vildagliptin, as confirmed by in vivo studies in DPP-4-deficient rats. Vildagliptin is not metabolized by cytochrome P450 (CYP450) enzymes to a quantitatively significant extent. Therefore, concomitant administration of drugs that are inhibitors and/or inducers of CYP450 is not expected to affect the metabolic clearance of vildagliptin. In vitro studies have shown that vildagliptin does not inhibit or induce CYP450 enzymes. Thus, vildagliptin does not affect the metabolic clearance of concomitantly administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Elimination

After oral administration of [14C] vildagliptin, approximately 85% of the dose is excreted in urine and 15% in feces. Renal excretion of unchanged vildagliptin accounts for 23% of an orally administered dose. After intravenous administration to healthy volunteers, 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 half-life after oral administration is approximately 3 hours.

Linearity/Non-linearity

Cmax and the area under the plasma concentration–time curve (AUC) of vildagliptin increase almost proportionally with dose within the therapeutic dose range.

Special Patient Populations

Gender

No differences in vildagliptin pharmacokinetics were observed between healthy male and female volunteers of various ages and body mass index (BMI). Inhibition of DPP-4 by vildagliptin is independent of patient gender.

Age

In otherwise healthy elderly patients (≥70 years), total AUC of vildagliptin (100 mg once daily) was increased by 32% and Cmax in plasma by 18% compared to younger healthy volunteers (18–40 years). However, these changes are not considered clinically significant. Inhibition of DPP-4 by vildagliptin is independent of patient age within the studied age groups.

Hepatic Impairment

In patients with mild, moderate, and severe hepatic impairment (Child–Pugh classes A, B, and C), no clinically significant changes in vildagliptin exposure were observed. The maximum change in AUC of vildagliptin was approximately 30%.

Renal Impairment

In patients with mild, moderate, and severe renal impairment, exposure to vildagliptin was increased (Cmax by 8–66%; AUC by 32–134%), and total body clearance was reduced compared to patients with normal renal function.

Race

Limited data suggest that race does not have a significant impact on the pharmacokinetics of vildagliptin.

Metformin

Absorption

After oral administration, the time to reach maximum plasma concentration (Cmax) of metformin is approximately 2.5 hours. The absolute bioavailability of the 500 mg tablet formulation of metformin is approximately 50–60% in healthy volunteers. The fraction not absorbed and excreted in feces after oral administration is 20–30%.

After oral administration, absorption of metformin is saturable and incomplete. The absorption pharmacokinetics of metformin are assumed to be nonlinear. 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 studies, maximum plasma levels (Cmax) of metformin did not exceed 4 µg/mL, even with maximum recommended doses.

Concomitant food intake reduces and slightly delays the absorption of metformin.

After oral administration of an 850 mg dose, a 40% reduction in maximum plasma concentration, a 25% decrease in AUC, and a 35-minute increase in time to reach maximum plasma concentration were observed. The clinical significance of these changes is unknown.

Distribution

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. The mean volume of distribution (Vd) ranges from 63 to 276 L.

Metabolism

Metformin is excreted unchanged in urine. No metabolites have been identified in humans.

Elimination

Metformin is excreted by the kidneys. Renal clearance of metformin exceeds 400 mL/min, indicating that metformin is eliminated by both glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged half-life and increased plasma levels of metformin.

Clinical characteristics.

Indications.

Glypivilo® MET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus:

• in patients with inadequate glycemic control on metformin hydrochloride alone;
• in patients already treated with vildagliptin and metformin hydrochloride as monotherapy;
• in combination with other antidiabetic medicinal products, including insulin, when treatment does not provide adequate glycemic control (for available data on various combinations, see sections “Pharmacokinetics”, “Interaction with other medicinal products and other forms of interaction”, and “Special precautions for use”).

Contraindications.

Hypersensitivity to vildagliptin or metformin or to any of the excipients of the medicinal product.

Any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis).

Diabetic precoma.

Severe renal impairment (glomerular filtration rate < 30 mL/min) (see section **“**Special precautions for use”).

Acute conditions associated with a risk of renal function impairment, such as:

• dehydration;
• severe infections;
• shock;
• intravascular administration of iodinated contrast agents (see section **“**Special precautions for use”).

Acute or chronic conditions that may lead to hypoxia, such as:

• cardiac or respiratory failure;
• recent myocardial infarction;
• shock.

Hepatic impairment (see sections “Posology and method of administration”, **“**Special precautions for use”, and “Undesirable effects”).

Acute alcohol intoxication, alcoholism.

Breastfeeding period (see section “Use during pregnancy or lactation”).

Interaction with other medicinal products and other forms of interaction.

No formal drug interaction studies have been conducted with Glypivilo® MET. The information below refers to the interactions of vildagliptin and metformin separately.

Vildagliptin

Vildagliptin has a low potential for interaction with other concurrently administered medicinal products. Since vildagliptin is not a substrate of cytochrome P (CYP450) enzymes and is neither an inhibitor nor an inducer of CYP450 enzymes, clinically relevant interactions with other medicinal products that are substrates, inhibitors, or inducers of these enzymes are unlikely.

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

Studies in healthy volunteers did not reveal clinically significant pharmacokinetic interactions when vildagliptin was co-administered with digoxin (a P-glycoprotein substrate) and warfarin (a CYP2C9 substrate).

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

Combination with angiotensin-converting enzyme (ACE) inhibitors

In patients taking ACE inhibitors concomitantly, there may be an increased risk of angioedema (see section “Undesirable effects”).

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

Metformin

Combinations not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly after fasting, undernutrition, or impaired liver function.

Administration of iodinated contrast agents

Metformin should be discontinued before or at the time of the procedure and not restarted earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of stable renal function (see sections “Special precautions for use” and “Posology and method of administration”).

Combinations requiring caution

Some medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, ACE inhibitors, angiotensin II receptor antagonists, and diuretics, particularly loop diuretics, may adversely affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when these medicinal products are used concomitantly with metformin.

Glucocorticoids, β-2 antagonists, and diuretics have a hyperglycemic effect. Patients should be informed and blood glucose levels monitored more frequently, especially at the beginning of treatment. The dose of Glypivilo® MET should be adjusted during and after concomitant therapy.

ACE inhibitors may reduce blood glucose levels. The dose of Glypivilo® MET should be adjusted during and after concomitant therapy.

Concomitant use of medicinal products that affect glomerular and renal tubular transport systems (e.g., inhibitors of organic cation transporter-2 [OCT2]/multidrug and toxin extrusion proteins [MATE], such as ranolazine, vandetanib, dolutegravir, and cimetidine) may reduce renal excretion of metformin, leading to increased plasma concentrations of metformin.

Special precautions for use.

Glibivlo® MET is not a substitute for insulin in insulin-dependent patients. The drug should not be used to treat patients with type 1 diabetes.

Lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring with acute worsening of renal function, cardiopulmonary diseases, or sepsis. Acute worsening of renal function leads to accumulation of metformin, increasing the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended and medical advice should be sought.

Patients taking metformin should start treatment with drugs that may acutely impair renal function (e.g., antihypertensive agents, diuretics, and NSAIDs) with caution. Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients and/or caregivers should be informed about the risk of developing lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia; coma may subsequently develop. If any symptoms of lactic acidosis occur, patients should discontinue metformin and seek immediate medical attention.

Diagnostic laboratory findings: decreased blood pH (< 7.35), elevated plasma lactate concentration in serum (> 5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Patients with established or suspected mitochondrial disorders

Metformin is not recommended in patients with established mitochondrial disorders such as mitochondrial encephalopathy with 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 worsen the course of the disease.

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

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued before or during the procedure and not resumed earlier than 48 hours after the procedure, only after re-evaluation and confirmation of stable renal function (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Renal impairment

Glomerular filtration rate (GFR) should be assessed before initiating treatment and regularly thereafter (see section "Dosage and administration"). Metformin is contraindicated in patients with GFR < 30 mL/min and should be temporarily discontinued in the presence of conditions altering renal function (see section "Contraindications").

Concomitant medicinal products that may affect renal function should be used with caution, as they may cause significant hemodynamic changes or reduce renal elimination of metformin, leading to increased plasma metformin concentrations (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment

Glibivlo® MET is not recommended for use in patients with hepatic impairment, as well as in patients whose alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceeded the upper limit of normal (ULN) by more than 3 times before treatment (see sections "Contraindications", "Dosage and administration", and "Undesirable effects").

Monitoring of liver function tests

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin use. In these cases, the course of the complication was mostly asymptomatic and without clinical consequences, and liver function test (LFT) results returned to normal after discontinuation of the drug. Prior to initiating Glibivlo**®** MET, LFTs should be performed to establish baseline values in the patient. Monitoring of LFTs is recommended during treatment and for the first year of therapy at 3-month intervals, and periodically thereafter.

Patients who show elevated transaminase levels should undergo repeat liver function testing to confirm positive results, followed by continued monitoring with frequent LFTs until values return to normal. If ALT or AST levels exceed ULN by more than 3 times, discontinuation of Glibivlo**®** MET is recommended. Patients who develop jaundice or other signs of hepatic dysfunction should discontinue Glibivlo**®** MET. After discontinuation of treatment and normalization of LFT results, re-initiation of Glibivlo**®** MET therapy is not recommended.

Skin disorders

In preclinical toxicological studies with vildagliptin, skin lesions including blistering and ulcers on extremities were reported in monkeys. Although no increased incidence of skin lesions was observed during clinical trials, experience regarding skin complications in patients with diabetes is limited. Furthermore, during the post-marketing period, cases of bullous and exfoliative skin reactions have been reported. Therefore, in accordance with standard care for patients with diabetes, monitoring for skin disorders such as blistering or ulceration is recommended.

Acute pancreatitis

The use of vildagliptin has been associated with a risk of acute pancreatitis. Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed, vildagliptin therapy should not be resumed. Caution should be exercised in patients with a history of acute pancreatitis.

Hypoglycemia

It is known that sulfonylureas may cause hypoglycemia. Patients taking vildagliptin in combination with sulfonylurea derivatives may be at risk of hypoglycemia. Therefore, to reduce the risk of hypoglycemia, lower doses of sulfonylureas may be considered.

Surgery

Since Glibivlo**®** MET contains metformin, treatment with this drug should be discontinued 48 hours prior to elective surgical procedures involving general, spinal, or epidural anesthesia. Therapy should not be resumed earlier than 48 hours after surgery or restoration of oral nutrition, provided renal function is normal.

Sodium

The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate studies on the use of Glibivlo**®** MET in pregnant women. Animal studies have shown reproductive toxicity with high doses of vildagliptin. Animal studies with metformin did not show reproductive toxicity. Animal studies using vildagliptin and metformin did not reveal teratogenic effects, but fetotoxic effects were observed at doses toxic to pregnant animals. The potential risk to humans is unknown. Glibivlo**®** MET should not be used during pregnancy.

Breastfeeding

Animal studies have shown excretion of vildagliptin and metformin into breast milk. It is unknown whether vildagliptin is excreted in human breast milk, but metformin is excreted in small amounts into human breast milk. Considering the potential risk of hypoglycemia in newborns associated with metformin and the lack of data on the effects of vildagliptin, Glibivlo**®** MET should not be administered to breastfeeding women (see section "Contraindications").

Fertility

No studies on the effect of the medicinal product on human fertility have been conducted.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Patients experiencing dizziness should avoid driving or operating machinery.

Dosage and Administration.

Adult patients with normal renal function (eGFR ≥ 90 mL/min)

The dosage of antihyperglycemic therapy with Glipvilo**®** MET should be individually adjusted according to the patient's current treatment regimen, efficacy, and tolerability, and the maximum recommended daily dose of vildagliptin (100 mg) should not be exceeded. Treatment with Glipvilo**®** MET should 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.

• Patients whose condition is not adequately controlled on monotherapy with metformin at the maximum tolerated doses: the initial dose of Glipvilo**®** MET should consist of vildagliptin 50 mg twice daily (total daily dose – 100 mg) and metformin at the dose the patient is already receiving.
• Patients switching from concomitant treatment with vildagliptin and metformin as monotherapies: the initial dose of Glipvilo**®** MET should correspond to the doses of vildagliptin and metformin the patient is already taking.
• Patients whose condition is not adequately controlled on dual therapy with metformin and a sulfonylurea: the recommended dose of Glipvilo**®** MET should correspond to a vildagliptin dose of 50 mg twice daily (total daily dose – 100 mg) and a metformin dose equivalent to the one the patient is already receiving. When used in combination with a sulfonylurea, lower doses of the sulfonylurea may be considered to reduce the risk of hypoglycemia.
• Patients whose condition is not adequately controlled on dual therapy with insulin and the maximum tolerated dose of metformin: the dose of Glipvilo**®** MET should correspond to a vildagliptin dose of 50 mg twice daily (total daily dose – 100 mg) and a metformin dose equivalent to the one the patient is already receiving.

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

Special patient groups

Elderly patients (≥ 65 years)

Since metformin is excreted by the kidneys and elderly patients tend to have reduced renal function, renal function should be regularly monitored in these patients when using Glipvilo**®** MET (see sections "Pharmacokinetics" and "Special precautions").

Patients with renal impairment

eGFR should be assessed before initiating therapy with metformin-containing medicinal products and during treatment, at least once a year. Patients at increased risk of further progression of renal impairment and elderly patients should have their renal function closely monitored more frequently, for example every 3–6 months.

The maximum daily dose of metformin should be divided into 2–3 doses. Before initiating metformin therapy in patients with eGFR < 60 mL/min, factors that may increase the risk of lactic acidosis should be considered (see section "Special precautions").

If the required dosage strength of Glipvilo**®** MET is not available, individual monocomponents should be used instead of the fixed-dose combination.

Glomerular filtration rate (mL/min)	Metformin	Vildagliptin
60−89	Maximum daily dose 3000 mg. In case of renal function impairment, dose reduction should be considered.	No dose adjustment required.
45−59	Maximum daily dose 2000 mg. Initial dose should not exceed half of the maximum dose.	Maximum daily dose 50 mg.
30−44	Total maximum daily dose 1000 mg. Initial dose should not exceed half of the maximum dose.
< 30	Metformin is contraindicated.

Patients with hepatic impairment

Glypivilo**®** MET is not recommended for use in patients with hepatic impairment, including patients in whom ALT or AST levels exceeded the ULN by more than 3 times prior to treatment (see sections "Contraindications", "Special precautions", and "Adverse reactions").

Method of administration

For oral use.

Glypivilo**®** MET taken during or immediately after a meal may reduce gastrointestinal symptoms associated with metformin use (see section "Pharmacokinetics").

Children

Glypivilo**®** MET is not recommended for use in children and adolescents under 18 years of age due to lack of data on safety and efficacy.

Overdose

There are no data on overdose with Glypivilo**®** MET.

Vildagliptin

Information on vildagliptin overdose is limited.

Symptoms

Information on potential overdose symptoms was obtained from a high-dose tolerability study in healthy volunteers who received vildagliptin for 10 days. At a dose of 400 mg vildagliptin, three cases of muscle pain were observed, along with isolated cases of mild and transient paraesthesia, fever, development of edema, and transient elevation of lipase levels. At a dose of 600 mg, one patient experienced swelling of the feet and hands, as well as a significant increase in creatine phosphokinase (CPK) levels, accompanied by increased AST, C-reactive protein, and myoglobin levels. In three other patients, bilateral foot swelling was observed, with paraesthesia in two additional cases. All symptoms and laboratory abnormalities resolved after discontinuation of the investigational drug.

Metformin

Significant overdose of metformin or concomitant risk factors may lead to lactic acidosis, which is a medical emergency requiring hospitalization and treatment.

Treatment

Hemodialysis is the most effective method for removing metformin. However, vildagliptin is not eliminated by hemodialysis, although most hydrolysis metabolites (LAY 151) can be removed. In case of overdose, 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.

There have been no therapeutic clinical studies conducted with vildagliptin/metformin hydrochloride. However, bioequivalence has been demonstrated between the fixed-dose combination of vildagliptin/metformin hydrochloride and the separate co-administration of vildagliptin and metformin (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 reported during double-blind studies in patients receiving vildagliptin as monotherapy or in combination therapy are listed below, categorized by system organ class and absolute frequency for each reaction. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (> 1/10,000, ≤ 1/1,000), very rare (≤ 1/10,000), frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

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

System organ and adverse reactions	Frequency
Infections and infestations
Upper respiratory tract infections	Common
Nasopharyngitis	Common
Metabolism and nutrition disorders
Hypoglycemia	Uncommon
Loss of appetite	Uncommon
Reduced 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 abdomen	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 Velidagliptin Hepatic impairment Rare cases of liver function abnormalities (including hepatitis) have been reported with the use of velidagliptin. 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 combination therapy studies of up to 24 weeks duration, the incidence of ALT or AST elevations ≥ 3 × ULN (at least at two consecutive measurements or at the last treatment visit) was 0.2%, 0.3%, and 0.2% with velidagliptin 50 mg once daily, velidagliptin 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 velidagliptin use, with a frequency similar to that in the control group. A higher incidence of angioedema events was observed when velidagliptin was used in combination with an ACE inhibitor. The events were mainly mild in severity and resolved with continued treatment with velidagliptin. Hypoglycemia Hypoglycemia was an uncommon event with velidagliptin (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 velidagliptin was used as add-on to metformin, hypoglycemia occurred in 1% of patients receiving velidagliptin and in 0.4% of patients receiving placebo. When pioglitazone was added, hypoglycemia occurred in 0.6% of patients receiving velidagliptin and in 1.9% of patients receiving placebo. When a sulfonylurea was added, hypoglycemia occurred in 1.2% of patients receiving velidagliptin and in 0.6% of patients receiving placebo. When a sulfonylurea and metformin were added, hypoglycemia occurred in 5.1% of patients receiving velidagliptin and in 1.9% of patients receiving placebo. In patients receiving velidagliptin in combination with insulin, the incidence of hypoglycemia was 14% in the velidagliptin group and 16% in the placebo group. Metformin Vitamin B12 absorption Very rare cases of decreased vitamin B12 absorption with reduced serum levels have been observed in patients treated with metformin over a long period. This etiology should be considered if a patient presents with megaloblastic anemia. Liver function Isolated cases of liver function test abnormalities 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. To prevent them, it is recommended to divide the daily dose of metformin into two doses taken with or after meals. Gradual dose escalation may also improve gastrointestinal tolerability. Reporting of suspected adverse reactions. Reporting of adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua. Shelf life. 2 years. Storage conditions. Store in the original packaging to protect from moisture. Store at temperatures not exceeding 30 °C. Keep out of reach of children. Packaging. 10 tablets per blister; 3 or 6 blisters per cardboard box. Prescription status. Prescription only. Manufacturer. KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia. TAD Pharma GmbH, Germany. Manufacturer's address and location of operations. Šmarješka cesta 6, 8501 Novo mesto, Slovenia/Smarješka cesta 6, 8501 Novo mesto, Slovenia. Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany/Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany.