Expiration date: 09/2025

The composition and form of issue: 

Tablets film-coated. 1 tablet contains:

active substances: 

Metformin hydrochloride 500 mg

glibenclamide 2.5 mg

excipients: 

core: croscarmellose sodium — 14 mg povidone K30 20 mg MKC — 56,5 mg magnesium stearate 7 mg 

shell: Opadry OY-L-24808 pink — 12 mg (lactose monohydrate — 36% hypromellose 15?? — 28% titanium dioxide — 24,39% macrogol — 10%, iron oxide yellow 1.3 percent of the iron oxide red — 0.3% of iron oxide black — 0,01% in purified water — q.s.) 

blistere in 15 PCs., in a cardboard pack 2 blisters or blistere 20 PCs., in a cardboard pack 3 blisters.

Tablets film-coated. 1 tablet contains:

active substances: 

Metformin hydrochloride 500 mg

glibenclamide 5 mg

excipients: 

core: croscarmellose sodium — 14 mg povidone K30 20 mg MKC — 54 mg magnesium stearate 7 mg 

shell: Opadry 31F22700 yellow — 12 mg (lactose monohydrate — 36% hypromellose 15cP — 28% titanium dioxide — 20,42% macrogol — 10% dye, quinoline yellow 3% iron oxide yellow 2.5% of iron oxide red — 0,08% purified water — q.s.) 

blistere in 15 PCs., in a cardboard pack 2 blisters or blistere 20 PCs., in a cardboard pack 3 blisters.

Description pharmaceutical form:

Pills 500/2. 5 mg: light orange, capsuleline biconvex, film-coated (film), engraved "to 2.5" on one side.

Tablet 500/5 mg: yellow, biconvex capsuleline-coated (film), engraved "5" on one side.

Pharmacokinetics:

Glibenclamide. Ingestion absorption from the gastrointestinal tract is 95%. Glibenclamide, a part of the drug Glucovance is micronized. Cmax in plasma is reached in about 4 h, Vd is about 10 L. the Connection with plasma proteins — 99%. Almost completely metabolized in the liver to form two active metabolites, which are excreted by the kidneys (40%) and jelchew (60%). T1/2 — from 4 to 11 hours.

Metformin. Once inside absorbed from the gastrointestinal tract adequately, Cmax in plasma is reached within 2.5 h. Approximately 20-30% of Metformin is excreted through the digestive tract unchanged. The absolute bioavailability is 50 to 60%. Metformin is rapidly distributed in the tissues, there is not associated with plasma proteins. Metabolized in very low extent and excreted by the kidneys. T1/2 is on average 6.5 h If impaired renal function the renal clearance decreases as creatinine clearance, while T1/2 increased, leading to increased concentrations of Metformin in plasma.

The combination of Metformin and glibenclamide in a single dosage form has the same bioavailability as when taking pills containing Metformin or glibenclamide in isolation. The bioavailability of Metformin combined with glibenclamide does not affect food intake, as well as on the bioavailability of glibenclamide. However, the rate of absorption of glibenclamide increases when eating.

Description pharmacological action:

Glucovance is a fixed combination of two oral hypoglycemic agents of different pharmacological groups: Metformin and glibenclamide.

Metformin belongs to the group of biguanides and lowers both basal and postprandial plasma glucose blood. 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 through inhibition of gluconeogenesis and glycogenolysis
  
• increases sensitivity of peripheral receptors to insulin, consumption and disposal of glucose by the cells in the muscles
  
• delays the absorption of glucose in the digestive tract.
  

The drug also has a beneficial effect on the lipid composition of blood, reducing total cholesterol, LDL and triglycerides.

Glibenclamide belongs to the group of sulfonylureas II generation. Glucose when receiving glibenclamide reduced as a result of stimulation of insulin secretion &beta-cells of the pancreas.

Metformin and glibenclamide have different mechanisms of action, but mutually complementary hypoglycemic activity of each other. The combination of two hypoglycemic agents has a synergistic effect in lowering glucose.

Indications:

Diabetes mellitus type 2 in adults:

• the poor diet, exercise, and previous therapy with Metformin or sulfonylureas
  
• to replace the previous therapy with two drugs (Metformin and sulfonylurea derivative) in patients with stable and well controlled blood glucose levels.
  

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 (Cl creatinine less than 60 ml/min)
  
• acute conditions that may cause changes in kidney function: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see "Special instructions")
  
• acute or chronic diseases that are accompanied by hypoxia of tissues: cardiac or respiratory failure, recent myocardial infarction, shock
  
• liver failure
  
• porphyria
  
• pregnancy
  
• breastfeeding
  
• concomitant use of miconazole
  
• extensive surgery
  
• chronic alcoholism, acute alcohol intoxication
  
• lactic acidosis (including history)
  
• adherence to a reduced-calorie diet (<1000 cal/day).
  

It is not recommended to use the drug in patients older than 60 years, performing heavy physical work that is associated with an increased risk of development of lactic acidosis.

Glucovance contains lactose and therefore its use is not recommended in patients with rare hereditary diseases associated with galactose intolerance, lactase deficiency or syndrome of glucose-galactose malabsorption.

Caution: febrile syndrome, adrenal insufficiency hypofunction of the anterior pituitary, thyroid disease with decompensated violation of its functions.

Application of pregnancy and breast-feeding:

The drug is contraindicated in pregnancy. The patient should be alerted to the fact that during the period of drug treatment Glucovance you must inform the doctor about planned pregnancy and pregnancy. When planning pregnancy, and in the case of pregnancy while taking Glucovance the drug should be withdrawn and treatment with insulin.

Glucovance contraindicated during breastfeeding because there is no data on its ability to penetrate into breast milk.

Side effects:

In the course of drug treatment Glucovance may experience the following side effects.The frequency of side effects is considered as follows: very often — &ge1/10 common — &ge1/100, <1/10 infrequent — &ge1/1000, <1/100 rare &ge1/10000, <1/1000 very rare <1/10000 isolated — can be evaluated with available data.

The metabolic disorders: hypoglycaemia (see sections "Overdose", "Special instructions"). Rare — attacks of hepatic porphyria and cutaneous porphyria very rare — lactic acidosis (see "Special instructions"). Reducing the absorption of vitamin B12 which led to a reduction of its concentration in serum with prolonged use of Metformin. Upon detection of megaloblastic anemia it is necessary to consider the possibility of such an etiology. Disulfiramopodobna reaction when alcohol.

The laboratory parameters: infrequently — increase in the concentrations of urea and creatinine in serum medium to a moderate extent very rarely — hyponatremia.

Blood and lymphatic system: these undesirable effects disappear after drug withdrawal. Rarely leukopenia and thrombocytopenia very rare agranulocytosis, haemolytic anaemia, bone marrow aplasia and pancytopenia.

Nervous system: often — violation of taste (metallic taste in the mouth).

Vision: at the beginning of treatment may cause temporary blurred vision due to the reduction of glucose in the blood.

Gastrointestinal disorders: 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 are themselves. To prevent these symptoms are advised to take the drug in 2 or 3 divided doses by slow increase in dosage also improves its portability.

Skin and subcutaneous tissue: rare — skin reactions such as pruritus, urticaria, maculopapular rash very rare — cutaneous or visceral allergic vasculitis, polymorphic erythema, exfoliative dermatitis, photosensitivity.

Immunological reactions: very rarely — anaphylactic shock. Can meet reactions cross hypersensitivity to sulphonamides and their derivatives.

Hepatobiliary disorders: very rarely — violation of the liver or hepatitis requiring discontinuation of treatment.

Drug interactions:

Contraindicated in combination

Associated with the use of glibenclamide

Miconazole: may provoke hypoglycemia (up to coma).

Associated with Metformin use

Iodinated contrast media: depending on renal function the drug should be discontinued 48 hours before or after I/V administration of iodinated contrast media.

Deprecated combination

Associated with the use of sulfonylureas

Alcohol: rarely observed precipitates reaction (intolerance to alcohol) while receiving alcohol and glibenclamide. Alcohol intake may increase hypoglycemic effect (by inhibiting compensatory reactions or delaying its metabolic inactivation) that can contribute to the development of hypoglycemic coma. During the period of drug treatment Glucovance should avoid alcohol and drugs containing alcohol.

Phenylbutazone: increases the hypoglycaemic effect of sulfonylureas (displaces sulfonylureas in the areas of protein binding and/or reduces their elimination). It is preferable to use other anti-inflammatory drugs, exhibiting less interaction, or to warn the patient of the need for self-monitoring of blood glucose levels you need to adjust the dose in a joint application anti-inflammatory agent and after its termination.

Associated with the use of glibenclamide

Bosentan: in combination with glibenclamide increases the risk of hepatotoxicity. It is recommended to avoid concomitant use of these drugs. Also may decrease hypoglycemic effect of glibenclamide.

Associated with Metformin use

Alcohol: the risk of lactic acidosis increases with acute alcohol intoxication, particularly in case of fasting or malnutrition or hepatic insufficiency. During the period of drug treatment Glucovance should avoid alcohol and drugs containing alcohol.

Combinations requiring caution

Associated with the use of all hypoglycemic agents

Chlorpromazine: at high doses (100 mg/day) causes an increase of blood glucose levels (reduced insulin release). Precautions: you should warn the patient about the need for self-monitoring of glucose in the blood and, if necessary, to adjust the dose of hypoglycemic drugs during the simultaneous use of antipsychotic and after the cessation of its use.

GKS and tetracosactrin: increase in blood glucose, sometimes accompanied by ketosis (corticosteroids decrease glucose tolerance). Precautions: you should warn the patient about the need for self-monitoring of glucose in the blood and, if necessary, to adjust the dose of hypoglycemic drugs during the simultaneous application of GCS and after the termination of their application.

The danazol: has a hyperglycemic effect. If necessary, the danazol treatment and discontinuation of the last required correction doses of the drug Glucovance under the control of blood glucose levels.

&beta2-agonists: due to the stimulation of &beta2-adrenergic receptors increase the concentration of glucose in the blood. Precautions: instruct the patient and establish control of glucose in the blood, may be transferred to insulin therapy.

Diuretics: increase of glucose in the blood. Precautions: you should warn the patient about the need for self-monitoring of glucose in the blood can require correction doses of hypoglycemic drugs during concurrent use with diuretics and after the termination of their application.

ACE inhibitors (captopril, enalapril): the use of ACE inhibitors contributes to decrease the content of glucose in the blood. If necessary, adjust the dose of the drug Glucovance during concurrent use with ACE inhibitors after termination of application.

Associated with Metformin use

Diuretics: lactic acidosis, occur when taking Metformin at the background of functional renal failure caused by diuretics, in particular loop.

Associated with the use of glibenclamide

&beta-blockers, clonidine, reserpine, guanetidin, and sympathomimetics mask some of the symptoms of hypoglycaemia: palpitations and tachycardia most nonselective &beta-blockers increase the frequency and severity of hypoglycemia. You should warn the patient about the need for self-monitoring of glucose in the blood, especially at the beginning of treatment.

Fluconazole: increase in T1/2 of glibenclamide with the possible occurrence of manifestations of hypoglycemia. You should warn the patient about the need for self-monitoring of glucose in the blood may be necessary to adjust the dose of hypoglycemic drugs during simultaneous treatment with fluconazole and after cessation of its use.

Other interaction: combination to be taken into account

Associated with the use of glibenclamide

Desmopressin: Glucovance may reduce the antidiuretic effect of desmopressin.

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

Method of application and dose:

Inside. The dose determined by the physician individually for each patient depending on the level of glycemia.

The initial dose is 1 tab. drug Glucovance 500/2. 5 mg or 500/5 mg 1 time a day. To avoid hypoglycemia, the initial dose should not exceed daily dose of glibenclamide (or equivalent dose of another previously received sulfonylurea drug) or Metformin, if they are 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 weeks or more to achieve adequate control of glucose in the blood.

The replacement of the previous combination therapy with Metformin and glibenclamide: initial dose should not exceed daily dose of glibenclamide (or equivalent dose of another sulfonylurea drug) and Metformin taken earlier. Every 2 weeks or more after initiation of treatment, dose adjusted depending on the level of glycemia.

The maximum daily dose is 4 tab. drug Glucovance 500/5 mg or 6 table. drug Glucovance 500/2. 5 mg.

The dosage regimen

The dosage depends on the individual purpose.

For dosages 500/2. 5 mg and 500/5 mg:

- once daily in the morning during Breakfast, when you assign 1 table. a day

twice a day, morning and evening, with the appointment of 2 or 4 PL. a day.

For the dose 500/2. 5 mg:

three times a day, morning, afternoon and evening, when you assign a 3, 5 or 6 table. a day.

For dosage 500/5 mg:

three times a day, morning, afternoon and evening, with the appointment of 3 tables. a day.

The tablets should be taken with food. Each drug must be accompanied by a meal with high content of carbohydrates to prevent hypoglycemia.

Elderly patients

The dose is chosen based on the state of renal function. The initial dose should not exceed 1 table. drug Glucovance 500/2. 5 mg. it is Necessary to conduct regular assessment of renal function.

Children

The drug Glucovance not recommended for use in children.

Overdose:

In case of overdose may develop hypoglycemia due to the presence of sulfonylurea derivative in the composition of the drug (see "Special instructions").

Light and moderate symptoms of hypoglycemia without loss of consciousness and neurological manifestations can be corrected by the immediate intake of sugar. It is necessary to adjust the dose and/or change the power mode. The occurrence of severe hypoglycemic reactions, accompanied by coma, seizure, or other neurological disorders, patients with diabetes require emergency care. Need in/with the introduction of dextrose immediately after diagnosis or if suspected hypoglycemia prior to hospitalization of the patient. After recovering consciousness should give the patient foods rich in easily digestible carbohydrates (to avoid a recurrence of hypoglycemia).

Long-term overdose or the presence of paired risk factors can trigger the development of lactic acidosis because the drug is Metformin (see "Special instructions").

Lactic acidosis is a condition requires urgent medical treatment of lactic acidosis should be performed in the clinic. The most effective method of treatment that can display the lactate and Metformin is hemodialysis.

Clearance of glibenclamide in plasma may increase in patients with liver disease. Because glibenclamide is actively associated with the blood protein, the drug is not eliminated by dialysis.

Special instructions:

On the background of drug treatment Glucovance should regularly monitor blood glucose levels fasting and after a meal.

Lactic acidosis

Lactic acidosis is extremely rare, but serious (high mortality in the absence of urgent treatment) complication that can occur because of Metformin accumulation. Cases of lactic acidosis in patients receiving Metformin have occurred primarily in diabetic patients with renal insufficiency.

Must be taken of other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with severe hypoxia.

You should consider the risk of lactic acidosis with the appearance of non-specific signs such as muscular cramps, accompanied by dyspeptic disorders, abdominal pain and severe malaise. In severe cases, there may be acidotic dyspnea, hypoxia, hypothermia and coma.

Diagnostic laboratory indicators are: low pH-value of blood concentration of lactate in the plasma above 5 mmol/l, increased anion spacing, and the ratio lactate/pyruvate.

Hypoglycemia

As Glucovance contains glibenclamide, the drug is accompanied by the 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 assigned to the patient, adhere to the regular meals (including Breakfast). It is important that the carbohydrate intake was regular, as the risk of hypoglycemia is increased when the later meal, insufficient or unbalanced intake of carbohydrates. Hypoglycemia most likely to occur when a hypocaloric diet, after intensive or prolonged exercise, when alcohol or the ingestion of a combination of hypoglycemic agents.

Because of compensatory reactions caused by hypoglycemia, you may experience sweating, fear, tachycardia, hypertension, palpitations, angina and arrhythmia. The latter symptoms can be absent if hypoglycaemia develops slowly in the case of autonomic neuropathy or while taking &beta-adrenoblokatorov, clonidine, rezerpina, guanetidina or sympathomimetic.

Other symptoms of hypoglycemia in patients with diabetes mellitus can be a headache, hunger, nausea, vomiting, severe fatigue, sleep disturbance, restlessness, aggression, impaired concentration and psychomotor reactions, depression, confusion, slurring of speech, blurred vision, tremors, paralysis, and paresthesia, dizziness, delirium, convulsions, somnolence, unconsciousness, shallow respiration and bradycardia.

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

The factors contributing to the development of hypoglycemia:

• simultaneous use of alcohol, especially when fasting
  
• refusal or (especially for older patients) incapacity of the patient to cooperate with doctor and follow the recommendations outlined in instructions for use
  
• poor nutrition, irregular meals, fasting or changes in diet
  
• imbalance between physical exercise and carbohydrate intake
  
• renal failure
  
• severe hepatic insufficiency
  
• an overdose of the drug Glucovance 
  
• separate endocrine disruption: failure of function of the thyroid gland, pituitary gland and adrenal glands
  
• simultaneous reception of separate medicines.
  

Kidney and liver failure

Pharmacokinetics and/or pharmacodynamics may vary in patients with hepatic impairment or severe renal impairment. Occur in such patients, hypoglycemia may be prolonged, in this case, should be initiated the appropriate treatment.

Instability of glucose in the blood

In the case of surgical intervention or other causes of decompensation of diabetes it is recommended to provide a temporary transition to insulin therapy. Symptoms of hyperglycemia are frequent urination, pronounced thirst, dry skin.

For 48 h before planned surgery, or on/in the introduction of iodinated contrast media drug Glucovance should be discontinued. Treatment to resume in 48 hours and only after renal function has been evaluated and found to normal.

Renal function

Because Metformin is excreted by the kidney, before starting treatment and regularly in subsequent you need to determine the Cl of creatinine and/or creatinine in the blood serum: at least once a year in patients with normal renal function, and 2-4 times per year in elderly patients and in patients with Cl creatinine in the ULN.

It is recommended to exercise special care in cases where renal function may be compromised, such as elderly patients or in the case of the initiation of antihypertensive therapy, diuretics or NSAIDs.

Other precautions

The patient should inform the doctor about bronchopulmonary infection or infectious diseases of the urinary organs.

Effects on ability to drive and use machines

Patients should be informed about the risk of occurrence of hypoglycemia and to take precautions while driving and operating machinery that require high concentration and psychomotor speed reactions.