Glidika^® M (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

ATC Code

A10BD02 (Metformin and sulfonamides)

Active Substances

Metformin (Rec.INN registered by WHO)

Glimepiride (Rec.INN registered by WHO)

Dosage Forms

	Glidika® M	Film-coated tablets, 1 mg+250 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 2 mg+500 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex.

Excipients: calcium stearate – 3.6 mg, croscarmellose sodium – 14 mg, macrogol (polyethylene glycol 6000) – 3.6 mg, mannitol – 43.6 mg, povidone K 30 – 14 mg, microcrystalline cellulose – 30.2 mg.

Film coating composition Opadry II white (polyvinyl alcohol – 5.159 mg, macrogol (polyethylene glycol) – 2.596 mg, talc – 1.914 mg, titanium dioxide – 1.331 mg) – 11 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
15 pcs. – contour cell packaging (2) – cardboard packs.
15 pcs. – contour cell packaging (4) – cardboard packs.
15 pcs. – contour cell packaging (6) – cardboard packs.

Film-coated tablets white or almost white, oval, biconvex.

Excipients: calcium stearate – 7.2 mg, croscarmellose sodium – 28 mg, macrogol (polyethylene glycol 6000) – 7.2 mg, mannitol – 87.2 mg, povidone K 30 – 28 mg, microcrystalline cellulose – 60.4 mg.

Film coating composition Opadry II white (polyvinyl alcohol – 10.318 mg, macrogol (polyethylene glycol) – 5.192 mg, talc – 3.828 mg, titanium dioxide – 2.662 mg) – 22 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; combinations of oral hypoglycemic drugs

Pharmacological Action

Combined hypoglycemic agent.

Glimepiride – an oral hypoglycemic drug, a third-generation sulfonylurea derivative.

It stimulates the secretion and release of insulin from pancreatic beta-cells (pancreatic action) and improves the sensitivity of peripheral tissues (muscle and adipose) to the action of endogenous insulin (extrapancreatic action).

Sulfonylurea derivatives increase insulin secretion by closing ATP-dependent potassium channels located in the cytoplasmic membrane of pancreatic beta-cells.

By closing potassium channels, they cause depolarization of beta-cells, which promotes the opening of calcium channels and increases calcium influx into the cells.

Glimepiride binds to and dissociates from the pancreatic beta-cell protein (molecular weight 65 kD/SURX), which is associated with ATP-dependent potassium channels, with a high replacement rate, but differs from the binding site of conventional sulfonylurea derivatives (protein with molecular weight 140 kD/SUR1).

This process leads to the release of insulin through exocytosis.

The minimal stimulating effect of glimepiride on insulin secretion also ensures a lower risk of hypoglycemia.

Like traditional sulfonylurea derivatives, but to a much greater extent, Glimepiride has pronounced extrapancreatic effects (reduction of insulin resistance, antiatherogenic, antiplatelet and antioxidant action).

Glucose utilization by peripheral tissues (muscle and adipose) occurs with the help of special transport proteins (GLUT1 and GLUT4) located in cell membranes.

Glucose transport into these tissues in type 2 diabetes mellitus is a rate-limiting step in glucose utilization.

Glimepiride very quickly increases the number and activity of glucose-transporting molecules (GLUT1 and GLUT4), promoting increased glucose uptake by peripheral tissues.

Glimepiride has a weaker inhibitory effect on ATP-dependent potassium channels of cardiomyocytes.

When taking glimepiride, the ability of myocardial metabolic adaptation to ischemia is preserved.

Glimepiride increases the activity of phospholipase C, resulting in a decrease in intracellular calcium concentration in muscle and fat cells, causing a decrease in protein kinase A activity, which in turn leads to stimulation of glucose metabolism.

Glimepiride inhibits glucose release from the liver by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn inhibits gluconeogenesis.

Glimepiride selectively inhibits COX and reduces the conversion of arachidonic acid to thromboxane A₂, an important endogenous platelet aggregation factor.

Glimepiride helps reduce lipid content, significantly reduces lipid peroxidation, which is associated with its antiatherogenic action.

Glimepiride increases the content of endogenous alpha-tocopherol, the activity of catalase, glutathione peroxidase and superoxide dismutase, which helps reduce the severity of oxidative stress in the patient’s body, which is constantly present in patients with type 2 diabetes mellitus.

Metformin is a hypoglycemic drug from the biguanide group.

Its hypoglycemic effect is only possible provided that insulin secretion is preserved (albeit reduced).

Metformin does not affect pancreatic beta-cells and does not increase insulin secretion.

Metformin in therapeutic doses does not cause hypoglycemia in humans.

The mechanism of action of metformin has not yet been fully elucidated.

It is assumed that metformin may potentiate the effects of insulin, or that it may enhance the effects of insulin at peripheral receptor sites.

Metformin increases tissue sensitivity to insulin by increasing the number of insulin receptors on the surface of cell membranes.

In addition, metformin inhibits gluconeogenesis in the liver, reduces the formation of free fatty acids and fat oxidation, and reduces the concentration of triglycerides (TG), LDL and VLDL in the blood.

Metformin slightly reduces appetite and reduces carbohydrate absorption in the intestine.

It improves the fibrinolytic properties of blood by suppressing the tissue plasminogen activator inhibitor.

Pharmacokinetics

Glimepiride

After multiple oral administration at a daily dose of 4 mg, C_max in blood serum is reached in approximately 2.5 hours and is 309 ng/ml.

There is a linear relationship between the dose and C_max of glimepiride in plasma, as well as between the dose and AUC.

When taken orally, the absolute bioavailability of glimepiride is complete.

Food intake does not have a significant effect on absorption, except for a slight slowdown in its rate.

Glimepiride is characterized by a very low V_d (about 8.8 L), approximately equal to the V_d of albumin, a high degree of binding to plasma proteins (more than 99%) and low clearance (about 48 ml/min).

It is excreted in breast milk and crosses the placental barrier.

It poorly penetrates the BBB.

It is metabolized in the liver to form two metabolites – hydroxylated and carboxylated derivatives, which are found in urine and feces.

T_1/2 at plasma drug concentrations in serum corresponding to multiple doses is approximately 5-8 hours.

After taking glimepiride in high doses, T_1/2 increases somewhat.

After a single oral dose, 58% of glimepiride is excreted by the kidneys (as metabolites) and 35% through the intestines.

No unchanged active substance is found in the urine.

The terminal T_1/2 of the hydroxylated and carboxylated metabolites of glimepiride is 3-5 hours and 5-6 hours, respectively.

Metformin

After oral administration, metformin is sufficiently completely absorbed from the gastrointestinal tract.

The absolute bioavailability is 50-60%.

C_max in plasma is approximately 2 µg/ml and is reached after 2.5 hours.

When taken simultaneously with food, the absorption of metformin is reduced and slowed down.

Metformin is rapidly distributed into tissues and practically does not bind to plasma proteins.

It is metabolized to a very weak extent.

T_1/2 is approximately 6.5 hours.

It is excreted by the kidneys.

Clearance in healthy volunteers is 440 ml/min (4 times greater than GFR), which indicates the presence of active tubular secretion of metformin.

In renal failure, there is a risk of drug accumulation.

.

Indications

Treatment of type 2 diabetes mellitus (in addition to diet, physical activity and weight loss): when glycemic control cannot be achieved with glimepiride or metformin monotherapy; when replacing combination therapy with glimepiride and metformin with a single combined drug containing Glimepiride and metformin in an appropriate fixed combination.

ICD codes

Dosage Regimen

As a rule, the dose is determined by the patient’s target blood glucose concentration.

The lowest dose sufficient to achieve the necessary metabolic control should be used.

During treatment, it is necessary to regularly determine the blood glucose concentration.

In addition, regular monitoring of the percentage of glycated hemoglobin in the blood is recommended.

Since improvement in metabolic control is associated with increased tissue sensitivity to insulin, during treatment with this combination, the need for glimepiride may decrease.

To avoid the development of hypoglycemia, it is necessary to reduce the doses or discontinue the drug in a timely manner.

Take orally 1-2 times/day with meals.

The maximum single dose of metformin is 1000 mg.

The maximum daily dose: for glimepiride – 8 mg, for metformin – 2000 mg.

Only a small number of patients are more effective with a daily dose of glimepiride greater than 6 mg.

To avoid the development of hypoglycemia, the initial dose should not exceed the daily doses of glimepiride and metformin that the patient is already taking.

When transferring patients from taking a combination of separate glimepiride and metformin drugs to this combination, its dose is determined based on the already taken doses of glimepiride and metformin in the form of separate drugs.

Treatment is usually long-term.

It is known that metformin is excreted mainly by the kidneys, and since the risk of severe adverse reactions to metformin in patients with impaired renal function is higher, it can only be used in patients with normal renal function.

Since renal function decreases with age, metformin should be used with caution in elderly patients.

The dose should be carefully selected and careful and regular monitoring of renal function should be ensured.

Adverse Reactions

Glimepiride

From the side of metabolism the development of hypoglycemia is possible, which may be prolonged.

Symptoms of developing hypoglycemia – headache, acute feeling of hunger, nausea, vomiting, weakness, lethargy, sleep disorders, anxiety, aggressiveness, decreased concentration, decreased alertness and slowed psychomotor reactions, depression, confusion, speech disorders, aphasia, visual disturbances, tremor, paresis, sensitivity disorders, dizziness, helplessness, loss of self-control, delirium, convulsions, drowsiness and loss of consciousness up to the development of coma, shallow breathing and bradycardia.

In addition, the development of symptoms of adrenergic counter-regulatory response to developing hypoglycemia is possible, such as increased sweating, clammy skin, increased anxiety, tachycardia, increased blood pressure, feeling of palpitations, angina and cardiac arrhythmias.

The clinical picture of a severe hypoglycemic attack may resemble an acute cerebrovascular accident.

Symptoms almost always resolve after hypoglycemia is eliminated.

From the organ of vision: temporary visual impairment, especially at the beginning of treatment, due to fluctuations in blood glucose concentration.

The cause of visual impairment is a temporary change in the swelling of the lenses, depending on the blood glucose concentration, and thereby a change in their refractive index.

From the digestive system: development of gastrointestinal symptoms such as nausea, vomiting, feeling of stomach fullness, abdominal pain and diarrhea.

From the liver and biliary tract: hepatitis, increased activity of liver enzymes and/or cholestasis and jaundice, which may progress to life-threatening liver failure, but may be reversible after discontinuation of glimepiride.

From the hematopoietic system: thrombocytopenia, in some cases – leukopenia or hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia; cases of severe thrombocytopenia (with platelet count less than 10,000/µl) and thrombocytopenic purpura have been reported.

From the immune system : allergic or pseudoallergic reactions (e.g., itching, urticaria or rash).

These reactions are almost always mild, but can progress to a severe form with shortness of breath or decreased blood pressure, up to the development of anaphylactic shock.

Allergic vasculitis.

Other: photosensitivity, hyponatremia.

Metformin

From the side of metabolism lactic acidosis.

From the digestive system: often – nausea, vomiting, diarrhea, abdominal pain, increased gas formation, flatulence and anorexia, the appearance of an unpleasant or metallic taste in the mouth, which usually disappears spontaneously.

From the liver and biliary tract: deviation from the norm of liver function test indicators or hepatitis, which were reversible when metformin was discontinued.

From the skin and subcutaneous tissues: erythema, itching, rash.

From the hematopoietic system: anemia, leukocytopenia or thrombocytopenia.

In patients taking metformin for a long time, there is usually an asymptomatic decrease in the concentration of vitamin B₁₂ in the blood serum due to a decrease in its intestinal absorption.

If a patient has megaloblastic anemia, the possibility of reduced vitamin B₁₂ absorption associated with metformin intake should be considered.

Contraindications

Type 1 diabetes mellitus; diabetic ketoacidosis (including history), diabetic coma and precoma; acute or chronic metabolic acidosis; severe liver dysfunction (no experience of use; insulin therapy is required to ensure adequate glycemic control); patients on hemodialysis (no experience of use); renal failure and impaired renal function (plasma creatinine concentration ≥1.5 mg/dl (135 µmol/L) in men and ≥1.2 mg/dl (110 µmol/L) in women or decreased GFR (increased risk of lactic acidosis and other side effects of metformin); acute conditions in which renal function may be impaired (dehydration, severe infections, shock, intravascular administration of iodine-containing contrast agents); acute and chronic diseases that can cause tissue hypoxia (cardiac or respiratory failure, acute and subacute myocardial infarction, shock); tendency to develop lactic acidosis, history of lactic acidosis; stressful situations (severe injuries, burns, surgical operations, severe infections with febrile condition, septicemia); exhaustion, starvation, adherence to a hypocaloric diet (less than 1000 cal/day); impaired absorption of food and drugs in the gastrointestinal tract (with intestinal obstruction, intestinal paresis, diarrhea, vomiting); chronic alcoholism, acute alcohol intoxication; pregnancy, pregnancy planning, breastfeeding period; age under 18 years; hypersensitivity to the components of the combination; hypersensitivity to sulfonylurea derivatives, sulfonamide drugs or biguanides.

With caution

In the first weeks of treatment, the risk of hypoglycemia increases, which requires especially careful monitoring.

Conditions in which the risk of developing hypoglycemia is increased (patients who are unwilling or unable to cooperate with a doctor, most often elderly patients; poorly nourished, irregularly eating, skipping meals patients; with a discrepancy between physical activity and carbohydrate intake; when changing diet; when consuming beverages containing ethanol, especially in combination with skipping meals; with impaired liver and kidney function; with some uncompensated endocrine disorders, such as thyroid dysfunction, insufficiency of anterior pituitary and adrenal cortex hormones that affect carbohydrate metabolism or the activation of mechanisms aimed at increasing blood glucose concentration during hypoglycemia; with the development of intercurrent diseases during treatment or when lifestyle changes (such patients require more careful monitoring of blood glucose concentration and signs of hypoglycemia, they may require dose adjustment of this combination).

With simultaneous use of some other drugs; in elderly patients (they often have asymptomatic decreased renal function); in situations where renal function may worsen, such as starting to take antihypertensive drugs or diuretics, as well as NSAIDs (increased risk of lactic acidosis and other side effects of metformin); when performing heavy physical work (the danger of developing lactic acidosis when taking metformin increases); with blurred or absent symptoms of adrenergic counter-regulatory response to developing hypoglycemia (in elderly patients, with autonomic neuropathy or with simultaneous therapy with beta-blockers, clonidine, guanethidine and other sympatholytics; such patients require more careful monitoring of blood glucose concentration); with glucose-6-phosphate dehydrogenase deficiency (in such patients, when taking sulfonylurea derivatives, the development of hemolytic anemia is possible, so the use of alternative hypoglycemic drugs that are not sulfonylurea derivatives in such patients should be considered).

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use is contraindicated in severe liver function disorders.

Use in Renal Impairment

Contraindicated in renal failure and impaired renal function (serum creatinine concentration ≥ 1.5 mg/dL (135 µmol/L) in men and ≥ 1.2 mg/dL (110 µmol/L) in women or decreased creatinine clearance (increased risk of lactic acidosis and other side effects of metformin); acute conditions that may impair renal function (dehydration, severe infections, shock, intravascular administration of iodine-containing contrast media).

Pediatric Use

The safety and efficacy of the drug in children with type 2 diabetes mellitus have not been studied.

Geriatric Use

Caution should be exercised when using the drug in elderly patients (they often have asymptomatic decline in renal function), in situations where renal function may deteriorate, such as initiation of antihypertensive drugs or diuretics, as well as NSAIDs (increased risk of lactic acidosis and other side effects of metformin).

Special Precautions

Lactic acidosis is a rare but serious (with high mortality if not treated properly) metabolic complication that develops as a result of metformin accumulation during treatment. Cases of lactic acidosis during metformin intake were observed mainly in diabetic patients with severe renal failure. The incidence of lactic acidosis can and should be reduced by assessing the presence of other associated risk factors for lactic acidosis in patients, such as poorly controlled diabetes, ketoacidosis, prolonged fasting, heavy consumption of ethanol-containing beverages, liver failure, and conditions accompanied by tissue hypoxia.

Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, and hypothermia, followed by coma. Diagnostic laboratory findings include increased blood lactate concentration (>5 mmol/L), decreased blood pH, electrolyte imbalance with an increased anion gap and lactate/pyruvate ratio. In cases where metformin is the cause of lactic acidosis, the plasma concentration of metformin is usually >5 µg/mL. If lactic acidosis is suspected, metformin should be discontinued immediately, and the patient should be hospitalized immediately.

The reported incidence of lactic acidosis in patients taking metformin is very low (about 0.03 cases/1000 patient-years). Reported cases occurred mainly in diabetic patients with severe renal failure, including congenital kidney disease and renal hypoperfusion, often in the presence of numerous comorbidities requiring medical and surgical treatment.

The risk of developing lactic acidosis increases with the severity of renal impairment and with age. The likelihood of lactic acidosis when taking metformin can be significantly reduced by regular monitoring of renal function and the use of the minimum effective doses of metformin. For the same reason, in conditions associated with hypoxemia or dehydration, the use of this combination should be avoided.

Since impaired liver function can significantly limit the excretion of lactate, the use of this combination should be avoided in patients with clinical or laboratory signs of liver disease.

In addition, administration should be temporarily discontinued before X-ray examinations with intravascular administration of iodine-containing contrast media and before surgical interventions. Metformin should be discontinued for a period of 48 hours before and 48 hours after surgery using general anesthesia.

Often, lactic acidosis develops gradually and manifests only with nonspecific symptoms, such as malaise, myalgia, respiratory distress, increasing drowsiness, and nonspecific gastrointestinal disorders. In more severe acidosis, hypothermia, decreased blood pressure, and resistant bradyarrhythmia may develop. Both the patient and the treating physician should be aware of how important these symptoms can be. The patient should be instructed to notify the doctor immediately if such symptoms occur. To clarify the diagnosis of lactic acidosis, it is necessary to determine the concentration of electrolytes and ketones in the blood, blood glucose concentration, blood pH, and the concentration of lactate and metformin in the blood. A fasting venous plasma lactate concentration exceeding the upper limit of normal but below 5 mmol/L in patients taking metformin does not necessarily indicate lactic acidosis; its increase may be explained by other mechanisms, such as poorly controlled diabetes or obesity, intense physical exertion, or technical errors in blood sampling.

Lactic acidosis should be suspected in a diabetic patient with metabolic acidosis in the absence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a critical condition requiring inpatient treatment. In case of lactic acidosis, this combination should be discontinued immediately and general supportive measures should be initiated. Metformin is removed from the blood by hemodialysis with a clearance of up to 170 ml/min, therefore, in the absence of hemodynamic disturbances, immediate hemodialysis is recommended to remove the accumulated metformin and lactate. Such measures often lead to rapid resolution of symptoms and recovery.

The effectiveness of any hypoglycemic therapy should be monitored by periodic monitoring of blood glucose and glycosylated hemoglobin concentrations. The goal of treatment is to normalize these parameters. The concentration of glycosylated hemoglobin allows assessment of glycemic control.

During the first week of treatment, careful monitoring is necessary due to the risk of hypoglycemia, especially in patients at increased risk of its development (patients who are unwilling or unable to follow the doctor’s recommendations, most often elderly patients; with poor nutrition, irregular meals, missed meals; with a mismatch between physical activity and carbohydrate intake; with changes in diet, with ethanol consumption especially in combination with missed meals; with impaired renal function; with severe liver dysfunction; with some uncompensated endocrine disorders (for example, some thyroid disorders and insufficiency of anterior pituitary hormones or adrenal cortex hormones; with simultaneous use of certain other drugs affecting carbohydrate metabolism.

In such cases, careful monitoring of blood glucose concentration is necessary. The patient should inform the doctor about these risk factors and about symptoms of hypoglycemia, if any. In the presence of risk factors for hypoglycemia, adjustment of the dose of this drug or the entire therapy may be required. This approach is used whenever any illness develops or the patient’s lifestyle changes during therapy. Symptoms of hypoglycemia, reflecting adrenergic counterregulatory responses to developing hypoglycemia, may be less pronounced or absent altogether if hypoglycemia develops gradually, as well as in elderly patients, with autonomic neuropathy, or with concomitant therapy with beta-blockers, clonidine, guanethidine, and other sympatholytics.

Hypoglycemia can almost always be quickly corrected by immediate intake of carbohydrates (glucose or sugar, for example, a lump of sugar, sugar-containing fruit juice, sweet tea). For this purpose, the patient should carry at least 20 grams of sugar with them. They may need the help of others to avoid complications. Sugar substitutes are ineffective.

Based on experience with other sulfonylurea drugs, it is known that, despite the initial effectiveness of the countermeasures taken, hypoglycemia may recur, so patients should remain under close observation. The development of severe hypoglycemia requires immediate treatment and medical supervision, in some cases – inpatient treatment.

Target glycemia should be maintained through comprehensive measures: diet and exercise, weight loss, and if necessary, regular intake of hypoglycemic drugs. Patients should be informed about the importance of following dietary prescriptions and performing regular physical exercises.

Clinical symptoms of inadequately regulated blood glycemia include oliguria, thirst, pathologically severe thirst, dry skin, and others.

If the patient is treated by someone other than the attending physician (for example, hospitalization, accident, need for a doctor’s visit on a day off), the patient must inform them about the diabetes mellitus and the treatment being carried out.

In stressful situations (for example, trauma, surgery, infectious disease with fever), glycemic control may be impaired, and a temporary switch to insulin therapy may be required to ensure the necessary metabolic control.

It is known that metformin is excreted mainly by the kidneys. In case of impaired renal function, the risk of metformin accumulation and the development of lactic acidosis increases. If the serum creatinine concentration exceeds the upper age limit of normal, it is not recommended to take this combination. For elderly patients, careful dose titration of metformin is necessary to select the minimum effective dose, as renal function declines with age. Renal function in elderly patients should be monitored regularly, and, as a rule, the metformin dose should not be increased to its maximum daily dose.

Concomitant use of other drugs may affect renal function or the excretion of metformin or cause significant hemodynamic changes.

Radiological examinations with intravascular administration of iodine-containing contrast media (for example, intravenous urography, intravenous cholangiography, angiography, and CT with contrast medium): intravenous iodine-containing contrast media intended for examinations can cause acute renal impairment, their use is associated with the development of lactic acidosis in patients taking metformin. If such an examination is planned, this combination must be discontinued before the procedure and not resumed for 48 hours after the procedure. Treatment can be resumed only after monitoring and obtaining normal renal function parameters.

Collapse or shock of any origin, acute heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia and tissue hypoxia can also cause prerenal renal failure and increase the risk of lactic acidosis. If such conditions occur in patients taking the drug containing this combination, the drug should be discontinued immediately.

For any planned surgical intervention, therapy with this combination must be discontinued 48 hours before (except for minor procedures that do not require restrictions on food and fluid intake), therapy should not be resumed until oral food intake is restored and renal function is deemed normal.

It is known that ethanol enhances the effect of metformin on lactate metabolism. Patients should be cautioned against consuming ethanol-containing beverages while taking this medication.

Since impaired liver function in some cases was accompanied by lactic acidosis, patients with clinical or laboratory signs of liver damage should avoid using this combination.

A diabetic patient previously well controlled with metformin should be examined immediately, especially in the case of a vaguely and poorly recognized illness, to rule out ketoacidosis and lactic acidosis. In the presence of any form of acidosis, this combination should be discontinued immediately and other drugs should be prescribed to maintain glycemic control.

A decrease in serum vitamin B₁₂ concentration below normal without clinical manifestations was observed in some cases in patients taking this combination. It was very rarely accompanied by anemia and was quickly reversible upon discontinuation of this drug or upon administration of vitamin B₁₂. Patients with insufficient intake or absorption of vitamin B₁₂ are predisposed to a decrease in vitamin B₁₂ concentration. For such patients, regular, every 2-3 years, determination of serum vitamin B₁₂ concentration may be useful.

Hematological parameters (hemoglobin or hematocrit, red blood cell count) and renal function parameters (serum creatinine concentration) should be monitored periodically at least once a year in patients with normal renal function, and at least 2-4 times a year in patients with serum creatinine concentration at the upper limit of normal and in elderly patients. If necessary, the patient should undergo appropriate examination and treatment of any obvious pathological changes. Although megaloblastic anemia has rarely been observed during metformin use, if it is suspected, an examination should be performed to rule out vitamin B₁₂ deficiency.

The patient’s reaction speed may be impaired as a result of hypoglycemia and hyperglycemia, especially at the beginning of treatment or after changes in treatment, or with irregular intake of the drug. This may affect the abilities necessary for driving vehicles and engaging in other potentially hazardous activities. Patients should be warned to exercise caution when driving vehicles, especially in case of a tendency to develop hypoglycemia and/or a decrease in the severity of its warning signs.

Drug Interactions

When other drugs are simultaneously prescribed or discontinued in a patient taking Glimepiride, adverse reactions are possible: enhancement or weakening of the hypoglycemic effect of glimepiride. Based on the clinical experience with glimepiride and other sulfonylurea drugs, the following drug interactions should be considered.

With drugs that are inducers and inhibitors of the CYP2C9 isoenzyme: Glimepiride is metabolized with the participation of the CYP2C9 isoenzyme. Its metabolism is affected by the simultaneous use of inducers of the CYP2C9 isoenzyme, for example, rifampicin (risk of reduction of the hypoglycemic effect of glimepiride when used concomitantly with inducers of the CYP2C9 isoenzyme and increased risk of hypoglycemia in case of their discontinuation without adjustment of the glimepiride dose) and inhibitors of the CYP2C9 isoenzyme, for example, fluconazole (increased risk of hypoglycemia and side effects of glimepiride when taken concomitantly with inhibitors of the CYP2C9 isoenzyme and risk of reduction of its hypoglycemic effect in case of their discontinuation without adjustment of the glimepiride dose).

With drugs that enhance the hypoglycemic effect of glimepiride: insulin and oral hypoglycemic drugs, ACE inhibitors, anabolic steroids, male sex hormones, chloramphenicol, indirect anticoagulants of the coumarin derivative type, cyclophosphamide, disopyramide, fenfluramine, phenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, MAO inhibitors, miconazole, fluconazole, aminosalicylic acid, pentoxifylline (high doses parenterally), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, antimicrobial drugs of the quinolone derivative type, salicylates, sulfinpyrazone, clarithromycin, sulfonamide antimicrobial drugs, tetracyclines, tritoqualine, trophosphamide: increased risk of hypoglycemia when these drugs are used concomitantly with glimepiride and risk of deterioration of glycemic control upon their discontinuation without adjustment of the glimepiride dose.

With drugs that weaken the hypoglycemic effect: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) or other sympathomimetics, glucagon, laxatives (long-term use), nicotinic acid (high doses), estrogens, progestogens, phenothiazines, phenytoin, rifampicin, thyroid hormones: risk of deterioration of glycemic control when used concomitantly with these drugs and increased risk of hypoglycemia in case of their discontinuation without adjustment of the glimepiride dose.

With histamine H₂-receptor blockers, beta-blockers, clonidine, reserpine, guanethidine: both enhancement and reduction of the hypoglycemic effect of glimepiride are possible. Careful monitoring of blood glucose concentration is necessary. Beta-blockers, clonidine, guanethidine, and reserpine, by blocking the reactions of the sympathetic nervous system in response to hypoglycemia, can make the development of hypoglycemia less noticeable to the patient and the doctor and thereby increase the risk of its occurrence.

With ethanol: acute and chronic consumption of ethanol can unpredictably either weaken or enhance the hypoglycemic effect of glimepiride. In acute alcohol intoxication, the risk of lactic acidosis increases, especially in case of missed or insufficient food intake, presence of liver failure. Consumption of alcohol (ethanol) and ethanol-containing preparations should be avoided.

With indirect anticoagulants, coumarin derivatives: Glimepiride can both enhance and reduce the effects of indirect anticoagulants, coumarin derivatives.

With bile acid sequestrants colesevelam binds to glimepiride and reduces the absorption of glimepiride from the gastrointestinal tract. If glimepiride is taken at least 4 hours before oral administration of colesevelam, no interaction is observed. Therefore, Glimepiride must be taken at least 4 hours before taking colesevelam.

With iodine-containing contrast media: intravascular administration of iodine-containing contrast preparations can lead to the development of renal failure, which in turn can lead to the accumulation of metformin and an increased risk of lactic acidosis. Metformin should be discontinued before the examination or during the examination and not resumed for 48 hours after it; resumption of metformin is possible only after the examination and obtaining normal renal function parameters.

With antibiotics with pronounced nephrotoxic effect (gentamicin): increased risk of lactic acidosis.

With corticosteroids (systemic and topical), beta₂-adrenergic agonists and diuretics with intrinsic hyperglycemic activity: the patient should be informed about the need for more frequent monitoring of morning blood glucose concentration, especially at the beginning of combination therapy. Adjustment of doses of hypoglycemic therapy may be required during use or after discontinuation of the above drugs.

With ACE inhibitors: ACE inhibitors may reduce blood glucose concentration. Adjustment of doses of hypoglycemic therapy may be required during use or after discontinuation of ACE inhibitors.

With drugs that enhance the hypoglycemic effect of metformin: insulin, sulfonylurea drugs, anabolic steroids, guanethidine, salicylates (including acetylsalicylic acid), beta-blockers (including propranolol), MAO inhibitors: in case of simultaneous use of these drugs with metformin, careful observation of the patient and monitoring of blood glucose concentration are necessary, as an enhancement of the hypoglycemic effect of metformin is possible.

With drugs that weaken the hypoglycemic effect of metformin: epinephrine, glucocorticosteroids, thyroid hormones, estrogens, pyrazinamide, isoniazid, nicotinic acid, phenothiazines, thiazide diuretics and diuretics of other groups, oral contraceptives, phenytoin, sympathomimetics, slow calcium channel blockers: in case of simultaneous use of these drugs with metformin, careful monitoring of the patient and control of blood glucose concentration is necessary, as a weakening of the hypoglycemic effect is possible.

With furosemide: in a clinical study of the interaction between metformin and furosemide during their single administration in healthy volunteers, it was shown that simultaneous use of these drugs affects their pharmacokinetic parameters. Furosemide increased the C_max of metformin in blood plasma by 22% and the AUC by 15% without any significant changes in the renal clearance of metformin. When used with metformin, the C_max and AUC of furosemide decreased by 31% and 12%, respectively, compared with furosemide monotherapy, and the terminal T_1/2 decreased by 32% without any significant changes in the renal clearance of furosemide. There is no information on the interaction between metformin and furosemide during long-term use.

With nifedipine: in a clinical study of the interaction between metformin and nifedipine during their single administration in healthy volunteers, it was shown that simultaneous use of nifedipine increases the C_max and AUC of metformin in blood plasma by 20% and 9%, respectively, and also increases the amount of metformin excreted by the kidneys. Metformin had a minimal effect on the pharmacokinetics of nifedipine.

With cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin): cationic drugs excreted by tubular secretion in the kidneys can theoretically interact with metformin as a result of competition for a common tubular transport system. Such an interaction between metformin and oral cimetidine was observed in healthy volunteers in clinical studies of the interaction between metformin and cimetidine during single and multiple administration, where a 60% increase in plasma C_max and the total blood concentration of metformin and a 40% increase in the plasma and total AUC of metformin were noted. No changes in T_1/2 were observed after a single dose. Metformin did not affect the pharmacokinetics of cimetidine. Although such interaction remains purely theoretical (except for cimetidine), careful monitoring of patients and dose adjustment of metformin and/or the interacting drug should be provided in case of simultaneous administration of cationic drugs excreted by the secretory system of the proximal renal tubules.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.