Glucovance, 5 mg+500 mg 60 pcs

Glucovans® is a fixed combination of two oral hypoglycemic agents of different pharmacological groups: metformin and glibenclamide.

Indications

Type 2 diabetes mellitus in adults:

if diet therapy, physical exercise and previous monotherapy with metformin or sulfonylurea derivatives are ineffective;
to replace previous therapy with two drugs (metformin and a sulfonylurea derivative) in patients with stable and well-controlled glycemic levels.

Pharmacological effect

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

Special instructions

During treatment with Glucovance®, it is necessary to regularly monitor the level of glycemia on an empty stomach and after meals.

Lactic acidosis
Lactic acidosis is an extremely rare but serious (high mortality rate if not treated urgently) complication that can occur due to the accumulation of metformin. Cases of lactic acidosis in patients receiving metformin occurred mainly in diabetic patients with severe renal failure.

Other associated risk factors should be considered, such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, liver failure and any condition associated with severe hypoxia.

The risk of developing lactic acidosis should be taken into account when nonspecific signs appear, such as muscle cramps, accompanied by dyspeptic disorders, abdominal pain and severe malaise. In severe cases, acidotic dyspnea, hypoxia, hypothermia and coma may occur.

Diagnostic laboratory parameters are: low blood pH, plasma lactate concentration above 5 mmol/L, increased anion gap and lactate/pyruvate ratio.

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

Due to compensatory reactions caused by hypoglycemia, sweating, fear, tachycardia, hypertension, palpitations, angina pectoris and arrhythmia may 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 mellitus may include headache, hunger, nausea, vomiting, severe fatigue, sleep disturbances, restlessness, aggression, impaired concentration and psychomotor reactions, depression, confusion, speech impairment, visual impairment, trembling, paralysis and paresthesia, dizziness, delirium, convulsions, somnolence, unconsciousness, shallow breathing and bradycardia.

Careful prescribing, dose selection, and appropriate patient instructions are important to reduce the risk of hypoglycemia. If the patient has recurrent episodes of hypoglycemia that are either severe or due to unawareness of symptoms, treatment with other hypoglycemic agents should be considered.

Factors contributing to the development of hypoglycemia:

Concomitant use of alcohol, especially during fasting,
Refusal or (especially for elderly patients) inability of the patient to interact with the doctor and follow the recommendations set out in the instructions for use,
Poor nutrition, irregular eating, fasting or changes in diet,
Imbalance between physical activity and carbohydrate intake,
Kidney failure
Severe liver failure,
Overdose of the drug Glucovance®,
Certain endocrine disorders: insufficiency of the thyroid gland, pituitary gland and adrenal glands,
Concomitant use of individual medications.

Kidney and liver failure
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 which case appropriate treatment should be started.

Instability of blood glucose
In case of surgery or other cause of diabetes decompensation, it is recommended to consider a temporary transition to insulin therapy. Symptoms of hyperglycemia include frequent urination, severe thirst, and dry skin.

48 hours before planned surgery or intravenous administration of an iodinated radiocontrast agent, Glucovance® should be discontinued. Treatment is recommended to be resumed after 48 hours, and only after renal function has been assessed and found to be normal.

Kidney function
Since metformin is eliminated by the kidneys, before starting treatment, and regularly thereafter, it is necessary to determine creatinine clearance and/or serum creatinine levels: 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.

Particular caution is recommended in cases where renal function may be impaired, for example in elderly patients, or when initiating antihypertensive therapy, diuretics or non-steroidal anti-inflammatory drugs (NSAIDs).

Other precautions
The patient should inform the doctor about the occurrence of a bronchopulmonary infection or infectious disease of the genitourinary organs.

Impact on the ability to drive a car and operate machinery
Patients should be informed about the risk of hypoglycemia and should take precautions when driving a car and operating machinery that requires increased concentration and speed of psychomotor reactions.

Active ingredient

Glibenclamide, Metformin

Composition

Active components:

glibenclamide – 5 mg,

metformin hydrochloride – 500 mg.

Auxiliary components:

Core:

croscarmellose sodium – 14.0 mg,

povidone K 30 – 20.0 mg,

microcrystalline cellulose – 54.0 mg,

magnesium stearate – 7.0 mg.

Shell:

opadry 31-F-22700 yellow – 12.0 mg: lactose monohydrate – 36.0%, hypromellose 15 cP – 28.0%, titanium dioxide – 20.42%, macrogol – 10.00%, dye quinoline yellow – 3.00%, iron oxide yellow – 2.50%, iron oxide red – 0.08%; purified water – q.s..

Pregnancy

The use of the drug is contraindicated during pregnancy.

The patient should be warned that during treatment with Glucovance® it is necessary to inform the doctor about the planned pregnancy and the occurrence of pregnancy.

When planning pregnancy, as well as in the event of pregnancy while taking Glucovance®, the drug should be discontinued and treatment with insulin should be prescribed.

Glucovance® is contraindicated during breastfeeding, as there is no data on its ability to pass into breast milk.

Contraindications

Hypersensitivity to metformin, glibenclamide or other sulfonylurea derivatives, as well as to excipients;
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 changes 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, recent myocardial infarction, shock;
liver failure;
porphyria;
pregnancy, breastfeeding period;
simultaneous use of miconazole;
extensive surgical operations;
chronic alcoholism, acute alcohol intoxication;
lactic acidosis (including history);
following a hypocaloric diet (less than 1000 cal/day);

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.

Glucovance® contains lactose, therefore its use is not recommended for 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, diseases of the thyroid gland with uncompensated impairment of its function.

Side Effects

During treatment with Glucovance®, the following side effects may occur.

The frequency of side effects of the drug is assessed as follows:
Very frequent: ≥ 1/10
Common: ≥ 1/100, Uncommon: ≥ 1/1000, Rare: ≥ 1/10,000, Very rare: Single: cannot be estimated with the available data.

Metabolic disorders:
Hypoglycemia (See “Overdose”, “Special instructions”).
Rare: Attacks of hepatic porphyria and cutaneous porphyria.
Very rare: lactic acidosis (See “Special Instructions”).

Decreased absorption of vitamin B12, accompanied by a decrease in its concentration in the blood serum with long-term use of metformin. When megaloblastic anemia is detected, the possibility of such an etiology must be taken into account.

Disulfiram-like reaction when drinking alcohol.

Laboratory indicators:
Uncommon: Moderate to moderate increases in serum urea and creatinine concentrations.
Very rare: Hyponatremia.

Circulatory and lymphatic systems:
These adverse events disappear after discontinuation of the drug.
Rare: Leukopenia and thrombocytopenia.
Very rare: Agranulocytosis, hemolytic anemia, bone marrow aplasia and pancytopenia.

Nervous system:
Common: Taste disturbance (metallic taste in the mouth).

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

Gastrointestinal disorders:
Very common: nausea, vomiting, diarrhea, abdominal pain and lack of appetite. These symptoms are more common at the beginning of treatment and in most cases go away on their own. To prevent the development of these symptoms, it is recommended to take the drug in 2 or 3 doses; Slowly increasing the dose of the drug also improves its tolerability.

Skin and subcutaneous tissue:
Rarely: skin reactions such as itching, urticaria, maculopapular rash.
Very rare: cutaneous or visceral allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity.

Immunological reactions:
Very rare: Anaphylactic shock.

Cross-hypersensitivity reactions to sulfonamides and their derivatives may occur.

Hepato-biliary disorders:
Very rare: Abnormal liver function tests or hepatitis requiring discontinuation of treatment.

Interaction

Contraindicated combinations

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

Related to the use of metformin
Iodinated contrast media: Depending on renal function, the drug should be discontinued 48 hours before or after intravenous administration of iodinated contrast media.

Combinations not recommended

Related to the use of sulfonylurea derivatives

Alcohol: An antabuse reaction (alcohol intolerance) is very rarely observed when taking alcohol and glibenclamide at the same time.

Alcohol intake may increase the hypoglycemic effect (by inhibiting compensatory reactions or delaying its metabolic inactivation), which may contribute to the development of hypoglycemic coma. During treatment with Glucovance®, you should avoid taking alcohol and medications containing alcohol.

Phenylbutazone increases the hypoglycemic effect of sulfonylurea derivatives (by replacing sulfonylurea derivatives at protein binding sites and/or reducing their elimination). It is preferable to use other anti-inflammatory drugs that exhibit fewer interactions, or to warn the patient about the need to self-monitor glycemic levels; If necessary, the dose should be adjusted when using an anti-inflammatory drug together and after its discontinuation.

Associated with the use of glibenclamide

Bosentan in combination with glibenclamide increases the risk of hepatotoxicity. It is recommended to avoid taking these drugs together. The hypoglycemic effect of glibenclamide may also be reduced.

Associated with metformin use

Alcohol: The risk of developing lactic acidosis increases with acute alcohol intoxication, especially in the case of fasting, or poor nutrition, or liver failure. During treatment with Glucovance®, you should avoid taking alcohol and medications containing alcohol.

Combinations requiring caution

Associated with the use of all hypoglycemic agents

Chlorpromazine: in high doses (100 mg/day) causes an increase in glycemic levels (reducing insulin release).

Precautions: the patient should be warned about the need to independently monitor blood glucose levels; If necessary, adjust the dose of the hypoglycemic agent during concurrent use of the antipsychotic and after discontinuation of its use.

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

Precautions: the patient should be warned about the need to independently monitor blood glucose levels; if necessary, the dose of the hypoglycemic agent should be adjusted during the simultaneous use of GCS and after discontinuation of their use.

Danazol has a hyperglycemic effect. If treatment with danazol is necessary and when taking the latter, a dose adjustment of the drug Glucovance is required under the control of glycemic levels.

b2-adrenergic agonists: by stimulating b2-adrenergic receptors, they increase the concentration of glucose in the blood.

Precautions: it is necessary to warn the patient and establish control of blood glucose levels; transfer to insulin therapy is possible.

Diuretics: increase blood glucose levels. Precautions: the patient should be warned about the need to independently monitor blood glucose levels; It may be necessary to adjust the dose of the hypoglycemic agent during simultaneous use with diuretics and after discontinuation of their use.

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

Associated with metformin use

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

Associated with the use of glibenclamide

b-blockers, clonidine, reserpine, guanethidine and sympathomimetics mask some symptoms of hypoglycemia: palpitations and tachycardia; Most non-selective beta-blockers increase the incidence and severity of hypoglycemia.

The patient should be warned about the need to independently monitor blood glucose levels, especially at the beginning of treatment.

Fluconazole: Increased half-life of glibenclamide with the possible occurrence of hypoglycemia. The patient should be warned about the need to self-monitor blood glucose levels; It may be necessary to adjust the dose of hypoglycemic drugs during concomitant treatment with fluconazole and after discontinuation of its use.

Other interactions: combinations to consider:

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 – the risk of developing hypoglycemia during the use of glibenclamide.

Overdose

In case of overdose, hypoglycemia may develop due to the presence of a sulfonylurea derivative in the drug (see “Special Instructions”).

Mild to moderate symptoms of hypoglycemia without loss of consciousness or neurological manifestations can be corrected by immediate consumption of sugar. It is necessary to adjust the dose and/or change the diet. The occurrence of severe hypoglycemic reactions in patients with diabetes mellitus, accompanied by coma, paroxysm or other neurological disorders, requires emergency medical care. Intravenous administration of dextrose solution is necessary immediately after diagnosis or suspicion of hypoglycemia, before hospitalization of the patient. After regaining consciousness, it is necessary to give the patient food rich in easily digestible carbohydrates (to avoid re-development of hypoglycemia).

Long-term overdose or the presence of associated risk factors can provoke the development of lactic acidosis, since the drug contains metformin (see “Special Instructions”).

Lactic acidosis is a medical emergency; Lactic acidosis should be treated in a clinic. The most effective treatment method for removing lactate and metformin is hemodialysis.

Plasma clearance of glibenclamide may be increased in patients with liver disease. Since glibenclamide actively binds to blood proteins, the drug is not eliminated during dialysis.

Storage conditions

At a temperature not exceeding 30 °C.

Shelf life

3 years.

Manufacturer

Merck Santé S.a.S., France