Glucovance, 5 mg+500 mg 30 pcs

Glucovans® 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. It has 3 mechanisms of action:

• reduces glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis;
• increases peripheral receptor sensitivity to insulin, glucose consumption and utilization by muscle cells;
• delays glucose absorption in the gastrointestinal tract.

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

Glibenclamide belongs to the group of sulfonylurea derivatives of the 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 each other’s hypoglycemic activity. The combination of the two hypoglycemic agents has a synergistic effect in reducing glucose.

Pharmacokinetics

Glibenclamide. When administered orally, absorption from the gastrointestinal tract is more than 95%. Glibenclamide contained in Glucovans® is micronized. Cmax in plasma is reached in about 4 h, Vd – about 10 l. Binding to plasma proteins is 99%. It is almost completely metabolized in the liver to form two inactive metabolites, which are excreted by the kidneys (40%) and with the bile (60%). T1/2 is from 4 to 11 hours.

Metformin. After oral administration is absorbed from the gastrointestinal tract quite completely, Cmax in plasma is reached within 2.5 hours. About 20-30% of metformin is excreted unchanged through the gastrointestinal tract. Absolute bioavailability is 50 to 60%. Metformin is rapidly distributed in tissues, almost does not bind with plasma proteins. It is very poorly metabolized and excreted by the kidneys. T1/2 is on average 6.5 hours. With impaired renal function, renal clearance is decreased, as well as creatinine clearance, while the T1/2 is increased, which leads to increased plasma concentrations of metformin.

The combination of metformin and glibenclamide in the same dosage form has the same bioavailability as tablets containing metformin or glibenclamide alone. 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

Type 2 diabetes mellitus in adults:

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

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Active ingredient

Glibenclamide, Metformin

Composition

Active substances:

glibenclamide;

metformin hydrochloride;

Associates:

croscarmellose sodium;

povidone K30;

MCC;

Magnesium stearate

How to take, the dosage

Ingestion.

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

The starting dose is 1 tablet of Glucovans® 2.5+500 mg or 5+500 mg once daily. To avoid hypoglycemia, the starting dose should not exceed the daily dose of glibenclamide (or the equivalent dose of another previously taken sulfonylurea drug) or metformin if used as first-line therapy. It is recommended that the dose be increased by no more than 5 mg of glibenclamide + 500 mg of metformin per day every 2 or more weeks to achieve adequate blood glucose control.

Replacement of prior combination therapy with metformin and glibenclamide: The starting dose should not exceed the daily dose of glibenclamide (or the equivalent dose of another sulfonylurea drug) and metformin taken previously. Every 2 or more weeks after the start of treatment, the dose of the drug is adjusted according to the level of glycemia.

The maximum daily dose is 4 tablets of Glucovans® 5+500 mg or 6 tablets of Glucovans® 2.5+500 mg.

The dosing regimen

The dosing regimen depends on the individual prescription.

For doses of 2.5+500 mg and 5+500 mg:

• 1 time daily, morning at breakfast, when prescribed 1 tablet per day;
• 2 times daily, morning and evening, when prescribed 2 or 4 tablets per day.

For 2.5+500 mg dosage:

• 3 times daily, morning, afternoon, and evening, when prescribing 3, 5, or 6 tablets daily.

For 5+500 mg dosage:

• 3 times daily, morning, afternoon, and evening, when 3 tablets per day are prescribed.

The tablets should be taken with meals. Each administration of the drug should be accompanied by a meal that is high enough in carbohydrates to prevent hypoglycemia.

Elderly patients

The dose of the drug is adjusted according to the state of renal function. The initial dose should not exceed 1 tablet of Glucovans® 2.5+500 mg. Regular renal function evaluation should be performed.

In children

The use of Glucovans® is not recommended in children.

Interaction

Contraindicated combinations

Involved with glibenclamide

Miconazole: may cause hypoglycemia (up to and including coma).

Related to metformin use

Iodine contrast agents: Depending on renal function, the drug should be discontinued 48 hours before or after IV administration of iodine contrast agents.

Unrecommended combinations

Related to the use of sulfonylurea derivatives

Alcohol: very rarely an antabuse reaction (alcohol intolerance) is observed when alcohol and glibenclamide are taken simultaneously. Alcohol intake may increase the hypoglycemic effect (by inhibiting the compensatory reactions or delaying its metabolic inactivation), which may contribute to the development of hypoglycemic coma. During treatment with Glucovans® , alcohol and drugs containing alcohol should be avoided.

Phenylbutazone increases hypoglycemic effect of sulfonylurea derivatives (replacing sulfonylurea derivatives at the sites of binding to the protein and/or reducing their elimination). It is preferable to use other anti-inflammatory agents that find fewer interactions, or to warn the patient about the need for self-control of glycemic levels; if necessary, the dose should be adjusted when co-administering the anti-inflammatory agent and after discontinuation.

Linked with glibenclamide

Bozentan: in combination with glibenclamide increases the risk of hepatotoxic effects. It is recommended to avoid concomitant administration of these drugs. The hypoglycemic effect of glibenclamide may also be reduced.

Related to the use of metformin

Alcohol: the risk of lactoacidosis is increased in acute alcohol intoxication, especially in case of starvation or poor nutrition, or liver failure. During the treatment with Glucovans® , alcohol and drugs containing alcohol should be avoided.

Combinations requiring caution

Bound with the use of all hypoglycemic agents

Chlorpromazine: in high doses (100 mg/day) causes an increase in glycemia (reducing insulin release). Precautions: the patient should be warned about the need for self-monitoring of blood glucose levels and, if necessary, the dose of hypoglycemic agent should be adjusted during concomitant use of neuroleptic and after discontinuation of its use.

GCS and tetracosactide: increase in blood glucose content, sometimes accompanied by ketosis (GCS cause decreased glucose tolerance). Precautions: the patient should be warned about the need for self-monitoring of blood glucose and, if necessary, the dose of hypoglycemic agent should be adjusted during concomitant use of GCS and after discontinuation of their use.

Danazol: has a hyperglycemic effect. It is necessary to adjust the dose of Glucovans® under glycemic control if treatment with Danazol is necessary and after discontinuation of Danazol.

β2-adrenomimetics: due to stimulation of β2-adrenoreceptors they increase the concentration of glucose in blood. Precautions: the patient should be warned and blood glucose control should be established; transfer to insulin therapy is possible.

Diuretics: increase in blood glucose concentration. Precautions: the patient should be warned about the necessity of independent control of blood glucose content; it may be necessary to correct the dose of hypoglycemic agent during concomitant use with diuretics and after discontinuation of their use.

ACE inhibitors (captopril, enalapril): the use of ACE inhibitors helps to reduce blood glucose. If necessary, the dose of Glucovans® should be adjusted during concomitant use with ACE inhibitors and after stopping their use.

Associated with metformin use

Diuretics: Lactoacidosis occurring with metformin administration against a background of functional renal failure caused by taking diuretics, particularly loop diuretics.

Associated with glibenclamide

The β-adrenoblockers, clonidine, reserpine, guanethidine, and sympathomimetics mask some symptoms of hypoglycemia: palpitation and tachycardia; most non-selective β-adrenoblockers increase the frequency and severity of hypoglycemia. Patients should be warned about the need for self-monitoring of blood glucose, especially at the beginning of treatment.

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

Other interactions: combinations to be considered

Involved with glibenclamide

Desmopressin: Glucovans® may decrease the antidiuretic effect of desmopressin.

Sulfonamide antibacterial drugs, fluoroquinolones, anticoagulants (coumarin derivatives), MAO inhibitors, chloramphenicol, pentoxifylline, hypolipidemic drugs from the group of fibrates, disopyramide: risk of hypoglycemia with glibenclamide.

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Special Instructions

During treatment with Glucovans® it is necessary to monitor glycemia levels regularly on an empty stomach and after meals.

Lactoacidosis

Lactoacidosis is an extremely rare but serious (high mortality in the absence of emergency treatment) complication that can occur due to metformin cumulation. Cases of lactoacidosis in patients treated with metformin occurred mainly in diabetic patients with severe renal insufficiency.

The risk of lactoacidosis should be considered if nonspecific signs occur, such as muscle cramps accompanied by dyspeptic disorders, abdominal pain, and severe malaise. In severe cases, acidotic dyspnea, hypoxia, hypothermia and coma may occur.

The diagnostic laboratory indicators are: low blood pH, plasma lactate concentration above 5 mmol/L, elevated anion interval and lactate/pyruvate ratio.

Hypoglycemia

Since Glucovans® contains glibenclamide, administration of the drug is accompanied by the risk of hypoglycemia in the patient. Gradual titration of the dose after initiation of treatment may prevent the occurrence of hypoglycemia. This treatment can be administered only to a patient who adheres to a regular meal regimen (including breakfast). It is important that carbohydrate intake should be regular, since the risk of hypoglycemia increases with late meals, insufficient or unbalanced intake of carbohydrates. The development of hypoglycemia is most likely in case of a hypocaloric diet, after intense or prolonged physical activity, when drinking alcohol or taking a combination of hypoglycemic agents.

Because of the compensatory reactions caused by hypoglycemia, sweating, anxiety, tachycardia, hypertension, palpitations, angina pectoris, and arrhythmia may occur. The latter symptoms may be absent if hypoglycemia develops slowly, in cases of autonomic neuropathy, or if β-adrenoblockers, clonidine, reserpine, guanethidine, or sympathomimetics are taken simultaneously.

. Other symptoms of hypoglycemia in diabetic patients may include headache, hunger, nausea, vomiting, marked fatigue, sleep disturbance, agitation, aggression, impaired concentration and psychomotor reactions, depression, confusion, impaired speech, visual disturbance, tremor, paralysis and paresthesia, dizziness, delirium, seizures, somnolence, unconsciousness, shallow breathing and bradycardia.

Cautious prescribing, dose selection, and proper patient instructions are important to reduce the risk of hypoglycemia. If a patient has repeated episodes of hypoglycemia, which are either severe or due to lack of knowledge of symptoms, treatment with other hypoglycemic agents should be considered.

Factors contributing to hypoglycemia:

• consumption of alcohol, especially when fasting;
• refusal or (especially in elderly patients) inability of the patient to interact with the physician and follow the recommendations in the instructions for use;
• severe hepatic impairment;
• overdose of Glucovance®;
• specific endocrine disorders: Thyroid, pituitary and adrenal gland function deficiencies;
• simultaneous administration of certain medications.

Hepatic and renal failure

Pharmacokinetics and/or pharmacodynamics may be altered in patients with hepatic failure or severe renal impairment. Hypoglycemia occurring in such patients may be prolonged, in which case appropriate treatment should be initiated.

Instability of blood glucose content

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

The use of Glucovans® should be discontinued 48 hours prior to elective surgery or intravenous administration of an iodine containing radiopaque contrast agent. It is recommended that treatment should be resumed 48 hours later and only after renal function has been evaluated and found to be normal.

Renal function

Because metformin is excreted by the kidneys, serum creatinine Cl and/or creatinine content should be determined before initiation of treatment and regularly thereafter: at least once a year in patients with normal renal function, and 2-4 times a year in older patients, and in patients with creatinine Cl at HGH.

Particular caution is recommended in cases where renal function may be impaired, such as in elderly patients or when starting antihypertensive therapy, taking diuretics or NSAIDs.

Other precautions

The patient should inform the physician if there is a bronchopulmonary infection or a urinary tract infection.

The effect on the ability to drive and operate machinery. Patients should be informed about the risk of hypoglycemia and take precautions when driving and operating machinery requiring increased concentration and rapid psychomotor reactions.

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Contraindications

• High sensitivity to metformin, glibenclamide, or other sulfonylurea derivatives or excipients;
• Diabetes mellitus type I;
• Diabetic ketocidosis, diabetic precomaDiabetic ketoacidosis, diabetic precoma, diabetic coma;
• renal insufficiency or impaired renal function (creatinine cl
• acute conditions that may lead to changes in renal function: dehydration, severe infection, shock, intravascular administration of iodine-containing contrast agents (see “
• Acute or chronic diseases that are accompanied by tissue hypoxia: cardiac or respiratory failure, recent myocardial infarction, shock;
• hepatic failure;
• porphyria;
• pregnancy;
• period of breastfeeding;
• concomitant use of miconazole;
• extensive surgical procedures;
• chronic alcoholism, acute alcohol intoxication;
• lactoacidosis (incl.
• Hypical alcohol intoxication;
• Lack of calories in a diet low in calories (

The drug is not recommended for persons older than 60 years of age who perform heavy physical work, because of the increased risk of lactoacidosis in them.

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

With caution: febrile syndrome, adrenal insufficiency, hypofunction of the anterior pituitary gland lobe, thyroid disease with uncompensated thyroid dysfunction.

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Side effects

Metabolic disorders: hypoglycemia (see “Overdose”, “Cautions”). Rarely – episodes of hepatic porphyria and cutaneous porphyria; very rare – lactoacidosis (see “Cautions”). Reduced absorption of vitamin B12, accompanied by a decrease in its serum concentrations with long-term use of metformin. If megaloblastic anemia is detected, the possibility of this etiology should be considered. Disulfiram-like reaction with alcohol use.

Laboratory parameters: infrequent – moderate to moderate increase in serum urea and creatinine concentrations; very rare – hyponatremia.

Hematological and lymphatic system disorders: these undesired effects disappear after discontinuation of the drug. Leukopenia and thrombocytopenia are rare; agranulocytosis, hemolytic anemia, aplasia of bone marrow and pancytopenia are very rare.

Nervous system disorders: often – taste disorders (metallic taste in the mouth).

Visual disorders: at the beginning of treatment there may be temporary visual impairment due to decreased blood glucose levels.

Gastrointestinal disorders: very often – nausea, vomiting, diarrhea, abdominal pain and lack of appetite. These symptoms occur more frequently at the beginning of treatment and in most cases disappear on their own. To prevent these symptoms, it is recommended that the drug be taken in 2 or 3 doses; a slow increase in dose also improves tolerability.

Skin and subcutaneous tissue disorders: rare – skin reactions such as itching, urticaria, maculopapular rash; very rare – cutaneous or visceral allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitization.

Immunological reactions: very rare – anaphylactic shock. Cross-sensitivity reactions to sulfonamides and their derivatives may occur.

Hepatobiliary disorders: very rare – disorders of liver function or hepatitis, requiring discontinuation of treatment.

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Similarities

Glibomet, Glukonorm, Glukonorm Plus, Metglyb Force