Glibenclamide+Metformin, 5 mg+500 mg 30 pcs

Pharmacotherapeutic group: oral hypoglycemic agents (sulfonylurea derivative of the II 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 both basal and postprandial plasma glucose levels. Metformin does not stimulate insulin secretion and therefore does not cause hypoglycemia.

Has 3 mechanisms of action:

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

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

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

Pharmacokinetics

Glibenclamide

Absorption

In oral administration, absorption from the GI tract is more than 95%. The maximum concentration (Cmax) in plasma is reached in about 4 hours.

Distribution

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

Metabolism and excretion

It is almost completely metabolized in the liver to form two inactive metabolites, which are excreted by the kidneys (40%) and through the intestine (60%). The elimination half-life (T1/2) is 4 to 11 hours.

Metformin

Absorption

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

Distribution

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

Metabolism

It is metabolized to a very low degree and is excreted by the kidneys. About 20-30% of metformin is excreted unchanged in the intestine. T1/2 is on average 6.5 hours.

In impaired renal function, renal clearance decreases as does creatinine clearance, with an increased T1/2 that leads to increased plasma concentrations of metformin.

The combination of metformin and glibenclamide in one tablet has the same bioavailability as when tablets containing metformin or glibenclamide are taken simultaneously separately.

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

Indications

Type 2 diabetes mellitus in adults:

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

Pharmacological effect

Pharmacotherapeutic group: hypoglycemic agent for oral use (second generation sulfonylurea derivative + 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 group of biguanides and reduces the content of both basal and postprandial glucose in the blood plasma. Metformin does not stimulate insulin secretion and therefore does not cause hypoglycemia.

Has 3 mechanisms of action:

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

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

Glibenclamide belongs to the group of sulfonylurea derivatives of the second generation. Glucose content when taking glibenclamide decreases as a result of stimulation of insulin secretion by pancreatic β-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

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

Distribution

Communication with plasma proteins is 99%. Distribution volume – about 10 l.

Metabolism and excretion

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%). Half-life (T1/2) – from 4 to 11 hours.

Metformin

Absorption

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

Distribution

Metformin is quickly distributed in tissues and practically does not bind to plasma proteins.

Metabolism

It is metabolized to a very weak extent and is excreted by the kidneys. Approximately 20-30% of metformin is excreted unchanged through the intestines. T1/2 is, on average, 6.5 hours.

When renal function is impaired, renal clearance decreases, as does creatinine clearance, while T1/2 increases, which leads to an increase in the concentration of metformin in the blood plasma.

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

The bioavailability of metformin in combination with glibenclamide is not affected by food intake, nor is the bioavailability of glibenclamide. However, the rate of absorption of glibenclamide increases with food intake.

Special instructions

While using the drug 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 (high mortality rate if not treated urgently) complication that can occur due to the accumulation of metformin. Cases of lactic acidosis in patients receiving metformin occurred mainly in diabetic patients with severe renal failure.

Other associated risk factors should 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 taken into account when nonspecific signs appear, 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 gap and lactate/pyruvate ratio.

Hypoglycemia

Since the drug Glibenclamide + Metformin contains glibenclamide, taking the drug is accompanied by a 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 diet (including breakfast). It is important that carbohydrate intake is regular, as the risk of hypoglycemia increases with late meals, insufficient or unbalanced carbohydrate intake. The development of hypoglycemia is most likely during a hypocaloric diet, after intense or prolonged physical activity, when drinking alcohol, or when taking a combination of hypoglycemic agents.

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

Factors contributing to the development of hypoglycemia:

– simultaneous consumption of alcohol, especially during fasting;
– refusal or (especially for older patients) inability of the patient to interact with the doctor and follow the recommendations set out in the instructions for use;
– undernutrition, irregular eating, fasting or changes in diet;
– imbalance between physical activity and carbohydrate intake;
– renal failure;
– severe liver failure;
– overdose of the drug Glibenclamide + Metformin;
– certain endocrine disorders: insufficiency of the thyroid gland, pituitary gland or adrenal glands;
– simultaneous use of individual drugs.

Kidney and liver failure

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

Instability of blood glucose levels

In case of surgery or other cause of decompensation of diabetes mellitus, it is recommended to consider a temporary transition to insulin therapy. Symptoms of hyperglycemia include frequent urination, severe thirst, and dry skin.

48 hours before planned surgery or intravenous administration of an iodinated radiocontrast agent, Glibenclamide + Metformin should be discontinued. 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 eliminated by the kidneys, before starting treatment, and regularly thereafter, it is necessary to determine creatinine clearance and/or serum creatinine levels: 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.
Particular caution is recommended in cases where renal function may be impaired, for example in elderly patients, or when initiating antihypertensive therapy, diuretics or non-steroidal anti-inflammatory drugs (NSAIDs).

Other Precautions

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

Impact on the ability to drive vehicles and machinery

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

Active ingredient

Glibenclamide, Metformin

Composition

Active ingredients:

Glibenclamide – 5.00 mg,

Metformin hydrochloride – 500.00 mg,

Excipients:

Microcrystalline cellulose – 77.5 mg,

Croscarmellose sodium – 30.00 mg,

Povidone-K25 – 54.00 mg,

Magnesium stearate – 3.5 mg,

Shell composition:

Hypromellose – 8.4 mg,

Macrogol-4000 – 2.1 mg,

Titanium dioxide – 4.5 mg.

Pregnancy

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 occurrence of pregnancy. When planning pregnancy, as well as in case of pregnancy while taking the drug Glibenclamide + Metformin, the drug should be discontinued and insulin therapy prescribed.

The drug Glibenclamide + Metformin is contraindicated during breastfeeding, since there is no data on the ability of glibenclamide to pass into breast milk.

Contraindications

hypersensitivity to metformin, glibenclamide or other sulfonylurea derivatives, as well as to excipients;
type 1 diabetes mellitus;
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 changes in kidney function: dehydration, severe infection, shock;
use within less than 48 hours before and within 48 hours after radioisotope or x-ray studies with the introduction of an iodinated contrast agent;
acute or chronic diseases that are accompanied by tissue hypoxia: cardiac or respiratory failure, recent myocardial infarction, shock;
liver failure;
porphyria:
pregnancy, breastfeeding period;
children under 18 years of age;
simultaneous use of miconazole;
extensive surgical operations and injuries, when insulin therapy is indicated (see section “Special Instructions”);
impaired absorption of food and medications in the gastrointestinal tract (including intestinal obstruction, intestinal paresis);
chronic alcoholism, acute alcohol intoxication;
lactic acidosis (including history);
following a hypocaloric diet (less than 1000 kcal/day);
simultaneous use with bosentan.
With caution

In persons over 60 years of age performing heavy physical work; which is associated with an increased risk of developing lactic acidosis; with febrile syndrome, diseases of the thyroid gland (with dysfunction), insufficiency of the function of the anterior lobe of the pituitary gland or adrenal cortex; in elderly patients due to the risk of developing hypoglycemia; with glucose-6-phosphate dehydrogenase deficiency; 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 assessed as follows:
Very common: ≥1/10
Frequent: ≥1/100, <1/10
Uncommon: ≥1/1000, <1/100
Rare: ≥1/10,000, <1/1000
Very rare: <1/10,000
Frequency unknown: cannot be estimated with available data.

Disorders of the blood and lymphatic system: rarely: leukopenia and thrombocytopenia; very rarely: agranulocytosis, hemolytic anemia, bone marrow aplasia and pancytopenia (these adverse effects 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: often: hypoglycemia (symptoms: headache, hunger, nausea, vomiting, severe fatigue, sleep disturbances, restlessness, aggression, impaired concentration and psychomotor reactions, depression, confusion, speech impairment, visual impairment, tremor, paralysis and paresthesia, dizziness, delirium, convulsions, somnolence, unconsciousness, shallow breathing and bradycardia). Due to compensatory reactions caused by hypoglycemia, increased sweating, fear, tachycardia, arterial hypertension, palpitations, angina pectoris and arrhythmia may occur. The latter symptoms may be absent if hypoglycemia develops slowly, in the case of autonomic neuropathy, or while taking beta-blockers, clonidine, reserpine, guanethidine or sympathomimetics.

Rarely: hepatic or cutaneous porphyria; very rarely: lactic acidosis; decreased absorption of vitamin B12 with long-term use of metformin, accompanied by a decrease in its concentration in the blood serum (if megaloblastic anemia is detected, the possibility of such an etiology must be taken into account); disulfiram-like reaction when drinking alcohol (vomiting, feeling of “heat” in the face and upper body, tachycardia, dizziness, headache).

Nervous system disorders: often: taste disturbances (“metallic” taste in the mouth).

Visual disturbances: At the beginning of treatment, temporary visual disturbances 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; Slowly increasing the dose of the drug also improves its tolerability.

Disorders of the liver and biliary tract: very rarely: impaired activity of liver enzymes, cholestasis or hepatitis, requiring discontinuation of treatment.

Disorders of the skin and subcutaneous tissues: rarely: skin reactions such as itching, urticaria, maculopapular rash; very rare: cutaneous or systemic allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity.

Laboratory and instrumental data: uncommon: increased concentrations of urea and creatinine in the blood serum; very rarely: hyponatremia.

Interaction

Contraindicated combinations

Associated with the use of glibenclamide

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

Associated with metformin use

Iodinated contrast media: Depending on renal function, the drug should be discontinued 48 hours before and 48 hours after intravenous administration of iodinated contrast media.

Combinations not recommended

Related to the use of sulfonylurea derivatives

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

Phenylbutazone increases the hypoglycemic effect of sulfonylurea derivatives (by replacing sulfonylurea derivatives at protein binding sites and/or reducing their excretion). It is preferable to use other anti-inflammatory drugs that exhibit less interaction, or to warn the patient about the need to self-monitor glycemic levels; If necessary, the dose should be adjusted when using an anti-inflammatory drug together and after its discontinuation.

Associated with the use of glibenclamide

Bosentan in combination with glibenclamide increases the risk of hepatotoxicity. The hypoglycemic effect of glibenclamide may also be reduced. The simultaneous use of these drugs is not recommended.

Associated with metformin use

Alcohol: The risk of developing lactic acidosis increases with acute alcohol intoxication, especially in cases of fasting, malnutrition or liver failure.
During treatment with the drug, you should avoid drinking alcohol and medications containing ethanol.

Combinations requiring caution

Associated with the use of all hypoglycemic agents

Chlorpromazine: in high doses (100 mg/day) causes an increase in glycemic levels (reducing insulin secretion).

Precautions: the patient should be warned about the need to independently monitor blood glucose levels; if necessary, the dose of the drug should be adjusted when used simultaneously with antipsychotics and after stopping their use.

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

Precautions: the patient should be warned about the need to independently monitor blood glucose levels; if necessary, the dose of the drug should be adjusted when used simultaneously with GCS and after stopping their use.

Danazol has a hyperglycemic effect. If treatment with danazol is necessary and when discontinuing the latter, a dose adjustment of the drug is required under the control of glycemic levels.

Beta2-adrenergic agonists: by stimulating beta2-adrenergic receptors, they increase the concentration of glucose in the blood.

Precautions: the patient must be warned about the need to independently monitor blood glucose levels; transfer to insulin therapy is possible.

Diuretics: increase blood glucose levels.

Precautions: the patient should be warned about the need to independently monitor blood glucose levels; It may be necessary to adjust the dose of the drug when used simultaneously with diuretics and after stopping their use.

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

Associated with metformin use

Diuretics: lactic acidosis that occurs when taking metformin against the background of functional renal failure caused by taking diuretics, especially loop diuretics. Associated with the use of glibenclamide

Beta-blockers, clonidine, reserpine, guanethidine and sympathomimetics mask some symptoms of hypoglycemia: palpitations and tachycardia; Most non-selective beta-blockers increase the incidence and severity of hypoglycemia.

The patient should be warned about the need to independently monitor blood glucose levels, especially at the beginning of treatment.

Fluconazole: an increase in T1/2 of glibenclamide with the possible development of hypoglycemia. The patient should be warned about the need to self-monitor blood glucose levels; 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:

Associated with 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 developing hypoglycemia during the use of glibenclamide.

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 or neurological manifestations can be corrected by immediate consumption 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, seizures or other neurological disorders, requires emergency medical care. Intravenous administration of dextrose solution is necessary immediately after diagnosis or suspicion of hypoglycemia, before hospitalization of the patient. After regaining consciousness, it is necessary to give the patient food rich in easily digestible carbohydrates (to avoid re-development of hypoglycemia).

Long-term overdose or the presence of associated risk factors can provoke the development of lactic acidosis, since the drug contains metformin. Lactic acidosis is a medical emergency; Lactic acidosis should be treated in a clinic. The most effective method for removing lactate and metformin is hemodialysis.

Plasma clearance of glibenclamide may be increased in patients with liver disease. Since glibenclamide actively binds to blood proteins, it is not excreted during dialysis.

Storage conditions

At a temperature not higher than 25°C.

Keep out of the reach of children.

Shelf life

3 years. Do not use after expiration date.

Manufacturer

Ozon, Russia