Glimeria-m®

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

Composition:

Active substances: metformin, glibenclamide;

1 tablet contains metformin hydrochloride 500 mg, glibenclamide 2 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate; crospovidone; povidone; magnesium stearate; coating: carnauba wax; film-coating mixture Opadry White: hypromellose (hydroxypropylmethylcellulose); polyethylene glycol (macrogol); titanium dioxide (E 171).

Pharmaceutical form. Coated tablets.

Main physicochemical properties: prolonged-shaped tablets with a biconvex surface, coated, white or almost white in color.

Pharmacotherapeutic group. Antidiabetic agents. Combination of oral hypoglycemic agents. Metformin and sulfonylureas. ATC code A10B D02.

Pharmacological Properties.

Pharmacodynamics.

Glimepiride is a substance with hypoglycemic activity upon oral administration and belongs to the sulfonylurea derivative group. It can be used in insulin-independent diabetes mellitus.

The effect of glimepiride is achieved by stimulating insulin release from pancreatic β-cells. Like other sulfonylurea derivatives, it enhances the sensitivity of pancreatic β-cells to physiological glucose stimulation. In addition, glimepiride, similar to other sulfonylurea derivatives, likely exerts a pronounced extrapancreatic effect.

Insulin release.

Sulfonylureas regulate insulin secretion by closing ATP-sensitive potassium channels in the β-cell membrane. This closure leads to depolarization of the cell membrane, resulting in the opening of calcium channels and a significant influx of calcium into the cell.

This stimulates insulin release via exocytosis.

Glimepiride binds with high affinity to a protein on the β-cell membrane associated with the ATP-sensitive potassium channel, but at a different site than where sulfonylureas typically bind.

Extrapancreatic activity.

The extrapancreatic effect includes, in particular, increased insulin sensitivity of peripheral tissues and reduced hepatic insulin uptake.

Glucose transport from blood into peripheral muscle and adipose tissue occurs via specific transport proteins located in the cell membrane. It is precisely the transport of glucose into these tissues that represents the rate-limiting step in glucose uptake. Glimepiride rapidly increases the number of active glucose transporters in the plasma membrane of muscle and fat cells, thereby enhancing glucose uptake.

Glimepiride increases the activity of phospholipase C specific to glycosylphosphatidylinositol; this may be associated with the enhanced lipogenesis and glycogenesis observed in isolated fat and muscle cells under the influence of this drug.

Glimepiride inhibits glucose production in the liver by increasing intracellular fructose-2,6-bisphosphate concentration, which, in turn, inhibits gluconeogenesis.

Metformin is a biguanide with hypoglycemic action, manifested by reducing both the basal plasma glucose level and postprandial plasma glucose levels. It does not stimulate insulin secretion and therefore does not cause hypoglycemia.

The action of metformin consists of:

• reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;
• in muscle tissue – increasing insulin sensitivity, improving peripheral glucose uptake and utilization;
• delaying glucose absorption in the intestine.

Metformin stimulates intracellular glycogen synthesis by affecting glycogen synthase.

Metformin enhances the transport capacity of specific membrane glucose transporters (GLUT-1 and GLUT-4).

In humans, regardless of blood glucose levels, metformin affects lipid metabolism. This has been demonstrated in studies using therapeutic doses: metformin reduces total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels.

Pharmacokinetics.

Glimepiride

Absorption. The bioavailability of glimepiride after oral administration is complete. Food intake does not significantly affect absorption, although it slightly reduces the absorption rate. Maximum concentration (Cmax) is reached approximately 2.5 hours after oral administration (on average 0.3 μg/mL after repeated administration of a 4 mg daily dose). A linear relationship exists between dose and both Cmax and the area under the plasma concentration-time curve (AUC).

Distribution. Glimepiride has a very low volume of distribution (approximately 8.8 L), roughly equivalent to the distribution volume of albumin, a high degree of plasma protein binding (>99%), and low clearance (approximately 48 mL/min).

In animals, glimepiride is excreted in milk. Glimepiride can cross the placenta. Penetration across the blood-brain barrier is minimal.

Metabolism and elimination. The mean elimination half-life, dependent on serum concentration, under repeated dosing conditions, is 5–8 hours. A slightly longer half-life was observed after high doses.

After administration of a single radiolabeled dose of glimepiride, 58% was recovered in urine and 35% in feces. The unchanged substance does not appear in urine. Two metabolites are excreted in urine and feces, most likely products of hepatic metabolism (the primary enzyme responsible for biotransformation is cytochrome P450 2C9): the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3–6 hours and 5–6 hours, respectively.

Comparative studies showed no significant differences in pharmacokinetics after single and multiple doses; intra-individual variability was very low. No significant accumulation was observed.

Pharmacokinetics were similar in men and women, as well as in young patients and elderly patients (aged 65 years and older). In patients with low creatinine clearance, there was a tendency toward increased clearance and reduced mean serum concentration of glimepiride, likely due to faster elimination resulting from poorer protein binding. Renal excretion of the two metabolites was reduced. However, there was generally no additional risk of drug accumulation in these patients.

In five non-diabetic patients after biliary tract surgery, pharmacokinetics were similar to those in healthy volunteers.

Metformin

Absorption. After oral administration of metformin, the time to reach maximum plasma concentration (tmax) is 2.5 hours. The absolute bioavailability of metformin following a 500 mg oral dose in healthy volunteers is approximately 50–60%. The unabsorbed fraction recovered in feces after oral administration was 20–30%.

Absorption of metformin after oral administration is saturable and incomplete. The pharmacokinetics of metformin absorption are assumed to be linear. At usual doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and typically do not exceed 1 μg/mL. During studies, Cmax of metformin in plasma did not exceed 4 μg/mL, even with the highest doses.

Food intake reduces the extent and slightly prolongs the absorption time of metformin. After an 850 mg dose taken with food, a 40% reduction in plasma Cmax, a 25% decrease in AUC, and a 35-minute prolongation of tmax were observed. The clinical significance of these changes is unknown.

Distribution. Plasma protein binding is negligible. Metformin distributes into erythrocytes. Cmax in whole blood is lower than in plasma and is reached at approximately the same time. Erythrocytes likely serve as a secondary distribution compartment. The mean Vd ranges between 63–276 L.

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

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

Clinical characteristics.

Indications.

As an adjunct to diet and physical exercise in patients with non-insulin-dependent diabetes mellitus (type 2):

• when monotherapy with glimepiride or metformin does not provide adequate glycemic control;
• when replacing combination therapy with glimepiride and metformin.

Contraindications.

• Insulin-dependent diabetes mellitus type 1 (e.g., diabetes with history of ketoacidosis), diabetic ketoacidosis, diabetic coma and precoma, acute or chronic metabolic acidosis.
• Hypersensitivity to any of the excipients contained in the medicinal product, or to sulfonylureas, sulfonamides, or biguanides.
• Hepatic insufficiency, severe impairment of liver function, hemodialysis (there is no experience with the use of the drug in such cases). In cases of severe hepatic and renal dysfunction, patients must be switched to insulin therapy to achieve adequate blood glucose control.
• Pregnancy; suspected pregnancy; breastfeeding period.
• Predisposition to lactic acidosis, history of lactic acidosis, renal insufficiency or impaired kidney function (e.g., plasma creatinine levels of 1.5 mg/dL in men and 1.4 mg/dL in women, or impaired creatinine clearance), which may also be caused by conditions such as cardiovascular collapse (shock), acute myocardial infarction, and sepsis.
• Radiological procedures involving intravascular administration of iodine-containing contrast agents (intravenous urography, intravenous cholangiography, angiography, and computed tomography): intravenously administered iodinated contrast agents used during such procedures may cause acute renal failure and lactic acidosis in patients taking this medicinal product. Therefore, patients scheduled for such procedures should temporarily discontinue the drug 48 hours before the procedure. Therapy should not be resumed until renal function has been re-evaluated and confirmed to be normal. Additionally, the drug is contraindicated in patients presenting with acute conditions that may impair renal function (dehydration, severe infection, shock).
• Severe infections, pre- and post-surgical states, serious trauma. The use of this medicinal product should be temporarily suspended during any surgical intervention (except minor procedures not requiring dietary or fluid restrictions). Treatment should not be resumed until the patient resumes normal food intake and renal function parameters are within normal limits.
• Undernutrition, starvation, or patient exhaustion.
• Hypopituitarism or adrenal insufficiency.
• Impaired liver function (since cases of lactic acidosis have been observed in patients with liver dysfunction, this drug is generally not prescribed to patients with clinical or laboratory signs of liver disease), pulmonary infarction, severe impairment of pulmonary function, and other conditions that may be associated with hypoxemia (cardiac or pulmonary insufficiency, recent myocardial infarction, shock), excessive alcohol abuse, dehydration, gastrointestinal disorders, including diarrhea and vomiting.
• Severe renal failure (glomerular filtration rate (GFR) < 30 mL/min).
• Severe infections.
• Congestive heart failure requiring pharmacological treatment, recent myocardial infarction, severe cardiovascular insufficiency, or respiratory impairment.

Special precautions.

Warnings

During treatment with the medicinal product:

• hypoglycemia or severe lactic acidosis may occur (see sections "Special instructions for use" and "Overdose");
• increased risk of cardiovascular mortality.

Increased risk of cardiovascular mortality

The use of oral antidiabetic agents compared to diet control alone, or diet with insulin therapy, leads to an increased risk of cardiovascular mortality. This warning is based on the University Group Diabetes Program (UGDP) study, which was conducted to evaluate the effectiveness of antidiabetic drugs in preventing or delaying the development of cardiovascular complications in patients with non-insulin-dependent diabetes mellitus. According to this study, patients treated for 5–8 years with diet control plus a fixed dose of either tolbutamide (1.5 g daily) or phenformin (100 mg daily) showed a 2.5-fold increase in cardiovascular mortality compared to patients treated with diet alone, leading to the discontinuation of tolbutamide or phenformin therapy. Despite differing interpretations of these data, the UGDP study results provide substantial grounds for safety warnings, and due to the similarity of mechanisms of action, these warnings may also apply to other antidiabetic drugs in these classes.

Patients should be informed about the potential risks and benefits of glimepiride use and alternative treatment regimens.

Although this study evaluated only one sulfonylurea derivative (tolbutamide) and one biguanide (phenformin), from a safety perspective it is reasonable to assume that this warning may also apply to other hypoglycemic agents in these classes due to similarities in their mechanisms of action and chemical structure.

Renal function

GFR should be assessed before initiating treatment and periodically thereafter. Metformin is contraindicated in patients with GFR < 30 mL/min and should be temporarily discontinued in conditions affecting renal function (see section "Contraindications").

Renal function impairment is common and often asymptomatic in elderly patients. Particular caution is required in situations where renal impairment is possible, such as initiation of antihypertensive agents or diuretics, or treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).

Long-term metformin therapy is associated with decreased serum vitamin B12 levels, which may lead to peripheral neuropathy. Monitoring of vitamin B12 levels is recommended.

Interaction with other medicinal products and other types of interactions.

If a patient taking this medicinal product simultaneously receives certain other drugs or discontinues their use, this may lead to either an undesirable enhancement or reduction of the glucose-lowering effect of glimepiride. Based on experience with this and other sulfonylurea derivatives, the following potential interactions between Glimeria-M® and other medicinal products should be considered.

This drug is metabolized by cytochrome P450 2C9 (CYP2C9), which should be taken into account when co-administering CYP2C9 inducers (e.g., rifampicin) or inhibitors (e.g., fluconazole).

Medicinal products that enhance the glucose-lowering effect: insulin and oral antidiabetic agents, NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, allopurinol, anabolic steroids, androgens, chloramphenicol, coumarin-derived anticoagulants, cyclophosphamide, disopyramide, fenfluramine, pheniramidol, fibrates, fluoxetine, guanethidine, isophosphamide, monoamine oxidase (MAO) inhibitors, miconazole, fluconazole, para-aminosalicylic acid, pentoxifylline (when administered parenterally in high doses), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolone antibiotics, salicylates, sulfinpyrazone, clarithromycin, sulfonamides, tetracyclines, troxipide, trofosfamide, sympatholytics.

Medicinal products that reduce the glucose-lowering effect: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) or sympathomimetics, glucagon, laxatives (with prolonged use), nicotinic acid (in high doses), estrogens, progestogens, oral contraceptives, phenothiazines, phenytoin, rifampicin, thyroid hormones, chlorpromazine, isoniazid.

Medicinal products capable of either enhancing or reducing the glucose-lowering effect: H2-receptor antagonists, clonidine, and reserpine.

β-adrenergic blockers reduce glucose tolerance. This may lead to impaired metabolic control in patients with diabetes. β-blockers may increase the risk of hypoglycemia (due to impaired counterregulation).

Medicinal products that impair or block the symptoms of adrenergic counterregulation of hypoglycemia: sympatholytic agents (e.g., β-adrenergic blockers, clonidine, guanethidine, reserpine).

Both single and regular alcohol consumption may unpredictably enhance or reduce the glucose-lowering effect of the drug.

Glimeria-M® may either enhance or reduce the effects of coumarin-derived anticoagulants.

Bile acid sequestrants. Colesevelam binds to glimepiride and reduces its absorption from the gastrointestinal tract. No interaction was observed when glimepiride was administered at least 4 hours before colesevelam. Therefore, glimepiride should be administered at least 4 hours before colesevelam.

Concomitant use of Glimeria-M® with certain medicinal products may lead to lactic acidosis. Patients should be closely monitored when used concomitantly with: aqueous radiographic contrast agents, antibiotics with strong nephrotoxic effects (e.g., gentamicin).

The glucose-lowering effect may be either enhanced or reduced when used concomitantly with certain medicinal products. Close monitoring of the patient and blood glucose levels is required when used concomitantly with:

• agents enhancing the glucose-lowering effect: insulin, sulfonamides, sulfonylurea agents, meglitinides (repaglinide), α-glucosidase inhibitors (acarbose), anabolic steroids, guanethidine, salicylates (acetylsalicylic acid), β-adrenergic blockers (propranolol), MAO inhibitors, ACE inhibitors;
• agents reducing the glucose-lowering effect: adrenaline, sympathomimetics, corticosteroids, thyroid hormones, estradiol, estrogens, oral contraceptives, thiazides and other diuretics, pyrazinamide, isoniazid, nicotinic acid, phenothiazines, phenytoin, calcium channel blockers, β2-agonists (salbutamol, formoterol).

Glibenclamide. In a single-dose interaction study in patients with type 2 diabetes, concomitant administration of metformin and glibenclamide did not result in any changes in the pharmacokinetics or pharmacodynamics of metformin. A reduction in the AUC and Cmax of glibenclamide was observed, but it was highly variable. Due to the single-dose nature of the study and the lack of correlation between plasma metformin levels and its pharmacodynamic effects, it is uncertain whether this interaction is clinically significant.

Furosemide. In a single-dose interaction study between metformin and furosemide in healthy volunteers, concomitant administration of these drugs was shown to affect their pharmacokinetic parameters. Furosemide increased the Cmax of metformin in plasma by 22% and AUC by 15%, without significant changes in renal clearance of metformin. When administered with metformin, the Cmax and AUC of furosemide decreased by 31% and 12%, respectively, compared to furosemide monotherapy, and the terminal half-life decreased by 32%, without significant changes in renal clearance of furosemide. Information on interactions between metformin and furosemide with long-term use is lacking.

Nifedipine. In a single-dose interaction study between metformin and nifedipine in healthy volunteers, concomitant administration of nifedipine increased the Cmax and AUC of metformin in plasma by 20% and 9%, respectively, and increased the amount of drug excreted in urine. No effect was observed on time to peak concentration (Tmax) or half-life of metformin. Nifedipine was shown to enhance the absorption of metformin, while metformin had almost no effect on the pharmacokinetics of nifedipine.

Cationic drugs. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin) that are eliminated by renal tubular secretion may theoretically interact with metformin due to competition for the common renal tubular transport system. Such an interaction between metformin and cimetidine was observed in interaction studies with single and multiple doses in healthy volunteers. These studies demonstrated a 60% increase in Cmax of metformin in plasma and whole blood, and a 40% increase in AUC of metformin in plasma and blood. In a single-dose study, no changes were observed in the half-life duration. Metformin did not affect the pharmacokinetics of cimetidine. Despite the theoretical possibility of such interactions (except for cimetidine), careful monitoring of patients and dose adjustment of metformin and/or the interacting drug are recommended when cationic drugs eliminated via proximal tubular secretion are used.

Others. In a single-dose interaction study in healthy volunteers, the pharmacokinetics of metformin with propranolol and metformin with ibuprofen were not altered when administered concomitantly.

The degree of plasma protein binding of metformin is low; therefore, its interaction with drugs that have a high degree of plasma protein binding, such as salicylates, sulfonamides, chloramphenicol, and probenecid, is less likely compared to sulfonylurea derivatives, which have a high degree of plasma protein binding.

Metformin may reduce the anticoagulant effect of phenprocoumon. Therefore, careful monitoring of the international normalized ratio (INR) is recommended.

Levothyroxine may reduce the glucose-lowering effect of metformin. Monitoring of blood glucose levels is recommended, especially at the beginning or discontinuation of thyroid hormone therapy, and metformin dosage should be adjusted if necessary.

Organic cation transporters (OCT).

Metformin is a substrate for OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (e.g., verapamil) may reduce the efficacy of metformin;
• OCT1 inducers (e.g., rifampicin) may enhance the absorption of metformin in the gastrointestinal tract and increase its efficacy;
• OCT2 inhibitors (e.g., cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal excretion of metformin, thereby increasing plasma metformin concentrations;
• inhibitors of both OCT1 and OCT2 (e.g., crizotinib, olaparib) may alter the efficacy and renal excretion of metformin.

Therefore, caution is recommended when co-administering these drugs with metformin, especially in patients with impaired renal function, as this may increase plasma metformin concentrations. Dose adjustment of metformin may be considered if necessary, since OCT inhibitors/inducers may alter the efficacy of metformin.

Special precautions for use.

Special precautions

Careful monitoring of the patient is required during the first week of treatment due to an increased risk of hypoglycemia. The risk of hypoglycemia exists in the following patients or conditions:

• unwillingness or inability of the patient to cooperate with the physician (more common in elderly patients);
• inadequate or irregular nutrition, skipping meals;
• imbalance between physical exertion and carbohydrate intake, strenuous exercise;
• alcohol consumption;
• impaired renal function (may lead to increased sensitivity to the glucose-lowering effect of glimepiride);
• severe impairment of liver function;
• drug overdose;
• certain decompensated endocrine disorders (e.g., thyroid dysfunction, adrenohypopituitarism or adrenal cortical insufficiency), which may affect carbohydrate metabolism and counter-regulation of hypoglycemia;
• concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

When such factors increasing the risk of hypoglycemia are present, the dose of Glimeria-M® or the entire treatment regimen should be adjusted. This should also be done in case of any illness or change in the patient's lifestyle. Symptoms of hypoglycemia caused by adrenergic counter-regulation (see section "General precautions") may be blunted or completely absent when hypoglycemia develops gradually: in elderly patients, in patients with autonomic neuropathy, or in those receiving concomitant treatment with sympatholytic agents.

General precautions

Hypoglycemia

Based on experience with other sulfonylurea drugs, it is known that despite initial success of preventive measures, recurrent episodes of hypoglycemia may occur. Therefore, the patient should remain under careful observation.

Possible symptoms of hypoglycemia include headache, intense hunger ("wolfish" appetite), nausea, vomiting, increased fatigue, drowsiness, apathy, insomnia, sleep disturbances, restlessness, aggressiveness, difficulty concentrating, reduced alertness and reaction speed, depression, confusion, speech disturbances, aphasia, visual disturbances, tremor, paresis, sensory disturbances, dizziness, loss of self-control, delirium, central-origin seizures, loss of consciousness, coma, shallow breathing and bradycardia. Additionally, signs of adrenergic counter-regulation may occur: excessive sweating, clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, angina attacks and cardiac arrhythmias.

The clinical picture of a severe episode of hypoglycemia may resemble a stroke. Severe hypoglycemia requires immediate treatment under medical supervision and, under certain circumstances, hospitalization of the patient. Hypoglycemia can almost always be rapidly corrected by immediate intake of carbohydrates (glucose or sugar, e.g., in the form of a piece of sugar, sugared fruit juice or sweetened tea). For this purpose, the patient should always carry at least 20 g of sugar. Patients and their families should be informed about the danger, symptoms, treatment methods and risk factors for the development of hypoglycemia. To avoid complications, the patient may require assistance from third parties. Artificial sweeteners have no effect on blood glucose control.

Lactic acidosis

Lactic acidosis is a rare but serious metabolic complication that may develop due to metformin accumulation during treatment with this drug. If this condition occurs, it ends fatally in nearly 50% of cases. Lactic acidosis may also occur in certain pathophysiological conditions, including diabetes mellitus, as well as against a background of significant tissue hypoperfusion and hypoxemia.

Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte imbalance with increased anion gap and increased lactate/pyruvate ratio. When lactic acidosis is caused by metformin, plasma metformin levels are usually above 5 µg/mL.

The incidence of reported cases of lactic acidosis in patients taking metformin hydrochloride is very low (approximately 0.03 cases per 1000 patients per year, with approximately 0.015 fatal cases per 1000 patients per year). Reported cases occurred predominantly in patients with diabetes mellitus and pronounced renal insufficiency, caused both by intrinsic kidney damage and renal hypoperfusion, often associated with multiple concomitant medical/surgical conditions and polypharmacy.

The risk of lactic acidosis increases proportionally with the severity of renal dysfunction and the patient's age. However, the risk of lactic acidosis in patients taking metformin can be significantly reduced by continuous monitoring of kidney function and use of the lowest effective metformin doses. Additionally, the drug should be discontinued immediately in case of any condition associated with hypoxemia, dehydration or sepsis.

Since impaired liver function may reduce lactate elimination capacity, the drug should not be administered to patients with clinical or laboratory signs of liver disease. Patients should be warned against excessive alcohol consumption (both acute and chronic) during treatment with this drug, as alcohol enhances the effect of metformin on lactate metabolism. Also, the drug should be temporarily discontinued before any procedures involving intravascular administration of contrast agents and before any surgical intervention.

Lactic acidosis often begins almost imperceptibly and is accompanied only by nonspecific symptoms such as malaise, myalgia, respiratory distress syndrome, increased drowsiness and nonspecific abdominal discomfort. In more pronounced acidosis, hypothermia, arterial hypotension and refractory bradyarrhythmia may occur. Both the patient and physician must be aware of the importance of such symptoms. Therefore, patients should be instructed to immediately inform their physician about the appearance of such symptoms.

Testing of parameters such as plasma electrolytes and ketone bodies, blood glucose, blood pH, lactate and metformin concentrations may be helpful in diagnosing lactic acidosis. After achieving stabilization on any dose of Glimeria-M®, gastrointestinal symptoms, which are often observed at the beginning of metformin therapy, are unlikely to be related to drug use. Gastrointestinal symptoms appearing later may be caused by lactic acidosis or another serious illness.

Elevated venous plasma lactate levels on an empty stomach, exceeding the upper limit of normal but below 5 mmol/L, in patients taking this drug do not necessarily indicate impending lactic acidosis. It may be explained by other mechanisms, such as poor control of diabetes mellitus or obesity, intense physical exertion, or technical problems during blood analysis.

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis but without signs of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is an emergency condition requiring hospital treatment. Patients with lactic acidosis who are receiving this drug should immediately discontinue it and receive appropriate supportive measures. Since metformin hydrochloride is eliminated by dialysis (with clearance up to 170 mL/min under adequate hemodynamics), immediate hemodialysis is recommended to correct acidosis and eliminate accumulated metformin. Such therapeutic measures often lead to rapid symptom resolution and elimination of lactic acidosis.

Patients with established or suspected mitochondrial disorders:

Metformin should not be used in patients with established mitochondrial disorders, such as mitochondrial encephalopathy, 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 immediately discontinued and a rapid diagnostic evaluation performed.

• Optimal blood glucose levels should be maintained by simultaneously adhering to a diet and adequate physical activity, and, if necessary, by weight reduction and regular intake of Glimeria-M®.

Clinical symptoms of poor blood glucose control include oliguria, thirst, polydipsia, and dry skin.

• At the beginning of treatment, patients should be informed about the benefits and potential risks associated with the use of Glimeria-M®, as well as the importance of diet and regular physical activity. Emphasis should be placed on the importance of positive patient cooperation.
• The patient's response to all diabetes treatment methods should be monitored by periodic measurement of fasting blood glucose and glycated hemoglobin to achieve normal levels of these parameters. Glycated hemoglobin levels may be particularly useful in assessing long-term glycemic control.
• If a patient is treated by another physician (e.g., during hospitalization, due to an accident, or when seeking medical help on weekends), they must inform about their current diabetes control status and previously taken medications.
• In exceptional stressful situations (e.g., trauma, surgery, infectious disease with high fever), blood glucose regulation may worsen, and temporary transition to insulin may be necessary to ensure adequate metabolic control.
• Treatment with Glimeria-M® should be initiated with the lowest doses. During treatment with this drug, blood glucose and urine glucose levels should be regularly monitored. Additionally, glycated hemoglobin levels should be determined. Treatment efficacy should also be evaluated, and if insufficient, the patient should be immediately switched to another therapy.
• Possible reduction in attention and reaction speed due to hypo- or hyperglycemia, especially at the beginning of treatment, when switching from one drug to another, or with irregular intake of Glimeria-M®, may negatively affect the ability to drive vehicles or operate machinery.
• Kidney function monitoring: it is known that metformin is primarily excreted by the kidneys; therefore, the risk of its accumulation and development of lactic acidosis increases proportionally with the severity of kidney pathology. Therefore, this drug should not be administered to patients whose serum creatinine levels exceed the upper age-specific normal limit. Elderly patients require cautious dose titration of Glimeria-M® to determine the minimum dose providing adequate glycemic effect, as kidney function declines with age. Kidney function should be regularly monitored in elderly patients, and the drug should not be titrated to the maximum dose. Kidney function should be evaluated and confirmed as normal before starting treatment and at least once a year after starting this drug. For patients in whom kidney dysfunction is expected, their condition should be checked more frequently, and if evidence of impairment appears, the drug should be discontinued.
• Concomitant use of other medicinal products that may negatively affect kidney function or metformin pharmacokinetics: concomitant use of drugs that may negatively affect kidney function or cause significant changes in hemodynamics, or affect the pharmacokinetics of Glimeria-M®, particularly cationic drugs, which are excreted by the kidneys via tubular secretion, should be used with caution. Particular caution is required in situations where kidney dysfunction may develop, e.g., at the beginning of antihypertensive therapy or during treatment with diuretics or NSAIDs.
• Diabetogenic symptoms: Glimeria-M® should only be prescribed to patients diagnosed with type 2 diabetes mellitus. Attention should also be paid to diseases accompanied by diabetogenic symptoms: renal glucosuria, age-related glucose metabolism disorders, thyroid dysfunction, including impaired glucose tolerance or presence of glucose in urine.
• Dose adjustment of Glimeria-M®: for some patients, discontinuation of oral antidiabetic drugs or dose reduction may be necessary. For many patients, the efficacy of oral antidiabetic drugs decreases over time due to progression of the underlying disease or development of infectious complications. Thus, decisions regarding continuation of treatment with this drug, selection of its dose and concomitant administration of another drug should be based on factors such as diet, weight changes, blood glucose levels, and presence of infection.
• Hypoxic conditions: cardiovascular collapse (shock) of any origin, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia may be accompanied by lactic acidosis development and may also cause prerenal azotemia. If such conditions occur in patients taking Glimeria-M®, the drug should be immediately discontinued.
• Alcohol consumption: alcohol is known to enhance metformin's effect on lactate metabolism. Therefore, patients should be warned against excessive acute or chronic alcohol consumption during Glimeria-M® intake.
• In patients taking metformin, decreased serum vitamin B12 levels below normal have been observed, without clinical manifestations. This decrease is likely due to the effect of the vitamin B12–intrinsic factor complex on vitamin B12 absorption, but it rarely leads to anemia and quickly resolves after discontinuation of the drug or vitamin B12 administration. Patients taking Glimeria-M® are recommended to have annual blood tests, and if abnormalities are detected, appropriate examination and treatment should be conducted. Some patients (with insufficient intake or absorption of vitamin B12 or calcium) may be prone to decreased vitamin B12 levels below normal. For such patients, regular determination of serum vitamin B12 levels every 2–3 years may be beneficial.
• Change in clinical status of a patient with previously controlled diabetes: appearance of laboratory parameter deviations from normal or clinical signs of malaise (especially such as increased fatigue, vague illness) in a patient with previously controlled diabetes on metformin tablets requires immediate examination to rule out ketoacidosis or lactic acidosis. Serum electrolyte and ketone body concentrations, blood glucose levels, and, if indicated, blood pH, lactate, pyruvate and metformin levels should be determined. If any form of acidosis occurs, Glimeria-M® should be immediately discontinued and other necessary corrective measures initiated.
• Loss of blood glucose control: temporary loss of blood glucose control may occur if a patient in stable condition on any treatment regimen experiences stress, e.g., high body temperature, tremor, infection or surgery. In such cases, discontinuation of this drug and temporary insulin administration may be necessary. In case of repeated loss of control during Glimeria-M® treatment, alternative treatment regimens, including initiation of insulin therapy, should be considered.
• Patients with special working conditions: patients working at heights or driving vehicles should be cautious, as severe lactic acidosis or severe late hypoglycemia may rarely occur. Such patients and their families should be fully warned about the dangers associated with lactic acidosis or hypoglycemia and be especially vigilant.

Patients should be informed about the safety, efficacy and alternative treatment methods when using Glimeria-M®. They should also be informed about the importance of regular food intake and adherence to diet, regular physical exercise, and the necessity of regular monitoring of blood glucose, glycated hemoglobin, kidney function and hematological parameters. Obese patients should follow a low-calorie diet.

Patients should be explained the dangers of lactic acidosis, its symptoms and conditions causing its development, as stated in the sections "Special safety precautions" and "General precautions." Patients should be advised to immediately discontinue this drug and seek medical help if symptoms such as unexplained hyperventilation, myalgia, malaise, unusual drowsiness or other unexplained nonspecific symptoms occur. After achieving stabilization on any dose of Glimeria-M®, gastrointestinal symptoms, often observed at the beginning of metformin therapy, are unlikely to be related to drug use. Gastrointestinal symptoms appearing later may be caused by lactic acidosis or another serious illness.

The physician should explain to the patient and their family the dangers of hypoglycemia, its symptoms and conditions causing its occurrence.

Patients should be warned against excessive alcohol consumption, both acute and chronic, during Glimeria-M® treatment.

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylurea drugs may lead to hemolytic anemia. Since glimepiride belongs to sulfonylurea derivatives, caution should be exercised with such patients, and the appropriateness of alternative treatment not containing sulfonylurea derivatives should be considered.

Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.

Use in elderly patients

Considering the reduced kidney function in elderly patients, metformin dosage should be adjusted based on kidney function status and kidney function should be monitored as necessary. It is known that metformin and glimepiride are primarily excreted by the kidneys. Since the risk of severe adverse reactions to Glimeria-M® in patients with impaired kidney function is significantly higher, the drug can only be used in patients with normal kidney function.

Use in children

The safety and efficacy of the drug in children (under 18 years of age) have not been established. Studies on the use of the drug in young patients with adult-type diabetes have not been conducted.

Metformin as monotherapy

Before starting metformin treatment, it is necessary to confirm that the patient suffers from type 2 diabetes mellitus. Although clinical studies have confirmed that metformin monotherapy does not negatively affect growth and sexual maturation of patients, long-term study results evaluating these specific aspects are still lacking. Therefore, careful monitoring of metformin's impact on these parameters is recommended when the drug is prescribed to children, especially those who have not reached puberty.

It is known that in a clinical study on metformin use in children during growth phase, patients aged 10 to 12 years participated. Although the efficacy and safety of metformin in children under 12 years of age did not differ from those in children aged 12 years and older, caution is necessary when prescribing metformin to children aged 10 to 12 years.

Other effects

Body weight effect. Glimeria-M® has more advantages compared to other drugs (sulfonylurea derivatives, thiazolidinediones) commonly prescribed to lower glucose levels, as this drug does not lead to body weight gain in patients with type 2 diabetes mellitus. Stabilization or reduction of body weight with this drug limits the adverse impact of other risk factors associated with weight gain. Long-term use of the drug achieves more stable glycemic control and reduces the risk of diabetic complications. The drug has demonstrated improved glycemic control without body weight gain or even with slight body weight reduction.

Drug abuse or dependence development

Metformin hydrochloride has neither primary nor secondary pharmacodynamic properties that could lead to its non-medical use as a recreational drug or to dependence development.

Laboratory tests

Blood parameters (e.g., hemoglobin/hematocrit and erythrocyte indices) and kidney function (plasma creatinine) should be periodically monitored, at least annually. Megaloblastic anemia is rarely observed with metformin use, but if its development is suspected, possible vitamin B12 deficiency should be ruled out.

Excipient

The drug contains lactose; therefore, it should not be used in patients with rare hereditary diseases such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Glimeria-M® should not be taken during pregnancy due to the existing risk of harmful effects on fetal development. Pregnant patients and patients planning pregnancy should inform their physician to reduce the risk of congenital fetal malformations caused by excessive blood glucose levels. Such patients should, if possible, be switched to insulin to maintain normal blood glucose levels.

Breastfeeding period

To avoid glimepiride and metformin passing into the infant's body through breast milk, the drug should not be taken by women during breastfeeding. If necessary, the patient should be switched to insulin or completely discontinue breastfeeding.

Carcinogenesis, mutagenesis, fertility impairment

Glimepiride

• Studies in rats using glimepiride at doses up to 5000 parts per million (approximately 340 times the maximum recommended human dose based on body surface area) with adequate nutrition for 30 months showed no evidence of carcinogenicity. In mice, 24-month glimepiride use led to increased incidence of benign pancreatic adenoma.

This effect is dose-dependent and considered a consequence of chronic pancreatic stimulation. The no-observed-effect level (NOEL) for pancreatic adenoma development in this mouse study was 320 parts per million with adequate nutrition, or 46–54 mg/kg body weight per day. This is approximately 35 times the maximum recommended human dose (8 mg once daily) based on body surface area.

• In vitro and in vivo mutagenesis studies, glimepiride showed no mutagenic effect.
• No effect on male mouse fertility was observed at doses up to 2500 mg/kg body weight (>1700 times the maximum recommended human dose based on body surface area). Glimepiride did not affect fertility in male and female rats at doses up to 4000 mg/kg body weight (approximately 4000 times the maximum recommended human dose based on body surface area).

Metformin

• Long-term carcinogenicity studies of metformin were conducted in rats and mice with treatment durations of 104 weeks and 91 weeks, respectively, using doses up to 900 mg/kg/day and 1500 mg/kg/day, respectively. Both doses were nearly three times the maximum recommended human daily dose based on body surface area. No evidence of metformin carcinogenicity was found in male or female mice. Similarly, no tumorigenic potential of metformin was found in male rats. However, in female rats receiving 900 mg/kg/day doses, an increased incidence of benign uterine stromal polyps was observed.
• No mutagenic effects of metformin were found in any of the following tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), chromosomal aberration test (human lymphocytes), and in vivo micronucleus test (mouse bone marrow).
• Metformin did not affect fertility in male and female rats at doses up to 600 mg/kg/day, i.e., doses approximately twice the maximum recommended human daily dose based on body surface area.

Ability to affect reaction speed when driving vehicles or operating machinery.

Patients should be warned to exercise caution when driving vehicles or operating machinery.

Dosage and Administration.

The doses of antidiabetic medicinal products should be determined individually, depending on the patient's blood glucose levels.

Treatment is recommended to start with the lowest effective dose, and the dose should be increased taking into account the medications currently being used by the patient, as well as the patient's blood glucose levels. Regular monitoring of blood glucose levels is necessary for this purpose.

The initial dose of the drug in the study was 2 mg glimepiride/500 mg metformin, which was gradually increased up to 8 mg glimepiride/2000 mg metformin, depending on the results of blood sugar monitoring. Although additional effects with glimepiride monotherapy were usually minimal when the drug was administered at doses of 4 mg per day or higher, improved metabolic control was observed in some patients when the dose was increased to 6 mg (or 8 mg).

The drug is intended for use in adults only.

The drug should be administered once or twice daily, taken with or during meals.

When switching from combination therapy with glimepiride and metformin given as separate tablets, the medicinal product Glimeria-M® should be prescribed considering the doses and administration regimen of glimepiride and metformin hydrochloride currently being used by the patient.

If a previous dose is missed, the next dose should not be doubled.

Children.

The safety and efficacy of the drug in children have not been established. Studies evaluating treatment of type 2 diabetes mellitus in pediatric patients have not been conducted.

Overdose.

Since Glimeria-M® contains glimepiride, overdose may lead to hypoglycemia. Immediate medical attention must be sought as soon as glimepiride overdose is suspected. The patient should immediately take sugar, preferably in the form of glucose, unless the physician assumes responsibility for managing the overdose. Mild hypoglycemia without loss of consciousness or neurological impairment should be actively treated with oral glucose intake and adjustment of the drug dose and/or diet. Careful monitoring must continue until the physician confirms that the patient is no longer at risk. Treatment primarily involves preventing drug absorption by inducing vomiting, followed by administration of sweet non-alcoholic beverages or water containing activated charcoal (adsorbent) and sodium sulfate (laxative). If a significant amount of the drug has been absorbed, gastric lavage should be performed, followed by administration of activated charcoal and sodium sulfate.

Cases of significant overdose and severe reactions, such as loss of consciousness and other serious neurological disturbances, are medical emergencies requiring immediate treatment and hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should receive a rapid intravenous injection of concentrated (50%) glucose solution or 40 mL of 20% glucose solution, followed by continuous infusion of a less concentrated (10%) glucose solution at a rate sufficient to maintain a stable blood glucose level above 100 mg/dL. As an alternative, glucagon may be administered intravenously, intramuscularly, or subcutaneously to adults, for example, at doses of 0.5–1.0 mg via intravenous, intramuscular, or subcutaneous injection. The patient must be carefully monitored for at least 24–48 hours, as hypoglycemia may recur even after apparent clinical improvement.

In cases of hypoglycemia due to accidental ingestion of glimepiride by infants and young children, careful titration of administered glucose and close monitoring of blood glucose levels are required.

Due to the presence of metformin in this drug, lactic acidosis may develop. Hypoglycemia has not been observed after ingestion of up to 85 g of metformin hydrochloride. Metformin is eliminated by dialysis (with a clearance of up to 170 mL/min under adequate hemodynamic conditions). Therefore, hemodialysis is the most effective measure for removing accumulated drug from the body in suspected metformin overdose.

Pancreatitis may develop in cases of metformin overdose.

Adverse Reactions

Lactic acidosis: see sections "Special Warnings and Precautions for Use" and "Overdose".

Hypoglycaemia: see sections "Special Warnings and Precautions for Use" and "Overdose".

Gastrointestinal disorders: Gastrointestinal symptoms (diarrhoea, nausea, vomiting, abdominal distension, loss of appetite, dyspepsia, constipation, abdominal pain) are the most common reactions to metformin. These occurred more frequently during monotherapy with metformin than with placebo, especially at the beginning of treatment. These symptoms are generally transient and resolve spontaneously with continued therapy. In individual cases, temporary dose reduction may be beneficial. During clinical trials, metformin had to be discontinued due to gastrointestinal adverse reactions in approximately 4% of patients.

Since gastrointestinal symptoms at the beginning of treatment are dose-dependent, their occurrence can be minimized by gradual dose escalation and administration with meals. As significant diarrhoea and/or vomiting may lead to dehydration and prerenal azotemia, in such cases the drug should be temporarily discontinued.

The occurrence of non-specific gastrointestinal symptoms in patients taking stable doses of Glimeria-M® may be related to concomitant diseases or lactic acidosis rather than to the use of the drug.

Glimipiride therapy may occasionally cause nausea, vomiting, epigastric fullness or discomfort, abdominal pain, and diarrhoea.

Sensory organ disorders: At the beginning of metformin therapy, patients may complain of an unpleasant or metallic taste in the mouth, which usually resolves spontaneously. Transient visual disturbances due to changes in blood glucose levels, particularly at the beginning of treatment, may also occur. Dysgeusia has been reported after glimepiride administration (frequency unknown).

Skin reactions and hypersensitivity: Allergic or pseudoallergic reactions (e.g., mild erythema (very rare − <0.01%), pruritus, urticaria, or rash) may occasionally occur. Most such reactions are mild but may progress to severe reactions accompanied by dyspnoea and hypotension, sometimes leading to shock. Immediate medical attention is required if urticaria occurs. Cross-allergic reactions with sulfonylureas, sulfonamides, or their derivatives are possible.

Blood and lymphatic system disorders: Rarely, thrombocytopenia may occur; in isolated cases, leucopenia or haemolytic anaemia, erythrocytopenia, granulocytopenia, agranulocytosis, or pancytopenia may occur. Careful monitoring of the patient is required, as cases of aplastic anaemia have been reported during treatment with this drug in combination with other sulfonylurea agents. If any of these events occur, the drug should be discontinued and appropriate treatment initiated. Cases of severe thrombocytopenia with platelet counts <10,000/µL and thrombocytopenic purpura have been reported (frequency unknown).

In patients receiving long-term metformin therapy, decreased absorption of vitamin B12 and reduced serum levels of vitamin B12 have been observed. This phenomenon is generally clinically insignificant (<0.01%). Cases of peripheral neuropathy associated with vitamin B12 deficiency have been reported (frequency unknown). Serum folate levels were not significantly reduced. Megaloblastic anaemia has been reported without increased incidence of neuropathic symptoms. Therefore, serum vitamin B12 levels should be carefully monitored, and parenteral vitamin B12 supplementation should be considered periodically.

Hepatobiliary disorders: In isolated cases, increased liver enzyme activity and impaired liver function (e.g., cholestasis and jaundice), as well as hepatitis which may progress to liver failure, are possible. Reports of abnormal liver function tests or hepatitis associated with metformin use have been received, which resolved after discontinuation of metformin.

Other reactions: In isolated cases, allergic vasculitis, photosensitivity, and hyponatraemia may occur.

Additionally, the following adverse reactions have been reported with unknown frequency:

• Decreased TSH levels in patients with hypothyroidism;
• Hypomagnesaemia associated with diarrhoea;
• Encephalopathy;
• Alopecia, weight gain (after glimepiride administration).

Adverse reactions in children receiving metformin monotherapy

Adverse reactions observed in a small group of children aged 10 to 16 years who received metformin for one year, as well as those reported in publications and during post-marketing surveillance, were similar in nature and severity to those observed in adults.

Adverse events from post-marketing surveillance

According to post-marketing surveillance data on the combination of metformin hydrochloride and glimepiride, regardless of causal relationship to the investigational drug, adverse events observed in patients with type 2 diabetes mellitus included: hypoglycaemia, abdominal pain, abdominal distension, vomiting, dyspepsia, benign prostatic hyperplasia, tachycardia, dizziness, diarrhoea, nausea, peripheral oedema, cardiac arrest, and colorectal cancer.

Adverse reactions for which a causal relationship to the investigational drug could not be ruled out included: hypoglycaemia, abdominal distension and abdominal pain (each), tachycardia, vomiting, dyspepsia, and dizziness. Serious adverse events included cardiac arrest and colorectal cancer, neither of which had a confirmed causal relationship to the investigational drug. Unexpected adverse events included dyspepsia, benign prostatic hyperplasia, peripheral oedema, and colorectal cancer. Among these, dyspepsia was the only adverse drug reaction for which a causal relationship to the drug could not be excluded.

Adverse events during post-marketing surveillance of glimepiride (oral) monotherapy

According to post-marketing surveillance data on medicinal products containing glimepiride as the active substance, adverse events have been reported regardless of causal relationship to the investigational drug. The most frequently observed adverse events were hypoglycaemia, vertigo (dizziness), liver dysfunction, and abdominal pain. Newly reported adverse events not previously observed in pre-registration clinical trials included arthralgia, dyspepsia, facial oedema, impotence, alopecia, hyperaemia, and gastritis (one case each).

If any of the above-mentioned adverse reactions or other adverse reactions or unexpected changes in health status occur, the patient must immediately inform their physician. Certain adverse reactions, including severe hypoglycaemia, certain blood parameter changes, severe allergic or pseudoallergic reactions, and hepatic failure, may be life-threatening under certain conditions. In such cases, the patient must immediately inform their physician and discontinue further use of the medicinal product until further instructions are received.

Shelf life: 2 years.

Storage conditions:

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

Keep out of reach and sight of children.

Packaging:

10 tablets in a blister; 3 blisters per carton.

10 tablets in a blister; 6 blisters per carton.

Prescription status: Prescription only.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of operations:

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua