Glibenclamide+metformin pills 2.5mg+500mg, 30pcs

Composition

For 1 tablet: Active ingredients: Glibenclamide-2.5 mg, Metformin hydrochloride-500.00 mg, Excipients: Microcrystalline cellulose – 80.0 mg, Croscarmellose sodium-30.0 mg, Povidone-K 25-54.0 mg, Magnesium stearate-3.5 mg. Shell composition: Hypromellose-8.4 mg, Macrogol-4000-2.1 mg, Titanium dioxide-4.3 mg, Iron oxide yellow dye-0.2 mg

Pharmacological action

Pharmacotherapy group: hypoglycemic agents for oral use (a derivative of sulfonylureas of the second generation + biguanide). ATX Code: A10BD02 Pharmacological properties

Pharmacodynamics

The drug is a fixed combination of two oral hypoglycemic agents of different pharmacological groups: metformin and glibenclamide. Metformin belongs to the biguanide group and reduces the content of both basal and postprandial glucose in blood plasma. Metformin does not stimulate insulin secretion and therefore does not cause hypoglycemia.

It has 3 mechanisms of action:

– reduces liver glucose production by inhibiting gluconeogenesis and glycogenolysis;- increases the sensitivity of peripheral insulin receptors, the consumption and utilization of glucose by cells in the muscles; – delays the absorption of glucose in the gastrointestinal tract (GIT).

Metformin also has a beneficial effect on the lipid composition of the blood, reducing the concentration of total cholesterol, low-density lipoproteins (LDL) and triglycerides.

Glibenclamide belongs to the group of second-generation sulfonylurea derivatives. The glucose content of glibenclamide decreases as a result of stimulation of insulin secretion by pancreatic beta cells. Metformin and glibenclamide have different mechanisms of action, but complement each other’s hypoglycemic activity. The combination of two hypoglycemic agents has a synergistic effect in reducing blood glucose.

Pharmacokinetics

Glibenclamide

Absorption rate

When taken orally, absorption from the gastrointestinal tract is more than 95%. The maximum concentration (Cmax) in blood plasma is reached in about 4 hours.

Distribution

Binding to plasma proteins is 99%. The volume of distribution is about 10 liters.

Metabolism and elimination

It is almost completely metabolized in the liver with the formation of two inactive metabolites, which are excreted by the kidneys (40%) and through the intestines (60%). The half-life (T 1/2) is from 4 to 11 hours –

Metformin

Absorption rate

After oral use, metformin is absorbed from the gastrointestinal tract quite completely, Cmax in blood plasma is reached within 2.5 hours. Absolute bioavailability is from 50 to 60%.

Distribution

Metformin is rapidly distributed in tissues, practically does not bind to plasma proteins.

Metabolism

It is metabolized to a very weak degree and is excreted by the kidneys. Approximately 20-30% of metformin is excreted unchanged through the intestine. T 1/2 is, on average,6.5 hours.

With impaired renal function, renal clearance decreases, as does creatinine clearance, while T 1/2 increases, which leads to an increase in the concentration of metformin in blood plasma.

The combination of metformin and glibenclamide in one tablet has the same bioavailability as when taking tablets containing metformin or glibenclamide separately at the same time.

The bioavailability of metformin in combination with glibenclamide is not affected by food intake, as is the bioavailability of glibenclamide. However, the rate of glibenclamide absorption increases with food intake.

Indications

Type 2 diabetes mellitus in adults:

• if diet therapy, exercise and previous monotherapy with metformin or sulfonylurea derivatives are ineffective;
• to replace the previous therapy with two drugs (metformin and a sulfonylurea derivative) in patients with stable and well-controlled glycemia levels.

Use during pregnancy and lactation

The use of the drug is contraindicated during pregnancy. The patient should be warned that during treatment with Glibenclamide + Metformin, it is necessary to inform the doctor about the planned pregnancy and the onset of pregnancy. When planning pregnancy, as well as in case of pregnancy while taking Glibenclamide + Metformin, the drug should be discontinued, and insulin therapy should be prescribed. The drug Glibenclamide + Metformin is contraindicated during breastfeeding, since there are no data on the ability of glibenclamide to penetrate into breast milk.

Contraindications

• hypersensitivity to Metformin, glyburide, or other derivatives of sulfonylurea, as well as auxiliary substances;
• diabetes mellitus, type 1;
• diabetic ketoacidosis, diabetic precoma, diabetic coma;
• renal failure or impaired renal function (creatinine clearance less than 60 ml/min);
• leukopenia;
• severe adrenal insufficiency;
• acute conditions that can lead to a change in kidney function, dehydration, severe infection, shock;
• application in less than 48 hours before and within 48 hours after the radioisotope or radiological examinations with use of iodinated contrast agents;
• acute or chronic diseases that are accompanied by hypoxia of tissues: cardiac or respiratory failure, recent myocardial infarction, shock;
• hepatic impairment;
• porphyria:
• pregnancy, lactation;
• children up to age 18 years;
• concomitant use of miconazole;
• extensive surgery and trauma, when shown holding insulin (see section “Special instructions”);
• malabsorption of food and drugs in the gastrointestinal tract (including intestinal obstruction, ileus);
• chronic alcoholism, acute alcohol intoxication,
• lactic acidosis (including history);
• adherence to a reduced-calorie diet (less than 1000 kcal/day);
• the simultaneous use of bosentan.

With caution

In people over 60 years of age who perform heavy physical work; which is associated with an increased risk of lactic acidosis; with fever syndrome, thyroid diseases (with impaired function), insufficiency of the anterior pituitary or adrenal cortex; in elderly patients due to the risk of hypoglycemia; with glucose-6-phosphate dehydrogenase insufficiency; in the first weeks of treatment (increased risk of hypoglycemia); in the presence of risk factors for hypoglycemia.

Side effects

The frequency of side effects of the drug is estimated as follows: Very frequent: ≥1/10 Frequent: ≥1/100, <1/10 Uncommon: ≥1/1000, <1/100 Rare: ≥1/10 000, <1/1000 Very rare: Blood and lymphatic system disorders: rare:  leukopenia and thrombocytopenia; very rare:  agranulocytosis, hemolytic anemia, bone marrow aplasia and pancytopenia (these adverse events disappear after discontinuation of the drug). Immune system disorders: very rare:  anaphylactic shock: cross-hypersensitivity reactions to sulfonamides and their derivatives. Metabolic and nutritional disorders: common:  hypoglycemia (symptoms: headache, hunger, nausea, vomiting, severe fatigue, sleep disorders, agitation, aggression, impaired concentration and psychomotor reactions, depression, confusion, speech disorders, visual disturbances, tremor, paralysis and paresthesia, dizziness, delirium, convulsions, somnolence, unconsciousness, shallow breathing and bradycardia). Due to compensatory reactions caused by hypoglycemia, increased sweating, fear, tachycardia, hypertension, palpitation, angina pectoris and arrhythmia may occur. The latter symptoms may be absent if hypoglycemia develops slowly, in the case of autonomic neuropathy, or when taking beta-blockers, clonidine, reserpine, guanethidine, or sympathomimetics at the same time. Rarely:  hepatic or cutaneous porphyria; very rare:  lactic acidosis; decreased absorption of vitamin B12 with prolonged use of metformin, accompanied by a decrease in its concentration in the blood serum (if megaloblastic anemia is detected, it is necessary to take into account the possibility of such an etiology); disulfiram-like reaction when drinking alcohol (vomiting, a feeling of “heat” in the face and upper body, tachycardia, dizziness, headache). Nervous system disorders: common:  taste disorder (“metallic” taste in the mouth). Visual disturbances:  at the beginning of treatment, temporary visual impairment may occur due to a decrease in blood glucose. Gastrointestinal disorders: very common:  nausea, vomiting, diarrhea, abdominal pain, and lack of appetite. These symptoms are more common at the beginning of treatment and in most cases go away on their own. To prevent the development of these symptoms, it is recommended to take the drug in 2 or 3 doses; a slow increase in the dose of the drug also improves its tolerability. Liver and biliary tract disorders: very rare:  impaired activity of “liver” enzymes, cholestasis or hepatitis that require discontinuation of treatment. Skin and subcutaneous tissue disorders: rare:  skin reactions such as pruritus, urticaria, maculopapular rash; very rare:  skin or systemic allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitization.Laboratory and instrumental data: infrequent: increased serum urea and creatinine concentrations; very rarely: hyponatremia.

Interaction

Contraindicated combinations

Related to the use of glibenclamide

Miconazole can provoke the development of hypoglycemia (up to the development of coma).

Metformin-related

iodine-containing contrast agents: depending on renal function, the drug should be discontinued 48 hours before and 48 hours after intravenous use of iodine-containing contrast agents.

Not recommended combinations

Related to the use of sulfonylurea derivatives

Alcohol: very rarely, a disulfiram-like reaction (alcohol intolerance) is observed when alcohol and glibenclamide are taken simultaneously. Alcohol intake may increase the hypoglycemic effect (by inhibiting compensatory responses or delaying its metabolic inactivation), which may contribute to the development of hypoglycemic coma. During treatment with the drug, you should avoid taking alcohol and drugs containing ethanol.

Phenylbutazone increases the hypoglycemic effect of sulfonylurea derivatives (replacing sulfonylurea derivatives at protein binding sites and / or reducing their excretion). It is preferable to use other anti-inflammatory drugs that show less interaction, or warn the patient about the need for self-monitoring of the level of glycemia; if necessary, the dose should be adjusted with the combined use of the anti-inflammatory agent and after its discontinuation.

Related to the use of glibenclamide

Bosentan in combination with glibenclamide increases the risk of hepatotoxic effects. The hypoglycemic effect of glibenclamide may also decrease. Concomitant use of these drugs is not recommended.

Related to the use of metformin

Alcohol: the risk of lactic acidosis increases with acute alcohol intoxication, especially in the case of starvation, malnutrition or liver failure. During treatment with the drug, you should avoid taking alcohol and drugs containing ethanol.

Combinations that require caution

Related to the use of all hypoglycemic agents

Chlorpromazine: in high doses (100 mg/day) causes an increase in the level of glycemia (reducing insulin secretion).

Precautions: the patient should be warned about the need for self-monitoring of blood glucose; if necessary, the dose of the drug should be adjusted when used simultaneously with neuroleptics and after discontinuation of their use.

Glucocorticosteroids (corticosteroids) and tetracosactide: an increase in blood glucose, sometimes accompanied by ketosis (corticosteroids cause a decrease in glucose tolerance).

Precautions: the patient should be warned about the need for self-monitoring of blood glucose; if necessary, the dose of the drug should be adjusted when used simultaneously with corticosteroids and after discontinuation of their use.

Danazol it has a hyperglycemic effect. If treatment with danazol is necessary and if the latter is discontinued, a dose adjustment of the drug is required under the control of the glycemic level.

Beta-2-adrenomimetics: due to the stimulation of beta-2-adrenergic receptors, they increase the concentration of glucose in the blood.

Precautions: it is necessary to warn the patient about the need for self-monitoring of blood glucose; it is possible to switch to insulin therapy.

Diuretics: increased blood glucose.

Precautions: the patient should be warned about the need for self-monitoring of blood glucose; it may be necessary to adjust the dose of the drug when used simultaneously with diuretics and after discontinuation of their use.

Angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril) : the use of ACE inhibitors helps to reduce blood glucose. If necessary, the dose of the drug should be adjusted when used simultaneously with ACE inhibitors and after discontinuation of their use.

Related to the use of metformin

Diuretics: lactic acidosis that occurs when taking metformin on the background of functional renal failure caused by taking diuretics, especially “loop”. Glibenclamide-associated

beta-blockers, clonidine, reserpine, guanethidine, and sympathomimetics mask some of the symptoms of hypoglycemia: palpitation and tachycardia; most non-selective beta-blockers increase the frequency and severity of hypoglycemia.

The patient should be warned about the need for self-monitoring of blood glucose, especially at the beginning of treatment.

Fluconazole: an increase in T 1/2 of glibenclamide with the possible development of hypoglycemia. The patient should be warned about the need for self-monitoring of blood glucose; it may be necessary to adjust the dose of the drug during simultaneous use with fluconazole and after discontinuation of its use.

Other interactions: combinations to consider:

Related to the use of glibenclamide

Desmopressin: Glibenclamide + Metformin may reduce the antidiuretic effect of desmopressin.

Antibacterial drugs (drugs) from the group of sulfonamides, fluoroquinolones, anticoagulants (coumarin derivatives), monoamine oxidase inhibitors, chloramphenicol, pentoxifylline, lipid-lowering drugs from the group of fibrates, disopyramide – the risk of hypoglycemia with the use of glibenclamide.

How to take, course of use and dosage

The dose of the drug is determined by the doctor individually for each patient, depending on the level of glycemia. The initial dose is 1 tablet (2.5 mg + 500 mg or 5 mg + 500 mg) of Glibenclamide + Metformin once a day. To avoid hypoglycemia, the initial dose should not exceed the daily dose of glibenclamide (or the equivalent dose of another previously taken sulfonylurea) or metformin, if they were used as first-line therapy. It is recommended to increase the dose by no more than 5 mg of glibenclamide + 500 mg of metformin per day every 2 or more weeks to achieve adequate glycemic control. Replacement of previous combination therapy with metformin and glibenclamide: the initial dose should not exceed the daily dose of glibenclamide (or an equivalent dose of another sulfonylurea) and metformin taken earlier. Every 2 or more weeks after starting treatment, the dose of the drug is adjusted depending on the level of glycemia. The maximum daily dose is 4 tablets of Glibenclamide + Metformin in a dosage of 5 mg + 500 mg or 6 tablets in a dosage of 2.5 mg + 500 mg. Dosage regimenthe dosage mode depends on the individual application:Three times a day, in the morning, afternoon and evening, when using 3,5 or 6 tablets a day. Tablets should be taken with a meal. Each dose of the drug should be accompanied by a meal with a sufficiently high carbohydrate content to prevent the occurrence of hypoglycemia. Use in elderly patientsdose of the drug is selected based on the state of renal function. The initial dose should not exceed 1 tablet of Glibenclamide + Metformin (2.5 mg + 500 mg). Regular assessment of renal function should be performed. Use in deteyapplication of Glibenclamide + Metformin is contraindicated in children.

Overdose

In case of overdose, hypoglycemia may develop due to the presence of glibenclamide in the drug. Mild to moderate symptoms of hypoglycemia without loss of consciousness and neurological manifestations can be corrected by immediate use of sugar. It is necessary to adjust the dose and / or change the diet. The occurrence of severe hypoglycemic reactions in patients with diabetes mellitus, accompanied by coma, convulsions or other neurological disorders, requires urgent medical attention. Intravenous use of dextrose solution is necessary immediately after diagnosis or suspicion of hypoglycemia, before the patient is hospitalized. After regaining consciousness, it is necessary to give the patient food rich in easily digestible carbohydrates (in order to avoid the re-development of hypoglycemia). Prolonged overdose or the presence of associated risk factors can trigger the development of lactic acidosis, since the drug contains metformin. Lactic acidosis is a condition that requires urgent medical attention; treatment of lactic acidosis should be carried out in a clinic. The most effective method for removing lactate and metformin is hemodialysis. Plasma clearance of glibenclamide may increase in patients with liver disease. Since glibenclamide actively binds to blood proteins, it is not eliminated during dialysis.

Special instructions

When using Glibenclamide + Metformin, it is necessary to regularly monitor the level of glycemia on an empty stomach and after meals.

Lactic acidosis

Lactic acidosis is an extremely rare but serious complication (high mortality in the absence of urgent treatment) that can occur due to the accumulation of metformin. Cases of lactic acidosis in patients treated with metformin occurred mainly in patients with diabetes mellitus with severe renal insufficiency.

Other associated risk factors should also be considered, such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, liver failure, and any condition associated with severe hypoxia.

The risk of developing lactic acidosis should be considered if there are non-specific signs, such as muscle cramps accompanied by dyspeptic disorders, abdominal pain and severe malaise. In severe cases, acidotic dyspnea, hypoxia, hypothermia, and coma may occur.

Diagnostic laboratory parameters are: low blood pH, plasma lactate concentration above 5 mmol / L, increased anion interval, and the lactate/pyruvate ratio.

Hypoglycemia

Since the drug Glibenclamide + Metformin contains glibenclamide, taking the drug is accompanied by the risk of hypoglycemia in the patient. Gradually increasing the dose of the drug after starting treatment can prevent the occurrence of hypoglycemia. This drug can only be prescribed to patients who adhere to a regular meal schedule (including breakfast). It is important that carbohydrate intake is regular, as the risk of hypoglycemia increases with late meals, insufficient or unbalanced carbohydrate intake. Hypoglycaemia is most likely to develop with a low-calorie diet, after intense or prolonged physical activity, with alcohol consumption, or when taking a combination of hypoglycaemic agents.

Careful use of the drug, dose selection and proper instructions for the patient are important to reduce the risk of hypoglycemia. If a patient has recurrent episodes of hypoglycemia that are either severe or associated with ignorance of symptoms, treatment with other hypoglycemic agents should be considered.

Factors contributing to the development of hypoglycemia:

– simultaneous use of alcohol, especially during fasting;- refusal or (especially for elderly patients) inability of the patient to interact with the doctor and follow the recommendations set out in the instructions for use; – insufficient nutrition, irregular food intake, fasting or changes in diet;- an imbalance between exercise and carbohydrate intake;- kidney failure;- severe hepatic insufficiency; – overdose of Glibenclamide + Metformin;- individual endocrine disorders: insufficient function of the thyroid gland, pituitary gland or adrenal glands;- simultaneous use of individual drugs.

Renal and hepatic insufficiency

The pharmacokinetics and/or pharmacodynamics of the drug may vary in patients with hepatic insufficiency or severe renal insufficiency. The hypoglycemia that occurs in such patients may be prolonged, in which case appropriate treatment should be initiated.

Unstable blood glucose levels

In case of surgical intervention or other cause of decompensation of diabetes mellitus, it is recommended to provide for a temporary transition to insulin therapy. Symptoms of hyperglycemia include frequent urination, extreme thirst, and dry skin.

Glibenclamide + Metformin should be discontinued 48 hours before elective surgery or intravenous use of an iodine-containing radiopaque agent. Treatment is recommended to be resumed after 48 hours, and only after renal function has been assessed and found to be normal.

Kidney function

Since metformin is excreted by the kidneys, before starting treatment, and regularly thereafter, it is necessary to determine the creatinine clearance and / or serum creatinine content: at least once a year in patients with normal renal function, and 2-4 times a year in elderly patients, as well as in patients with creatinine clearance at the upper limit of normal. Special caution is recommended in cases where renal function may be impaired, such as in elderly patients, or when starting antihypertensive therapy, diuretics, or nonsteroidal anti-inflammatory drugs (NSAIDs).

Other safety measures

The patient should inform the doctor about the appearance of a bronchopulmonary infection or an infectious disease of the genitourinary organs.

Influence on the ability to drive vehicles and mechanisms

Patients should be informed about the risk of hypoglycemia and should take precautions when driving vehicles and working with mechanisms that require increased concentration of attention and speed of psychomotor reactions.

Storage conditions

At a temperature not exceeding 25°C. Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date.

Active ingredient

Glibenclamide, Metformin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets