Description
Pharmacological action
Pharmacotherapeutic group: Hypoglycemic agent for oral administration (second-generation sulfonylurea derivative + biguanide)
ATX:
A.10.BD02 Metformin and
sulfonamides Pharmacodynamics: A fixed combination of two oral hypoglycemic agents of various pharmacological groups: glibenclamide and metformin.
Metformin belongs to the group of biguanides and reduces the concentration 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: it reduces the production of glucose by the liver 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). The drug 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 sulfonylurea derivatives of the second generation. The glucose concentration when taking glibenclamide decreases as a result of stimulation of insulin secretion by beta cells of the pancreas.
Metformin and glibenclamide have different mechanisms of action, but mutually complement each other’s hypoglycemic activity. The combination of two hypoglycemic agents has a synergistic effect in lowering glucose concentrations.
Pharmacokinetics: Glibenclamide
Absorption of
When taken orally, absorption from the gastrointestinal tract is more than 95%. The time to reach maximum concentration is 4 hours, the volume of distribution is about 10 liters.
Distribution of
Communication with blood plasma proteins is high (99%).
Metabolism and excretion
Almost completely metabolized in the liver to form two inactive metabolites, which are excreted by the kidneys (40%) and through the intestines (60%). The elimination half-life is from 4 to 11 hours.
Metformin
Absorption of
After oral administration, it is absorbed from the gastrointestinal tract completely enough, the maximum plasma concentration is reached within 2.5 hours. Absolute bioavailability is from 50 to 60%.
Distribution
Metformin is rapidly distributed in tissues and practically does not bind to plasma proteins.
Metabolism and excretion
Metabolized to a very low degree and excreted by the kidneys. About 20-30% of metformin is excreted through the intestine unchanged. The elimination half-life is an average of 6.5 hours.
Pharmacokinetics in special patient groups
In case of impaired renal function, the renal clearance of metformin decreases, as does the clearance of creatinine, while the half-life 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 in isolation. The bioavailability of metformin in combination with glibenclamide is not affected by food intake, as well as the bioavailability of glibenclamide, however, the rate of absorption of glibenclamide increases with food intake.
Indications
Type 2 diabetes mellitus in adults:
with ineffective diet therapy, physical exercise and previous monotherapy with metformin or
sulfonylurea derivatives to replace previous therapy with two drugs (metformin and sulfonylurea derivatives) in patients with stable and adequate control.
Contraindications
Hypersensitivity to metformin, glibenclamide or other sulfonylurea derivatives, as well as other excipients of the drug, type 1 diabetes mellitus, diabetic ketoacidosis, diabetic precoma, diabetic coma, renal failure or impaired renal function (creatinine clearance less than 60 ml / min) acute conditions that can lead to a change in kidney function: dehydration, severe infection, shock, intravascular administration of iodine-containing contrast agents (see. Special instructions) acute or chronic diseases that are accompanied by tissue hypoxia: cardiac or respiratory failure s, recent myocardial infarction liver failure, porphyria, pregnancy, breast-feeding simultaneous reception of miconazole major surgery, trauma, extensive burns and other conditions requiring insulin therapy chronic alcoholism, acute alcohol intoxication lactic acidosis (including history) adhering to a low-calorie diet (less than 1000 kcal / day) children under 18 years of age.
It is not recommended to use the drug in people over 60 years old who perform heavy physical work, which is associated with an increased risk of developing lactic acidosis in them.
Caution: Fever syndrome, adrenal insufficiency, hypofunction of the anterior pituitary of the thyroid gland disease (with uncompensated impairment of its function) in the elderly due to the risk of hypoglycemia.
Use during pregnancy and lactation
During pregnancy, the use of a combination of glibenclamide and metformin is contraindicated. The patient should be warned that that during the treatment with Glibenfage, it is necessary to inform the doctor about the planned pregnancy and the onset of pregnancy. When planning pregnancy, as well as in the case of pregnancy during the period of taking the drug, it should be canceled and insulin therapy should be prescribed.
The combination of glibenclamide and metformin is contraindicated in breastfeeding, as there is no evidence of its ability to pass into breast milk. If it is necessary to use the drug during breastfeeding, you should switch to insulin therapy or stop breastfeeding.
Special instructions
Treatment with Glibenfage is carried out only under medical supervision! When taking the drug, it is necessary to strictly follow the doctor’s recommendations on dieting and self-monitoring of glucose concentration in the blood. It is necessary to regularly monitor the concentration of glucose in the blood on an empty stomach and after eating.
Lactic acidosis
Lactic acidosis is an extremely rare, but serious (high mortality rate in the absence of emergency treatment) complication that may occur due to cumulation of metformin. Cases of lactic acidosis with the use of metformin occurred mainly in patients with diabetes mellitus and severe renal failure. Other associated risk factors should be considered, such as poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, liver failure, and any condition associated with severe hypoxia.
The risk of lactic acidosis should be considered when non-specific symptoms appear, such as muscle cramps accompanied by dyspeptic disorders, abdominal pain and severe malaise. In severe cases, acidotic shortness of breath, hypoxia, hypothermia, and coma may occur.
Diagnostic laboratory parameters are: low blood pH, plasma lactate concentration above 5 mmol / l, increased anionic interval and lactate / pyruvate ratio.
Hypoglycemia
Since the drug Glibenfage contains glibenclamide, taking the drug is associated with a risk of hypoglycemia in the patient. Gradual titration of the dose after the start of treatment can prevent the occurrence of hypoglycemia. This treatment can only be prescribed to a patient who adheres to a regular meal (including breakfast). It ² ¢s important that your carbohydrate intake is regular, as the risk of developing hypoglycemia increases with a late meal, insufficient or unbalanced intake of carbohydrates.
The development of hypoglycemia is most likely with a hypocaloric diet, after intense or prolonged physical activity, with alcoholic beverages, or with a combination of hypoglycemic agents. Due to compensatory reactions caused by hypoglycemia, increased sweating, a sense of fear, tachycardia, increased blood pressure, a feeling of palpitations, angina pectoris and arrhythmia can 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.
Other symptoms of hypoglycemia in patients with diabetes may include headache, hunger, nausea, vomiting, severe fatigue, sleep disorders, excited state, aggression, impaired concentration and psychomotor reactions, depression, confusion, speech impairment, blurred vision, trembling, paralysis and paresthesia, dizziness, delirium, cramps, somnolence, unconsciousness, shallow breathing and bradycardia.
Cautious use of the drug, dosage selection and proper instructions for the patient are important to reduce the risk of hypoglycemia. If the patient recurs attacks of hypoglycemia, which are either severe or associated with ignorance of the symptoms, consideration should be given to treatment with other hypoglycemic agents. Factors contributing to the development of hypoglycemia: the simultaneous use of alcoholic beverages, especially during fasting, refusal or (especially for elderly patients) the patient ² ¢s inability to interact with the doctor and follow the recommendations in the instructions for use poor nutrition, irregular eating, fasting or changes in diet, imbalance between physical activity and carbohydrate intake: renal failure severe liver failure overdose of the drug Glibenfage individual endocrine disorders: insufficiency of the thyroid gland, pituitary gland and adrenal glands simultaneous administration of fittings for pharmaceuticals.
Renal and Hepatic Insufficiency
Pharmacokinetics and / or pharmacodynamics may vary in patients with hepatic impairment or severe renal impairment. The hypoglycemia that occurs in such patients can be prolonged, in this case, appropriate treatment should be started.
Instability of blood glucose
In case of surgical intervention or other cause of decompensation of diabetes mellitus, it is recommended to provide a temporary transition to insulin therapy. Symptoms of hyperglycemia are frequent urination, severe thirst, dry skin. 48 hours before the planned surgical intervention or intravenous administration of an iodine-containing radiopaque agent, the administration of the drug Glibenfage should be discontinued. Treatment is recommended to be resumed after 48 hours, and only after renal function has been evaluated and recognized as 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 concentration: 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.
It is recommended to be especially careful in cases where kidney function may be impaired, for example, in elderly patients, or in the case of initiation of antihypertensive therapy, diuretics or non-steroidal anti-inflammatory drugs (NSAIDs).
Other Precautions
The patient should inform the doctor if infectious diseases of the lower respiratory tract, genitals, kidneys, and urinary tract develop.
Impact on the ability to drive transp. Wed and fur .: Patients should be informed about the risk of hypoglycemia and should observe precautions when driving a vehicle and working with mechanisms that require an increased concentration of attention and speed of psychomotor reactions.
Composition
Active ingredients: glibenclamide 2.5 mg + metformin hydrochloride 500 mg
Excipients:
Core: hypromellose – 16.0 mg, croscarmellose sodium – 20.5 mg, sodium stearyl fumarate – 7.0 – 15 povidone , 0 mg, povidone (collidone F90) – 19.0 mg
Film composition: hypromellose E15 – 7.0 mg, macrogol 6000 (polyethylene glycol 6000) – 0.9 mg, titanium dioxide – 2.0 mg, polysorbate 80 ( Tween 80) – 0.1 mg.
Dosage and Administration
Inside.
The dose of the drug is determined by the doctor individually for each patient, depending on the concentration of glucose in the blood.
The initial dose is: 1 tablet of the drug Glibenfage 2.5 mg + 500 mg or 5 mg + 500 mg 1 time per 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 that the dose be increased by no more than 5 mg of glibenclamide and 500 mg of metformin per day every 2 or more weeks to achieve adequate control of blood glucose.
Substitution of previous combination therapy with metformin and glibenclamide: the initial dose should not exceed the daily dose of glibenclamide (or the equivalent dose of another sulfonylurea) and metformin taken previously. Every 2 or more weeks after the start of treatment, the dose is adjusted depending on the concentration of glucose in the blood. The maximum daily dose is 4 tablets of Glibenfage 5 mg + 500 mg or 6 tablets of Glibenfage 2.5 mg + 500 mg.
Dosing regimen: The dosage regimen depends on the individual purpose: For dosages of 2.5 mg + 500 mg and 5 mg + 500 mg
Once a day, in the morning during breakfast, with the appointment of 1 tablet per day. Twice a day, morning and evening, with the appointment of 2 or 4 tablets per day.
For a dosage of 2.5 mg + 500 mg
Three times a day, morning, afternoon and evening, with the appointment of 3, 5 or 6 tablets per day.
For a dosage of 5 mg + 500 mg
Three times a day, in the morning, afternoon and evening, with the appointment of 3 tablets per day. Tablets should be taken with meals. Each meal should be accompanied by a meal with a high enough carbohydrate content to prevent the occurrence of hypoglycemia.
Elderly patients
The dose of the drug is selected based on the state of renal function. The initial dose should not exceed 1 tablet of the drug Glibenfazh 2.5 mg + 500 mg. Regular assessment of renal function is necessary.
Children
Glibenfage is not recommended for use in children.
Side effects
The following adverse reactions may occur during treatment with Glibenfage.
WHO Classification of Adverse Reactions: very often -? 1/10 appointments, often – from? 1/100 to <1/10 appointments, infrequently - from? 1/1000 to <1/100 appointments, rarely - from? 1/10000 to <1/1000 appointments very rarely - <1/10000 appointments. Classification of unwanted adverse reactions according to damage to organs and organ systems (medical dictionary for regulatory activity Med-DRA). Disorders from the blood and lymphatic system: These adverse events disappear after discontinuation of the drug. Rarely: leukopenia and thrombocytopenia. Very rare: agranulocytosis, hemolytic anemia, bone marrow aplasia, and pancytopenia. Disorders of the immune system: Very rare: anaphylactic shock. Cross-hypersensitivity reactions to sulfonamides and their derivatives may occur. Metabolic and nutritional disorders: Hypoglycemia (See Overdose, Special Instructions). Rarely: attacks of porphyria (hepatic or cutaneous). Very rare: lactic acidosis (See Special Instructions). Decreased absorption of vitamin B12, accompanied by a decrease in its concentration in serum with prolonged use of metformin. If megaloblastic anemia is detected, the possibility of such an etiology must be considered. Disulfiram-like reaction with ethanol. Disorders of the nervous system: Often: taste disturbance (metallic taste in the mouth). Disorders of the organ of vision: At the beginning of treatment, temporary visual impairment may occur due to a decrease in the concentration of glucose in the blood. Disorders of the gastrointestinal tract: Very often: nausea, vomiting, diarrhea, abdominal pain and lack of appetite. These symptoms are more common at the beginning of treatment and in most cases pass 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 tolerance. Disorders from the liver and biliary tract: Very rarely: impaired liver function or hepatitis requiring discontinuation of treatment. Disorders of the skin and subcutaneous tissue: Rarely: skin reactions, such as: itching, urticaria, maculopapular rash. Very rarely: photosensitivity, skin or visceral allergic vasculitis, polymorphic erythema, exfoliative dermatitis. Laboratory and instrumental data: Infrequently: moderate increase in serum urea and creatinine concentrations. Very rarely: hyponatremia. Overdose In case of an overdose, hypoglycemia may occur due to the presence of a sulfonylurea derivative in the preparation (see Special instructions). Symptoms of mild to moderate hypoglycemia without loss of consciousness and neurological symptoms can be stopped by the immediate intake of easily digestible carbohydrates. Need to adjust the dose of the drug and / or change in diet. The occurrence of severe hypoglycemic reactions in patients with diabetes, accompanied by coma, convulsions or other neurological disorders, requires emergency medical care. Intravenous administration of a dextrose solution is necessary immediately after diagnosis or suspicion of hypoglycemia occurs, before the patient is hospitalized. After regaining consciousness, it is necessary to take food rich in easily digestible carbohydrates (in order to avoid the re-development of hypoglycemia). Plasma glibenclamide clearance may increase in patients with liver disease. Since glibenclamide is actively associated with blood proteins, the drug is not excreted during dialysis. An overdose or the presence of conjugated risk factors can provoke the development of lactic acidosis, as metformin is part of the drug (see. Special instructions). Lactic acidosis is a condition requiring emergency medical care treatment of lactic acidosis should be carried out in a hospital. The most effective treatment option to remove lactate and metformin is hemodialysis. Storage conditions In the original packaging of the manufacturer at a temperature not exceeding 25 ° C. Keep out of the reach of children. The Expiration of is 3 years. Deystvuyuschee substances Hlybenklamyd, Metformin Pharmacy Prescription Dosage form table eti
