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:

• when diet therapy, exercise, and prior monotherapy 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 ingredients:

Glibenclamide – 5 mg,

metformin hydrochloride – 500 mg.

Auxiliary components:

Kernel:

croscarmellose sodium – 14.0 mg,

povidone K 30 – 20.0 mg,

microcrystalline cellulose – 54.0 mg,

magnesium stearate – 7.0 mg.

Shell:

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

How to take, the dosage

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

The starting dose is 1 tablet of Glucovans® 2.5 mg+500 mg or Glucovans® 5 mg+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 mg + 500 mg or 6 tablets of Glucovans® 2.5 mg + 500 mg.

Dosing regimen:
The dosing regimen depends on the individual prescription:

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

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

For 2.5 mg+500 mg dosage

• Three times daily, morning, afternoon, and evening, when prescribing 3, 5, or 6 pills per day.

For doses of 5 mg+500 mg

• Three 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 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 mg+500 mg. Regular renal function evaluation should be carried out.

In children
Glucovans® is not recommended for use in children.

Interaction

Contraindicated combinations

Associated with the use of glibenclamide
Myconazole may provoke hypoglycemia (up to the development of coma).

Associated with the use of metformin
Iodine contrast agents: Depending on renal function, the drug should be discontinued 48 hours before or after intravenous administration of iodine contrast agents.

Unrecommended combinations

Related to the use of sulfonylurea derivatives

Alcohol: A very rare 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 medicinal products 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.

Risk of lactoacidosis is increased in acute alcohol intoxication, especially in case of starvation, or poor nutrition, or liver failure. Alcohol and medicinal products containing alcohol should be avoided during treatment with Glucovans®.

Combinations requiring caution

Related to the use of all hypoglycemic agents

Chlorpromazine: at high doses (100 mg/day) causes increased glycemia (reducing insulin release).

Precautionary measures: advise patient to monitor blood glucose on their own; if necessary, adjust the dose of hypoglycemic agent during concomitant use of neuroleptic and after discontinuation of the drug.

Glucocorticosteroids (GCS) and tetracosactide: Increased blood glucose, sometimes accompanied by ketosis (GCS cause decreased glucose tolerance).

Precautionary measures: the patient should be advised to self-monitor blood glucose; if necessary, the dose of hypoglycemic agent should be adjusted during concomitant use of GCS and after stopping their use.

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

b2-adrenomimetics: due to stimulation of b2-adrenoreceptors they increase the concentration of glucose in the blood.

Precautionary measures: the patient should be warned and blood glucose should be controlled; transfer to insulin therapy is possible.

Diuretics: increase blood glucose levels. 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.

Angiotensin-converting enzyme (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 discontinuation of their use.

Associated with metformin use

Diuretics: Lactoacidosis occurring when taking metformin against the background of functional renal failure caused by taking diuretics, especially loop diuretics.

Associated with the use of glibenclamide

b-adrenoblockers, clonidine, reserpine, guanethidine, and sympathomimetics mask some symptoms of hypoglycemia: palpitation and tachycardia; most non-selective beta-adrenoblockers increase the frequency and severity of hypoglycemia.

Patients should be advised to self-monitor blood glucose, especially at the beginning of treatment.

Fluconazole: Increased elimination half-life of glibenclamide with possible occurrence of hypoglycemia. Patients should be cautioned about the need for self-monitoring of blood glucose; adjustment of the dose of hypoglycemic drugs may be required during concomitant treatment with fluconazole and after discontinuation of its use.

Other interactions: combinations to consider:

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 regularly monitor glycemic levels 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, the drug administration is accompanied by the risk of hypoglycemia in the patient. Gradual titration of the dose after the start 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 when 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 beta-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 disturbances, agitation, aggression, impaired concentration and psychomotor reactions, depression, confusion, impaired speech, visual disturbances, 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,
• Discontinuation or (especially in elderly patients) failure of the patient to interact with the physician and follow the recommendations in the instructions for use,
• Poor diet, irregular meal intake, starvation, or changes in diet,
• An imbalance between physical activity and carbohydrate intake,
• Renal insufficiency,
• Severe hepatic insufficiency,
• An overdose of Glucovans®,
• Separate endocrine disorders: Thyroid, pituitary and adrenal gland function deficiencies,
• Simultaneous administration of certain medications.

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

Instability of blood glucose
In the case of surgery or other cause of decompensation of diabetes, it is recommended to provide for 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 to restart the treatment 48 hours later and only after renal function has been evaluated and recognized as normal.

Renal function
Because metformin is excreted by the kidneys, creatinine clearance and/or serum creatinine content should be determined before starting 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 clearance at the upper limit of normal.

Particular caution is recommended in cases where renal function may be impaired, such as in elderly patients, or if antihypertensive therapy, diuretics or non-steroidal anti-inflammatory drugs (NSAIDs) are started.

Other precautions
The patient should inform the physician if a bronchopulmonary infection or urinary tract infection occurs.

Impact on driving and operating machinery
Patients should be advised of the risk of hypoglycemia and should take precautions when driving and operating machinery that require increased concentration and rapid psychomotor reactions.

Contraindications

• High sensitivity to metformin, glibenclamide or other sulfonylurea derivatives or excipients;
• Diabetes mellitus type 1;
• Diabetic ketocidosis, diabetic precomadiabetic ketoacidosis, diabetic precoma, diabetic coma;
• renal insufficiency or impaired renal function (creatinine clearance less than 60 ml/min);
• 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, breastfeeding period;
• concomitant use of miconazole;
• extensive surgical procedures;
• chronic alcoholism, acute alcohol intoxication;
• lactoacidosis (incl.
• Hypophilic acidosis (including history);
• Hypophilic diet (less than 1000 calories per day)

The drug is not recommended in patients older than 60 years of age who do 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, thyroid disease with uncompensated thyroid dysfunction.

Side effects

The following side effects may occur during treatment with Glucovans®.

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

Metabolic disorders:
Hypoglycemia (See Overdose, Special Indications).
Rare: Episodes of hepatic porphyria and cutaneous porphyria.
Very rare: Lactoacidosis (See “Special Indications”).

Decreased 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 must be considered.

Disulfiram-like reactions with alcohol use.

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

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

Nervous system:
Often: Taste disorder (metallic taste in the mouth).

Vision:
Temporary visual impairment may occur at the beginning of treatment due to decreased blood glucose levels.

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 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:
Rarely: skin reactions such as itching, urticaria, maculopapular rash.
Very rare: cutaneous or visceral allergic vasculitis, erythema polymorphicum, exfoliative dermatitis, photosensitization.

Immunological reactions:
Very rare: Anaphylactic shock.

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

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

Overdose

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

Mild to moderate symptoms of hypoglycemia without loss of consciousness and neurological manifestations may be corrected by immediate consumption of sugar. It is necessary to perform a dose adjustment 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. It is necessary to administer intravenous dextrose solution immediately after establishing the diagnosis or suspicion of hypoglycemia, before hospitalization of the patient. After recovery of consciousness, the patient should be given food rich in easily digestible carbohydrates (to avoid the recurrence of hypoglycemia).

Long-term overdose or concomitant risk factors can provoke lactoacidosis because the drug contains metformin (see Special Precautions).

Lactoacidosis is a condition requiring urgent medical care; treatment of lactoacidosis should be performed in the clinic. Hemodialysis is the most effective treatment to eliminate lactate and metformin.

The plasma clearance of glibenclamide may increase in patients with liver disease. Since glibenclamide actively binds to blood proteins, the drug is not eliminated by dialysis.

Pregnancy use

The use of the drug is contraindicated during pregnancy.

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

If a pregnancy is planned or if pregnancy occurs while taking Glucovans®, the drug should be discontinued and insulin treatment should be prescribed.

Glucovans® is contraindicated in breastfeeding because there is no data on its ability to penetrate into breast milk.

Similarities

Glibomet, Glukonorm, Glukonorm Plus, Metglyb Force