Glybenfage - instructions for use, doses, side effects, contraindications

Core: hypromellose - 16.0 mg, croscarmellose sodium - 20.5 mg, sodium stearyl fumarate - 7.0, povidone K30 - 15.0 mg, povidone (kollidone F90) - 19.0 mg;

Composition of the film shell: 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 of 5 mg + 500 mg:

Active substances: glibenclamide 5 mg + metformin hydrochloride 500 mg;

Excipients:

Core: hypromellose - 16.0 mg, croscarmellose sodium - 18.0 mg, sodium stearyl fumarate - 7.0, povidone K30 - 15.0 mg, povidone (kollidone F90) - 19.0 mg;

Composition of the film shell: 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.

Description:

Tablets 2.5 mg + 500 mg: oval biconvex tablets, coated with a white film coating. On the cross section, the nucleus is white or almost white in color. Tablets 5 mg + 500 mg: capsular biconvex tablets, coated with a white film coating. On the cross section, the nucleus is white or almost white color.

Pharmacotherapeutic group:Hypoglycemic agent for oral administration (derivative of sulfonylurea of the second generation + biguanide)

ATX: & nbsp

A.10.B.D.02 Metformin and sulfonamides

Pharmacodynamics:

A fixed combination of two oral hypoglycemic agents of various pharmacological groups: glibenclamide and metformin.

Metformin belongs to the biguanide group and reduces the concentration of both basal and postprandial glucose in the blood plasma. Metformin does not stimulate the secretion of insulin, and in this regard does not cause hypoglycemia. Has 3 mechanisms of action: reduces the production of glucose by the liver due to inhibition gluconeogenesis and glycogenolysis; increases the sensitivity of peripheral receptors to insulin, intake and utilization of glucose by cells in 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 lipoprotein (LDL) and triglycerides.

Glibenclamide belongs to the group of derivatives of sulfonylurea of the second generation. The concentration of glucose in the intake of glibenclamide is reduced as a result of stimulation of the secretion of insulin 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 decreasing glucose concentration.

Pharmacokinetics:

Glibenclamide

Absorption

If taken orally, the absorption from the digestive tract is more than 95%. The time to reach the maximum concentration is 4 hours, the volume of distribution is about 10 liters.

Distribution

Communication with plasma proteins is high (99%).

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 intestine (60%). Half-life is from 4 to 11 hours.

Metformin

Absorption

After oral intake absorbed from the gastrointestinal tract is sufficiently complete, the maximum concentration in the 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 and excretion

Exposed to a very weak degree of metabolism and excreted by the kidneys. Approximately 20-30% of metformin is excreted through the intestine in unchanged form. The half-life period averages 6.5 hours.

Pharmacokinetics in specific patient groups

In case of renal dysfunction, renal clearance of metformin decreases, as well as clearance of creatinine, while the half-life 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 in isolation.The bioavailability of metformin in combination with glibenclamide is not affected by ingestion, as well as on the bioavailability of glibenclamide, however, the rate of absorption of glibenclamide increases with food intake.

Indications:

Diabetes mellitus type 2 in adults:

- with ineffectiveness of diet therapy, exercise and previous monotherapy with metformin or sulfonylurea derivatives;

- to replace the previous therapy with two drugs (metformin and sulfonylureas) in patients with stable and adequate glycemic control.

Contraindications:

Hypersensitivity to metformin, glibenclamide or other sulfonylurea derivatives, as well as to 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 injection of iodine-containing contrast agents (see "Special instructions"); acute or chronic diseases that are accompanied by tissue hypoxia: cardiac or respiratory failure, recently suffered myocardial infarction; liver failure; porphyria; pregnancy, the period of breastfeeding; simultaneous administration of miconazole; large surgical interventions, trauma, extensive burns and other conditions requiring insulin therapy; chronic alcoholism, acute alcohol intoxication; lactoacidosis (including in the anamnesis); compliance with hypocaloric diet (less than 1000 kcal / day); children's age till 18 years.

It is not recommended to use the drug in people over 60 years of age who perform heavy physical work, which is associated with an increased risk of developing lactic acidosis.

Carefully:

Feverish syndrome; adrenal insufficiency; hypofunction of the anterior lobe of the pituitary gland; diseases of the thyroid gland (with uncompensated violation of its function); in the elderly due to the danger of developing hypoglycemia.

Pregnancy and lactation:

During pregnancy, the use of a combination of glibenclamide and metformin is contraindicated. The patient should be warned that during the period of treatment with Glybenfage, the doctor should be informed about the planned pregnancy and about the onset of pregnancy.When planning pregnancy, as well as in case of pregnancy during the period of taking the drug, it should be canceled and insulin therapy prescribed.

The combination of glibenclamide and metformin is contraindicated in breastfeeding, as there is no evidence of its ability to enter breast milk. If it is necessary to use the medication during breastfeeding, you should switch to insulin therapy or stop breastfeeding.

Dosing 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 Glybenfage 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 drug) or metformin if they were used as first-line therapy. It is recommended to increase the dose by no more than 5 mg glibenclamide and 500 mg metformin per day every 2 or more weeks to achieve adequate control of blood glucose.

Replacement of previous combination therapy with metformin and glibenclamide: the initial dose should not exceed the daily dose glibenclamide (or equivalent dose of another sulfonylurea drug) and metformin taken earlier. Every 2 or more weeks after the start of treatment, the dose of the drug is adjusted depending on the concentration of glucose in the blood. The maximum daily dose is 4 tablets Glybenfage 5 mg + 500 mg or 6 tablets Glybenfage 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 a 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 in day.

For a dosage of 5 mg + 500 mg

Three times a day, morning, afternoon and evening, with the appointment of 3 tablets a day. Tablets should be taken with meals. Each intake of the drug should be accompanied by a meal with a sufficiently high carbohydrate content to prevent the occurrence of hypoglycemia.

Elderly patients

The dose of the drug is selected based on the state of kidney function.The initial dose should not exceed 1 tablet Glybenfage 2.5 mg + 500 mg. It is necessary to conduct a regular assessment of kidney function.

Children

The drug Glibenfage is not recommended for use in children.

Side effects:

The following adverse reactions may occur during treatment with Glybenfage.

WHO classification of incidence 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 / 10,000 appointments.

Classification of undesirable adverse reactions in accordance with the damage to organs and organ systems (medical dictionary for regulatory activities Med-DRA).

Violations from the blood and lymphatic system:

These undesirable effects disappear after the drug is discontinued.

Rarely: leukopenia and thrombocytopenia.

Very rarely: agranulocytosis, hemolytic anemia, bone marrow aplasia and pancytopenia.

Immune system disorders:

Very rarely: anaphylactic shock.

There may be cross-reactivity reactions to sulfonamides and their derivatives.

Disorders from the metabolism and nutrition:

Hypoglycemia (See "Overdose", "Special instructions").

Rarely: attacks of porphyria (hepatic or cutaneous).

Very rarely: lactic acidosis (See "Special instructions").

Decreased absorption of vitamin B12, accompanied by a decrease in its concentration in the serum with prolonged use of metformin. When detecting megaloblastic anemia, it is necessary to consider the possibility of such etiology. Disulfiram-like reaction with ethanol.

Impaired nervous system:

Often: a taste disorder ("metallic" taste in the mouth).

Disorders from the side of the organ of vision:

At the beginning of treatment, a temporary visual impairment may occur due to a decrease in the concentration of glucose in the blood.

Disorders from 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 go by themselves.

To prevent the development of these symptoms, it is recommended to take the drug in 2 or 3 admission; A slow increase in the dose of the drug also improves its tolerability.

Disorders from the liver and bile ducts:

Very rarely: a violation of liver function or hepatitis, requiring discontinuation of treatment.

Disturbances from the skin and subcutaneous tissues:

Rarely: skin reactions, such as: itching, hives, maculopapular rash. Very rarely: photosensitization, cutaneous or visceral allergic vasculitis, polymorphic erythema, exfoliative dermatitis.

Laboratory and instrumental data:

Infrequent: moderate increase in urea and creatinine concentrations in serum. Very rarely: hyponatremia.

Overdose:

In case of an overdose it is possible to develop hypoglycemia due to the presence of a sulfonylurea derivative in the formulation (see "Special instructions").

Symptoms of mild to moderate hypoglycemia without loss of consciousness and neurological symptoms can be stopped by an immediate intake of digestible carbohydrates. It is necessary to adjust the dose of the drug 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 the provision of emergency medical care. An intravenous dextrose solution should be administered immediately after diagnosis is established or suspected hypoglycaemia, prior to hospitalization of the patient.After the restoration of consciousness it is necessary to take food rich in easily digestible carbohydrates (in order to avoid the re-development of hypoglycemia).

The clearance of glibenclamide in the blood plasma can increase in patients with liver disease. Because the glibenclamide actively binds to blood proteins, the drug is not excreted during dialysis.

Overdose or presence of conjugated risk factors can provoke the development of lactic acidosis, since the composition of the drug includes metformin (see "Special instructions").

Lactic acidosis is a condition requiring urgent medical attention; treatment of lactic acidosis should be carried out in a hospital. The most effective method of treatment, allowing to withdraw lactate and metformin, is hemodialysis.

Interaction:

Contraindicated combinations

Associated with the use of glibenclamide

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

Related to the use of metformin

Iodine-containing contrast media: depending on the function of the kidneys, the drug should be discontinued 48 hours before or after intravenous administration of iodine-containing contrast media.

Unrecommended combinations

Related to the use of sulfonylureas derivatives

Alcohol: a disulfiram-like reaction is very rarely observed (alcohol intolerance) with simultaneous intake of alcohol and glibenclamide. Alcohol can increase the hypoglycemic effect of the drug (by inhibiting compensatory reactions or delaying its metabolic inactivation), which can contribute to the development of hypoglycemic coma. During treatment with Glybenfage, alcoholic beverages and medications containing ethanol.

Boszentan in combination with glibenclamide increases the risk of hepatotoxic effects. It is recommended to avoid simultaneous administration of these drugs. Also hypoglycemic effect of glibenclamide may decrease.

Phenylbutazone increases the hypoglycemic effect of sulfonylurea derivatives (replacing the sulfonylurea derivatives in places associated with the protein and / or reducing their elimination). Preferably, other anti-inflammatory agents are used that exhibit lesser interactions,or to warn the patient about the need to independently control the concentration of glucose in the blood; if necessary, the dose should be adjusted by the joint use of the anti-inflammatory agent and after its termination.

Related to the use of metformin

Alcohol: The risk of developing lactic acidosis increases with acute alcohol intoxication, especially in case of fasting, or poor nutrition, or liver failure. During treatment with Glybenfage, alcoholic beverages and medications containing ethanol.

Combinations that require caution

Associated with the use of all hypoglycemic agents

Chlorpromazine: in high doses (100 mg / day) causes an increase in the concentration of glucose in the blood (reducing the release of insulin).

Measures precautions: the patient should be warned about the need for self-monitoring of the concentration of glucose in the blood; if necessary, adjust the dose of hypoglycemic agent during simultaneous application of neuroleptic and after discontinuation of its use.

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

Measures precautions: the patient should be warned about the need for self-monitoring of the concentration of glucose in the blood; if necessary, the dose of the hypoglycemic agent should be adjusted during simultaneous application of GCS and after discontinuation of their use.

Danazol has a hyperglycemic effect. If you need treatment with danazol, and when you stop taking the latter, you need to adjust the dose of Glibenfage under the control of the glucose concentration in the blood.

β2-adrenomimetics: due to stimulation of β2-adrenoreceptors increase the concentration of glucose in the blood.

Precautions: it is necessary to warn the patient and establish a control of the concentration of glucose in the blood, transfer to insulin therapy is possible.

Diuretics: increase in the concentration of glucose in the blood.

Precautions: should warn the patient about the need for self-monitoring of the concentration of glucose in the blood; it may be necessary to correct the dose of hypoglycemic agent during simultaneous use withdiuretics and after discontinuation of their use.

Angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril): the use of ACE inhibitors helps to reduce the concentration of glucose in the blood. If necessary, the dose of Glybenfage should be adjusted during simultaneous use with ACE inhibitors and after discontinuation of their use.

Related to the use of metformin

Diuretics: Lactic acidosis, which occurs when taking metformin against a background of functional renal failure caused by the intake of diuretics, especially loop ones.

Associated with the use of glibenclamide

β2-adrenoblockers, clonidine, reserpine, guanethidine and sympathomimetics mask some of the symptoms of hypoglycemia: a feeling of heartbeat and tachycardia: most non-selective beta-blockers increase the incidence and severity of hypoglycemia. It is necessary to warn the patient about the need to independently control the concentration of glucose in the blood, especially at the beginning of treatment.

Fluconazole: Increase in the half-life of glibenclamide with the possible occurrence of hypoglycemia.It is necessary to warn the patient about the need to independently control the concentration of glucose in the blood; it may be necessary to adjust the dose of hypoglycemic drugs during simultaneous treatment with fluconazole and after discontinuation of its use.

Sequestants of bile acids: Simultaneous use with the drug Glibenfage reduces the concentration of glibenclamide in the blood plasma, which can lead to a decrease in the hypoglycemic effect. Glybenfage should be taken at least 4 hours before bile acid sequestrants are taken.

Other interactions: combinations, which should be taken into account:

Associated with the use of glibenclamide

Desmopressin: The combination of glibenclamide and metformin can reduce the antidiuretic effect of desmopressin.

Antibacterial drugs (JIC) from the group of sulfonamides, fluoroquinolones, anticoagulants (coumarin derivatives), MAO inhibitors, chloramphenicol, pentoxifylline, lipid-lowering drugs from the group of fibrates, disopyramide - the risk of developing hypoglycemia against the background of glibenclamide.

Special instructions:

Treatment with Glibenfage is performed only under the supervision of a doctor! When taking the drug, it is necessary to strictly follow the doctor's recommendations for diet compliance 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 extremely rare, but serious (high mortality in the absence of emergency treatment) complication, which may occur due to the cumulation of metformin. The cases of lactic acidosis with the use of metformin appeared mainly in patients with diabetes mellitus and expressed renal insufficiency. Other associated risk factors, such as poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, liver failure and any condition associated with severe hypoxia, should be considered.

Consider the risk of developing lactic acidosis when non-specific signs appear, such as muscle cramps accompanied by dyspeptic disorders, abdominal pain and severe malaise.In severe cases, there may be acid dyspnea, hypoxia, hypothermia, and coma.

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

Hypoglycaemia

Since the preparation Glybenfage contains glibenclamide, then taking the drug is accompanied by 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 be prescribed only to a patient who adheres to a regular meal regimen (including breakfast). It is important that the intake of carbohydrates is regular, since the risk of developing hypoglycemia increases with late eating, inadequate or unbalanced consumption of carbohydrates.

The development of hypoglycemia is most likely with a hypocaloric diet, after intense or prolonged physical exertion, with the use of alcoholic beverages or when taking a combination of hypoglycemic agents. Due to compensatory reactions caused by hypoglycemia, there may be increased sweating, a sense of fear,tachycardia, increased blood pressure, palpitations, angina and arrhythmia. The last symptoms may be absent if hypoglycemia develops slowly, in the case of vegetative neuropathy or with the simultaneous administration of beta-blockers, clonidine, reserpine, guanethidine or sympathomimetics.

Other symptoms of hypoglycemia in patients with diabetes mellitus may include headache, hunger, nausea, vomiting, severe fatigue, sleep disorders, nervous state, aggression, impaired concentration and psychomotor reactions, depression, confusion, speech impairment, visual impairment, tremor, paralysis and paresthesia, dizziness, delirium, convulsions, doubt, unconsciousness, shallow breathing and bradycardia.

Careful use of the drug, dose selection and appropriate instructions for the patient are important to reduce the risk of developing hypoglycemia. If a patient experiences repeated hypoglycemia, which is either severe or associated with ignorance of the symptoms, consideration should be given to the possibility of treatment with other hypoglycemic agents.Factors contributing to the development of hypoglycemia: the simultaneous use of alcoholic beverages, especially when fasting; failure or (especially in elderly patients) the inability of the patient to interact with a doctor and follow the recommendations in the instructions for use; poor diet, irregular eating, fasting, or changes in diet; an imbalance between exercise and carbohydrate intake: kidney failure; severe hepatic impairment; an overdose of Glybenfage; individual endocrine disorders: insufficiency of thyroid gland function, pituitary gland and adrenal glands; simultaneous reception of individual medications.

Renal and hepatic impairment

Pharmacokinetics and / or pharmacodynamics 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 started.

Instability of blood glucose

In the case of surgery or other cause of decompensation of diabetes, it is recommended to provide a temporary transition to insulin therapy.Symptoms Hyperglycemia is frequent urination, severe thirst, dry skin. 48 hours before elective surgery or intravenous administration of iodinated contrast media reception Glibenfazh drug should be discontinued. Treatment is recommended to resume after 48 hours, and only after the kidney function has been evaluated and recognized normal.

Kidney function

Because the metformin excreted by the kidneys, before initiating treatment and regularly thereafter, it is necessary to determine creatinine clearance and / or the concentration of creatinine in serum: at least once a year in patients with normal renal function, and 2-4 times per year in elderly patients, as well as in patients with creatinine clearance at the upper limit of the norm.

Exercise caution is recommended in cases where renal function may be compromised, for example, elderly patients, or in case of antihypertensive therapy, diuretics or non-steroidal anti-inflammatory drugs (NSAIDs).

Other Precautions

The patient should inform the doctor in case of development of infectious diseases of the lower respiratory tract, genitals, kidneys and urinary tract.

Effect on the ability to drive transp. cf. and fur:

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

Form release / dosage:Tablets, film-coated, 2.5 mg + 500 mg and 5 mg + 500 mg.

Packaging:

Primary packaging of medicinal product.

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30, 40, 60, 90, 100 or 120 tablets in a polymer can of polyethylene with a cover pulled with the control of the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing, or from polymer materials, self-adhesive.

Secondary packaging of medicinal product.

By 1,2, 3, 4, 6, 9 or 10 contour cell packs of 10 tablets together with the instruction for use are placed in a pack of cardboard for consumer containers.

On 1 bank together with the instruction on application place in a pack from a cardboard for consumer tare.

Storage conditions:

In the original packaging of the manufacturer at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004612

Date of registration:25.12.2017

Expiration Date:25.12.2022

The owner of the registration certificate:Pharmasintez-Tyumen, Open CompanyPharmasintez-Tyumen, Open Company Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Pharmasintez-Tyumen, Open Company Russia

Information update date: & nbsp24.01.2018

Illustrated instructions

Instructions

Glybenfage (Glibenfazh)