Gliptar®-m

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLIPTAR®-M (GLIPTAR-M)

Composition:

Active substances: metformin, vildagliptin;

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

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

Excipients: lactose, hydroxypropylcellulose, microcrystalline cellulose, sodium croscarmellose, stearyl fumarate;

film-coating mixture contains: hypromellose, titanium dioxide (E 171), polyethylene glycol/PEG, talc, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties:

Film-coated tablets, 50 mg/850 mg: yellow, oval, film-coated tablets with a score line 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 line between "V" and "B" on one side and a score line on the other side. Tablet length: 21.1±0.5 mm.

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

Pharmacological Properties.

Pharmacodynamics.

Gliptar®-M is a combination of two antihyperglycemic agents with complementary 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 DPP-4 inhibitor. Metformin acts primarily by reducing 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 rapid and complete elevation of endogenous levels of the incretin hormones GLP-1 and GIP after both food intake and fasting.

By increasing endogenous levels of these incretin hormones, vildagliptin enhances the glucose sensitivity of beta cells, thereby improving glucose-dependent insulin secretion. Treatment of patients with type 2 diabetes with vildagliptin at doses of 50 to 100 mg daily significantly improved markers of beta-cell function, including HOMA-β (homeostasis model assessment of beta-cell function), proinsulin-to-insulin ratio, and beta-cell sensitivity 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 the glucose sensitivity of pancreatic alpha cells, thereby increasing glucose-responsive glucagon secretion. The enhanced insulin-to-glucagon ratio during hyperglycemia results in increased incretin hormone activity, leading to reduced hepatic glucose production in both fasting and postprandial states, thus lowering glucose levels.

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

Metformin Hydrochloride

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 via three mechanisms:

• Hepatic glucose production largely contributes to fasting hyperglycemia. Metformin reduces hepatic glucose production, which is enhanced by insulin resistance, by inhibiting gluconeogenesis and glycogenolysis, thereby counteracting the hyperglycemic effect of glucagon. This mechanism enables metformin to reduce fasting hyperglycemia.
• Impaired peripheral glucose uptake and utilization primarily contribute to postprandial hyperglycemia. Metformin enhances cellular insulin sensitivity by stimulating tyrosine kinase activity of insulin receptors, thus promoting cellular glucose uptake. Metformin increases the transport capacity of all cellular glucose transporters (GLUT). This effect of metformin is particularly evident during hyperglycemia. Intracellular glycogen synthesis is increased by stimulation of the key enzyme glycogen synthase. This mechanism enables metformin to reduce postprandial hyperglycemia.
• Metformin reduces glucose absorption in the intestinal tract, thereby reducing the 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 lipoproteins, and triglycerides.

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

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

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

Clinical Efficacy and Safety

Vildagliptin was administered to patients whose glycemic control was inadequate with metformin monotherapy, resulting in an additional statistically significant mean reduction in HbA1c levels 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 HbA1c reduction ≥ 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 who did not achieve adequate glycemic control with metformin (mean daily dose: 2020 mg). The mean reduction from baseline HbA1c of 8.4% was -0.9% in the vildagliptin + metformin group and -1.0% in the pioglitazone + metformin group. Mean body weight gain of +1.9 kg was observed in patients receiving pioglitazone + metformin compared to +0.3 kg in those receiving vildagliptin + metformin.

In a 52-week study, vildagliptin (50 mg twice daily) was compared with glipizide (mean daily dose: 229.5 mg) in patients who did not achieve adequate glycemic control with metformin (baseline 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 glipizide + metformin group (mean baseline HbA1c 8.5%); statistical non-inferiority was achieved (95% CI -0.11 to 0.20). Weight gain with vildagliptin was +0.1 kg compared to +1.4 kg with glipizide.

In a 24-week study evaluating the efficacy of fixed-dose combination vildagliptin/metformin (with gradual titration to 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy 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 assessing the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥1500 mg daily) and glimepiride (≥4 mg daily) (318 patients) showed that vildagliptin in combination with metformin and glimepiride significantly reduced HbA1c compared to placebo. The mean placebo-corrected reduction from a mean baseline HbA1c of 8.8% was -0.76%.

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 stable doses of basal or mixed insulin (mean daily dose 41 units) with or without concomitant metformin (N = 276) or without metformin (N = 173). Vildagliptin in combination with insulin significantly reduced HbA1c compared to placebo. In the overall population, the mean placebo-corrected reduction from a mean baseline HbA1c of 8.8% was -0.72%. In subgroups receiving insulin with or without metformin, the mean placebo-corrected HbA1c reductions were -0.63% and -0.84%, respectively. Hypoglycemia incidence in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients receiving vildagliptin showed no body weight gain (+0.2 kg), whereas those receiving placebo experienced weight loss (-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 to initial monotherapy with metformin followed by addition of vildagliptin (sequential therapy 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 reduction in the risk of "time to confirmed initial treatment failure" (HbA1c ≥7%) compared to metformin monotherapy in previously untreated patients with type 2 diabetes, over a 5-year study period (HR [95% CI]: 0.51 [0.45, 0.58]; p<0.001). The frequency of initial treatment failure (HbA1c ≥7%) was 429 (43.6%) patients in the combination therapy group and 614 (62.1%) patients in the sequential therapy group.

In another 24-week study in patients with more advanced type 2 diabetes inadequately controlled by insulin (short- and long-acting, mean insulin dose 80 IU/day), the mean reduction in HbA1c with vildagliptin (50 mg twice daily) added to insulin was statistically significantly greater than with placebo added to 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 clinical trials of monotherapy and combination therapy lasting over 2 years (mean exposure 50 weeks for vildagliptin and 49 weeks for comparators) showed that treatment with vildagliptin was not associated with an increased cardiovascular risk compared to comparators. The composite endpoint of major adverse cardiovascular events (MACE), including acute myocardial infarction, stroke, or cardiovascular death, was similar for vildagliptin compared to comparators and placebo [Mantel-Haenszel risk ratio (M-H RR) 0.82 (95% CI 0.61–1.11)]. MACE occurred in 83 of 9599 (0.86%) patients receiving vildagliptin and in 85 of 7102 (1.20%) patients in the comparator group. Assessment of each individual MACE component did not show increased risk (similar M-H RR). Confirmed cases of heart failure (HF), defined as HF requiring hospitalization or new-onset HF, were reported in 41 (0.43%) patients receiving vildagliptin and in 32 (0.45%) patients receiving the comparator, with M-H RR 1.08 (95% CI 0.68–1.70).

Pharmacokinetics.

Absorption

Vildagliptin with Metformin

In a bioequivalence study, vildagliptin with metformin tablets at different strengths (50 mg/500 mg, 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 vildagliptin with metformin tablets. The maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of metformin hydrochloride were reduced by 26% and 7%, respectively, when vildagliptin with metformin 50 mg/1000 mg was taken with food, and the time to reach maximum concentration (Tmax) was delayed (from 2.0 to 4.0 hours).

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

Vildagliptin

Absorption. After oral administration on an empty stomach, vildagliptin is rapidly absorbed, with Cmax observed at 1.7 hours. Concomitant food intake slightly delays the time to reach Cmax in plasma—to 2.5 hours—but does not affect total exposure (AUC). Administration of vildagliptin with food results in a 19% reduction in maximum concentration (Cmax). Despite this, the magnitude of changes is not clinically significant; therefore, vildagliptin can be administered regardless of food intake. Absolute bioavailability is 85%.

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

Metabolism. Metabolism is the main elimination pathway of vildagliptin in humans, accounting for 69% of the administered dose. The primary metabolite (LAY151) is pharmacologically inactive and results from hydrolysis of the cyanide moiety, accounting for 57% of the dose, along with glucuronide (BQS867) and amide hydrolysis (4% of dose). Data obtained from in vitro studies using human kidney microsomes indicate that the kidneys may be one of the main organs responsible for hydrolysis of vildagliptin to its primary inactive metabolite LAY151. DPP-4 partially participates in the hydrolysis of vildagliptin, as confirmed by in vivo studies in DPP-4-deficient rats.

Vildagliptin is not metabolized by cytochrome P450 enzymes to a clinically significant extent. Therefore, concomitant administration of drugs such as inhibitors and/or inducers of CYP450 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. Thus, vildagliptin is unlikely to affect the metabolic clearance of concomitantly administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Excretion. 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 the 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 elimination half-life after oral administration is approximately 3 hours.

Linearity/Non-linearity. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of vildagliptin increase almost proportionally with dose across the entire therapeutic dose range.

Special Patient Populations.

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

Elderly Patients. In healthy elderly subjects (aged 70 years and older), total exposure to vildagliptin (100 mg once daily) increased by 32% and maximum plasma concentration by 18% compared to younger healthy volunteers (aged 18 to 40 years).

These changes, however, are not considered clinically significant. DPP-4 inhibition by vildagliptin is independent of patient age in the studied age groups.

Hepatic Impairment. In patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A-C), no clinically significant changes (maximum ~30%) in vildagliptin exposure were observed.

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 individuals 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 concentration (Cmax) of metformin is approximately 2.5 hours (Tmax). The absolute bioavailability of the 500 mg metformin tablet formulation is approximately 50–60% in healthy volunteers. The fraction of orally administered metformin that is unabsorbed and excreted in feces is 20–30%.

After oral administration, metformin absorption is saturable and incomplete.

Non-linear absorption of metformin is expected. 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 plasma concentrations (Cmax) of metformin did not exceed 4 µg/mL even at maximum doses.

Concomitant food intake reduces and slightly delays metformin absorption.

After oral administration of 850 mg, a 40% reduction in maximum plasma concentration, a 25% reduction in AUC, and a 35-minute increase in time to 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.

Excretion.

Metformin is excreted via renal excretion. Renal clearance of metformin exceeds 400 mL/min, indicating that metformin is eliminated by 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, thus prolonging the elimination half-life and leading to increased plasma metformin levels.

Clinical characteristics.

Indications.

Glyptar®-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 whose glucose levels are not adequately controlled with metformin monotherapy;
• in adult patients already receiving the combination of vildagliptin and metformin as separate tablets;
• in combination with other antidiabetic medicinal products, including insulin, when they do not provide adequate glucose control (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics").

Contraindications.

• hypersensitivity to vildagliptin, metformin, or to any of the excipients;
• any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis);
• diabetic precoma;
• renal insufficiency or impaired renal function (creatinine clearance <30 mL/min) (see section "Special precautions for use");
• acute conditions that may alter renal function, such as dehydration, severe infection, shock, or intravascular administration of iodinated contrast agents (see section "Special precautions for use");
• acute or chronic conditions that may lead to tissue hypoxia, such as cardiac or respiratory failure, recent myocardial infarction, or shock;
• hepatic impairment (see sections "Special precautions 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 forms of interaction.

Drug interaction studies of the vildagliptin and metformin combination product have not been conducted. Information below refers to interactions of the individual active substances, vildagliptin and metformin, separately.

Vildagliptin

Vildagliptin has a low potential for interactions with concomitantly administered medicinal products. Since vildagliptin is not a substrate of cytochrome P (CYP) 450 enzymes and does not inhibit or induce CYP450 enzymes, clinically relevant interactions with substrates, inhibitors, or inducers of these enzymes are unlikely.

Clinical studies have been conducted with oral antidiabetic agents in patients with type 2 diabetes or with drugs having a narrow therapeutic window. These studies did not show clinically significant pharmacokinetic interactions with oral antidiabetic agents (glyburide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan, or warfarin.

Use with ACE inhibitors

Patients taking angiotensin-converting enzyme (ACE) inhibitors concomitantly may have an increased risk of angioedema (see section "Adverse reactions").

As with other oral antidiabetic medicinal products, the hypoglycemic effect of vildagliptin may be reduced when used concomitantly with other medicinal products, including thiazides, corticosteroids, thyroid hormones, and sympathomimetics.

Metformin

Not recommended combinations

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

Iodinated contrast agents. Metformin should be discontinued before or during radiological procedures involving intravascular administration of iodinated contrast agents and should not be restarted for at least 48 hours thereafter, provided that renal function has been reassessed and found to be stable (see sections "Method of administration and dosage", "Special precautions for use").

Combinations requiring caution

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

Glucocorticoids, beta-2 agonists, and diuretics have intrinsic hyperglycemic activity. Patients should be informed of the need for more frequent blood glucose monitoring, especially at the beginning of treatment. The dosage of Glyptar®-M may need to be adjusted during concomitant therapy, if necessary.

Angiotensin-converting enzyme (ACE) inhibitors may reduce blood glucose levels. If necessary, the dosage of antihyperglycemic medicinal products should be adjusted during concomitant therapy.

Concomitant use of medicinal products that affect common renal tubular transport systems may influence the elimination of metformin via the kidneys (e.g., organic cation transporter-2 [OCT2]/MATE transporter [MATE], such as ranolazine, vandetanib, dolutegravir, and cimetidine), potentially increasing systemic exposure to metformin.

Special precautions for use.

General

Gliptar®-M does not replace 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 commonly occurs in association with impaired kidney function, cardiorespiratory disorders, or sepsis. Accumulation of metformin occurs in acute kidney dysfunction and increases the risk of lactic acidosis.

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

Medicinal products that may cause acute kidney dysfunction (such as antihypertensive agents, diuretics, and NSAIDs) should be prescribed with caution in patients receiving metformin. 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 induce 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. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, hypothermia, and may progress to coma. If symptoms of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention. Laboratory diagnosis includes decreased blood pH (<7.35), elevated plasma lactate levels (>5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Use 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. Therefore, due to the presence of metformin, Gliptar®-M should be discontinued prior to or during such procedures and should not be restarted until at least 48 hours after the procedure, and only if kidney function remains normal.

Radiological examinations

Intravascular administration of iodinated contrast agents during radiological procedures may lead to acute kidney dysfunction. Therefore, due to the presence of metformin, Gliptar®-M should be discontinued prior to or during such procedures and should not be restarted until at least 48 hours after the procedure, and only if kidney function remains normal.

Renal impairment

eGFR should be assessed before initiating treatment and monitored regularly during therapy (see section "Dosage and administration"). Metformin is contraindicated in patients with eGFR <30 mL/min, and temporary discontinuation is recommended in the presence of conditions affecting kidney function (see section "Contraindications").

Use with caution when co-administering medicinal products that may affect kidney function, cause significant hemodynamic changes, or inhibit renal transport and thereby increase systemic exposure to metformin (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment

Vildagliptin should not be used to treat 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 (see sections "Contraindications", "Dosage and administration", "Adverse reactions").

Monitoring of liver enzymes

Rare cases of hepatic dysfunction (including hepatitis) have been reported during vildagliptin use. In these cases, patients typically did not exhibit symptoms or clinical complications, and liver function tests (LFTs) returned to normal after discontinuation of treatment. Prior to initiating Gliptar®-M, LFTs should be performed to establish baseline values. 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 more frequent LFT monitoring until values return to normal. If AST and ALT levels remain persistently elevated more than 3 times above ULN, discontinuation of Gliptar®-M is recommended. Patients who develop jaundice or other signs suggestive of hepatic dysfunction should discontinue Gliptar®-M.

After discontinuation of Gliptar®-M and normalization of LFTs, reinitiation of therapy with this drug is not recommended.

Skin disorders

In preclinical toxicological studies with vildagliptin, skin lesions including blistering and ulceration on the extremities of monkeys were reported. Although clinical trials did not show an increased incidence of skin lesions, 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 abnormalities such as blistering or ulceration is recommended.

Acute pancreatitis

Post-marketing surveillance has reported adverse events of acute pancreatitis. Patients should be informed about the characteristic symptom of acute pancreatitis—persistent, severe abdominal pain.

Pancreatitis symptoms resolved after discontinuation of vildagliptin. If acute pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed, vildagliptin should not be reinitiated. Use with caution in patients with a history of acute pancreatitis.

Hypoglycemia

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

Surgery

Since Gliptar®-M contains metformin, treatment should be discontinued 48 hours prior to elective surgery involving general, spinal, or epidural anesthesia and should not be resumed earlier than 48 hours after surgery (provided kidney function is normal and oral intake has resumed).

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 using a combination of vildagliptin and metformin did not reveal teratogenic effects, but fetotoxic effects were observed at doses toxic to pregnant dams. The potential risk in humans is unknown. Gliptar®-M should not be used during pregnancy.

Breastfeeding

Animal studies have shown excretion of both metformin and vildagliptin into milk. It is known that metformin is excreted into human breast milk in small amounts. Considering 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 who are breastfeeding.

Fertility

Studies on the effects of vildagliptin with metformin on human fertility have not been conducted.

Effect on ability to drive and use machines.

No studies on the effect of the medicinal product on the ability to drive and use machines have been conducted. Therefore, patients who may experience dizziness should avoid driving or operating machinery.

Dosage and Administration

The dosage of antihyperglycemic therapy for the control of type 2 diabetes should be individually selected based on the current treatment regimen, efficacy, and tolerability. When using Gliptar®-M, the maximum daily dose of vildagliptin (100 mg) must not be exceeded. Gliptar®-M tablets should be taken twice daily, in the morning and evening.

Administration

For oral use.

Taking Gliptar®-M with food or immediately after meals may reduce gastrointestinal symptoms associated with metformin use.

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

The initial dose of Gliptar®-M should consist of vildagliptin 50 mg twice daily (total daily dose – 100 mg) and metformin at the dose the patient is already receiving.

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

The initial dose of Gliptar®-M should correspond to the previously administered doses of vildagliptin and metformin.

For patients whose condition is not adequately controlled on metformin and sulfonylurea agents.

The initial dose of Gliptar®-M should consist of vildagliptin 50 mg twice daily (total daily dose – 100 mg) and metformin at 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.

Use in combination with insulin and maximum tolerated doses of metformin.

The initial dose of Gliptar®-M should consist of vildagliptin 50 mg twice daily (total daily dose – 100 mg) and metformin at the dose the patient is already receiving.

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 (aged 65 years and older)

Since metformin is eliminated via the kidneys and elderly patients tend to have reduced renal function, regular monitoring of renal function is required during treatment with Gliptar®-M.

Renal impairment

eGFR should be assessed before initiating treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in elderly patients, renal function should be assessed more frequently, e.g., every 3–6 months.

The maximum daily dose of metformin should preferably be divided into 2–3 daily doses. Before initiating treatment with metformin-containing products in patients with eGFR <60 mL/min, the presence of factors that may increase the risk of lactic acidosis should be evaluated (see section "Special Warnings and Precautions for Use"). The need for metformin therapy should be reassessed in such patients.

If the required dosage strength of Gliptar®-M is not available, individual monotherapy agents should be used instead of the fixed-dose combination.

eGFR mL/min	Metformin	Velagliflozin
60-89	Maximum daily dose is 3000 mg. Dose reduction may be considered with decreasing renal function.	No need for dose adjustment.
45-59	Maximum daily dose is 2000 mg. Initial dose should be at most half of the maximum dose.	Maximum daily dose - 50 mg.
30-44	Maximum daily dose is 1000 mg. Initial dose should be at most half of the maximum dose.
<30	Metformin is contraindicated.

Hepatic impairment

Gliptar®-M should not be used to treat patients with hepatic impairment, including patients in whom baseline ALT or AST levels exceed the ULN by more than 3 times.

Children

Gliptar®-M is not recommended for use in children and adolescents (under 18 years of age). Safety and efficacy in pediatric patients have not been established. Data are lacking.

Overdose

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

Vildagliptin

Information on vildagliptin overdose is limited.

Symptoms

Information on the potential symptoms of vildagliptin overdose was obtained from a rising-dose tolerance study in healthy subjects who received vildagliptin for 10 days. At a dose of 400 mg, there were three cases of muscle pain, as well as isolated cases of mild and transient paraesthesia, fever, oedema, and transient elevation of lipase levels. At a dose of 600 mg, one subject experienced swelling of the legs and hands and increased levels of creatine phosphokinase (CPK), AST, C-reactive protein (CRP), and myoglobin. In three other subjects, leg oedema was observed, and paraesthesia occurred in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the investigational medicinal product.

Metformin

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

Treatment

In case of overdose, the medicinal product should be discontinued and symptomatic and supportive treatment should be provided. Hemodialysis is the most effective method for removing metformin. Vildagliptin is not dialyzable, but the primary hydrolytic metabolite of vildagliptin can be removed by hemodialysis.

Adverse Reactions

The data presented below refer to the concomitant use of vildagliptin and metformin when vildagliptin was added to metformin.

Safety Profile Summary

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

There was no observed association between adverse reactions and age, ethnicity, duration of treatment, or daily dose.

Rare cases of liver function disorders (including hepatitis) have been reported with vildagliptin use. These were generally asymptomatic, had no clinical consequences, and liver function returned to normal after discontinuation of treatment. In controlled monotherapy and combination therapy studies of up to 24 weeks duration, the incidence of ALT or AST elevation ≥3 × ULN (defined as present in at least two consecutive measurements or at the final visit) was 0.2% for vildagliptin 50 mg once daily, 0.3% for vildagliptin 50 mg twice daily, and 0.2% for all comparator treatments. These transaminase elevations were typically asymptomatic, non-progressive, and not associated with cholestasis or jaundice.

Rare cases of angioedema have been reported with vildagliptin use, occurring at a similar frequency as in control groups. A higher incidence was observed when vildagliptin was administered concomitantly with an ACE inhibitor. Most cases were mild and resolved without discontinuation of vildagliptin.

Adverse reactions reported in patients receiving either monotherapy or add-on therapy during double-blind clinical trials are listed below by system organ class and frequency: 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), and not known (cannot be estimated from available data).

Within each frequency category, adverse events are listed in decreasing order of severity.

Adverse reactions reported in patients receiving vildagliptin 100 mg/day added to metformin compared to placebo plus metformin in double-blind studies:

Metabolism and Nutrition Disorders

Common: hypoglycaemia.

Nervous System Disorders

Common: dizziness, tremor, headache.
Uncommon: fatigue.

Gastrointestinal Disorders

Common: nausea.

Description of Selected Adverse Reactions

In controlled clinical studies of the combination of vildagliptin 100 mg/day with metformin, there were no reports of treatment discontinuation due to adverse reactions in either the vildagliptin+metformin or placebo+metformin groups.

In clinical trials, the incidence of hypoglycaemia was 1% in patients receiving vildagliptin+metformin and 0.4% in those receiving placebo+metformin.

No serious hypoglycaemic events were reported in the vildagliptin treatment group.

In clinical trials, body weight remained essentially unchanged when 100 mg/day vildagliptin was added to metformin (+0.2 kg – vildagliptin+metformin vs. -1.0 kg – placebo+metformin).

Clinical trials of more than 2 years’ duration revealed no additional safety signals or unexpected risks associated with adding vildagliptin to metformin.

Adverse reactions reported in patients receiving vildagliptin 50 mg twice daily in combination with metformin and a sulfonylurea

Metabolism and Nutrition Disorders

Common: hypoglycaemia.

Nervous System Disorders

Common: dizziness, tremor.

Skin and Subcutaneous Tissue Disorders

Common: hyperhidrosis.

General Disorders and Administration Site Conditions

Common: asthenia.

Description of Selected Adverse Reactions

There were no discontinuations due to adverse reactions in the vildagliptin+metformin+glimepiride group, compared to 0.6% in the placebo+metformin+glimepiride group.

The incidence of hypoglycaemia was higher in both treatment groups (5.1% – vildagliptin+metformin+glimepiride vs. 1.9% – placebo+metformin+glimepiride). One severe hypoglycaemic event was reported in the vildagliptin+metformin+glimepiride group.

There was virtually no effect on mean body weight at the end of the study (+0.6 kg in the vildagliptin+metformin+glimepiride group vs. -0.1 kg in the placebo+metformin+glimepiride group).

Adverse reactions reported in patients receiving vildagliptin 100 mg/day in combination with insulin (with or without metformin)

Metabolism and Nutrition Disorders

Common: decreased blood glucose.

Nervous System Disorders

Headache, chills.

Gastrointestinal Disorders

Common: nausea, gastro-oesophageal reflux.
Uncommon: diarrhoea, flatulence.

Description of Selected Adverse Reactions

In controlled clinical studies using vildagliptin 50 mg twice daily in combination with insulin (with or without metformin), the overall discontinuation rate due to adverse reactions was 0.3% in the vildagliptin group and 0% in the placebo group.

The incidence of hypoglycaemia was similar in both treatment groups (14.0% in the vildagliptin group vs. 16.4% in the placebo group). Serious hypoglycaemic events were reported in two patients in the vildagliptin group and six patients in the placebo group.

There was virtually no effect on mean body weight at the end of the study (+0.6 kg from baseline in the vildagliptin group vs. no change in the placebo group).

Additional Information on Individual Components of the Combination

Vildagliptin

Adverse reactions reported in patients receiving vildagliptin monotherapy at a dose of 100 mg/day

Infections and Infestations

Very rare: upper respiratory tract infections, nasopharyngitis.

Metabolism and Nutrition Disorders

Uncommon: hypoglycaemia.

Nervous System Disorders

Common: dizziness.
Uncommon: headache.

Eye Disorders

Uncommon: peripheral oedema.

Gastrointestinal Disorders

Uncommon: constipation.

Musculoskeletal and Connective Tissue Disorders

Uncommon: arthralgia.

Description of Selected Adverse Reactions

The overall rate of discontinuation due to adverse reactions was 0.3% in patients receiving vildagliptin 100 mg/day, 0.6% in the placebo group, and 0.5% in the comparator treatment group.

In comparative controlled monotherapy studies, hypoglycaemia was reported in 0.4% (7 out of 1855) of patients receiving vildagliptin 100 mg/day, compared to 0.2% (2 out of 1082) in the comparator or placebo groups, with no reports of serious or severe events.

No change in body weight was observed with vildagliptin 100 mg/day as monotherapy (-0.3 kg in the vildagliptin group vs. -1.3 kg in the placebo group).

Clinical trials of up to 2 years’ duration revealed no additional safety signals or unexpected risks associated with vildagliptin monotherapy.

Metformin

Adverse reactions associated with metformin use

Metabolism and Nutrition Disorders

Very rare: vitamin B12 malabsorption and lactic acidosis (vitamin B12 malabsorption with decreased serum levels has been observed very rarely in patients on long-term metformin therapy. Vitamin B12 deficiency should be considered in patients diagnosed with megaloblastic anaemia).

Nervous System Disorders

Common: metallic taste.

Gastrointestinal Disorders

Very common: nausea, vomiting, diarrhoea, abdominal pain, loss of appetite.

Hepatobiliary Disorders

Very rare: abnormal liver function tests, e.g., elevated transaminases or hepatitis (reversible upon discontinuation of metformin).

Skin and Subcutaneous Tissue Disorders

Very rare: skin reactions such as erythema, pruritus, urticaria.

Gastrointestinal adverse reactions most commonly occur at the start of treatment and usually resolve spontaneously. To minimize these effects, metformin should be taken twice daily with meals. Gradual dose escalation may also improve tolerability.

Post-Marketing Experience

Adverse reactions have been reported from spontaneous post-marketing reports and in the literature. As these reports come from an undefined population size, it is not possible to reliably estimate their frequency; therefore, they are classified as "frequency not known".

Gastrointestinal Disorders

Frequency not known: pancreatitis.

Hepatobiliary Disorders

Frequency not known: hepatitis and abnormal liver function tests (reversible upon discontinuation of metformin).

Musculoskeletal and Connective Tissue Disorders

Frequency not known: myalgia.

Skin and Subcutaneous Tissue Disorders

Frequency not known: urticaria, bullous and exfoliative skin reactions, including bullous pemphigoid.

Shelf Life.

2 years.

Storage Conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 tablets in a blister, 6 blisters in a carton.

Prescription Category.

Prescription only.

Manufacturer.

1. SAG MANUFACTURING, S.L.U., Spain
2. Galenicum Health, S.L.U., Spain

Manufacturer’s Address and Location of Operations.

1. Carretera Nacional 1 Km 36, San Agustin del Guadalix, 28750 Madrid, Spain
2. Sant Gabriel, 50, Esplugues de Llobregat, 08950 Barcelona, Spain