Glucovance, 2.5mg+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 GI 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 it 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 mellitus in adults:

Active ingredient

Composition

Active ingredients:

Glibenclamide;

metformin hydrochloride;

Auxiliary substances:

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:

For 2.5+500 mg dosage:

For 5+500 mg dosage:

The tablets should be taken with meals. Each administration of the drug should be accompanied by a meal 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

All hypoglycemic agents related to use

Chlorpromazine: in high doses (100 mg/day) causes increased 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 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.

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.

Contraindications

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.

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.

Similarities