Glimecomb (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

A10BD02 (Metformin and sulfonamides)

Active Substances

Metformin (Rec.INN registered by WHO)

Gliclazide (Rec.INN registered by WHO)

Dosage Form

Glimecomb

Tablets 40 mg+500 mg: 30, 60, or 120 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to white with a creamy or yellowish tint, round, flat-cylindrical, with a bevel and a score; the presence of “marbling” is allowed.

Excipients: sorbitol, povidone, croscarmellose sodium, magnesium stearate.

30 pcs. – polyethylene bottles (1) – cardboard packs.
60 pcs. – polyethylene bottles (1) – cardboard packs.
120 pcs. – polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; combinations of oral hypoglycemic drugs

Pharmacological Action

Combined hypoglycemic drug for oral administration. Glimecomb is a fixed combination of two oral hypoglycemic agents from the biguanide group and the sulfonylurea derivatives group.

It has pancreatic and extrapancreatic effects.

Gliclazide – a sulfonylurea derivative. It stimulates insulin secretion by the pancreas and increases the sensitivity of peripheral tissues to insulin. It stimulates the activity of intracellular enzymes – muscle glycogen synthase. It restores the early peak of insulin secretion, reduces the time interval from food intake to the start of insulin secretion, and reduces postprandial hyperglycemia.

In addition to its effect on carbohydrate metabolism, it affects microcirculation, reduces platelet adhesion and aggregation, delays the development of parietal thrombosis, normalizes vascular permeability and prevents the development of microthrombosis and atherosclerosis, restores the process of physiological parietal fibrinolysis, and counteracts the increased reaction of blood vessels to adrenaline in microangiopathies.

It slows down the development of diabetic retinopathy at the non-proliferative stage; in diabetic nephropathy, long-term use leads to a significant reduction in proteinuria. It does not lead to weight gain because it primarily affects the early peak of insulin secretion and does not cause hyperinsulinemia; it promotes weight loss in obese patients while following an appropriate diet.

Metformin belongs to the biguanide group. It reduces blood glucose concentration by inhibiting gluconeogenesis in the liver, reducing glucose absorption from the gastrointestinal tract, and increasing its utilization in tissues. It reduces the concentration of triglycerides, cholesterol, and LDL (determined on an empty stomach) in the blood serum and does not change the concentration of other density lipoproteins.

It promotes stabilization or reduction of body weight. In the absence of insulin in the blood, the therapeutic effect does not occur. It does not cause hypoglycemic reactions. It improves the fibrinolytic properties of blood by suppressing the tissue-type plasminogen activator inhibitor.

Pharmacokinetics

Gliclazide

Absorption and Distribution

After oral administration, absorption is high. When taken in a dose of 40 mg, C_max in blood plasma is reached in 2-3 hours and is 2-3 µg/ml. Plasma protein binding is 85-97%.

Metabolism and Excretion

It is metabolized in the liver. T_1/2 is 8-20 hours. It is excreted mainly by the kidneys as metabolites – 70%, through the intestines – 12%.

In elderly patients, no clinically significant changes in pharmacokinetic parameters are noted.

Metformin

Absorption and Distribution

After oral administration, absorption is 48-52%. It is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability (on an empty stomach) is 50-60%. C_max in blood plasma is reached in 1.81-2.69 hours and does not exceed 1 µg/ml. Taking with food reduces C_max in plasma by 40% and delays its achievement by 35 minutes. Plasma protein binding is negligible. Metformin can accumulate in erythrocytes.

Excretion

T_1/2 is 6.2 hours. It is excreted by the kidneys, mainly unchanged (glomerular filtration and tubular secretion) and through the intestines (up to 30%).

Indications

• type 2 diabetes mellitus (non-insulin-dependent) when diet therapy, physical exercise, and prior therapy with metformin or gliclazide are ineffective;
• Replacement of prior therapy with two drugs (metformin and gliclazide) in patients with type 2 diabetes mellitus (non-insulin-dependent) with stable and well-controlled blood glucose levels.

ICD codes

Dosage Regimen

The drug is taken orally during or immediately after a meal. The dose of the drug is determined by the doctor individually for each patient depending on the blood glucose level.

The initial dose is usually 1-3 tablets/day with a gradual dose titration until stable compensation of the disease is achieved. The maximum daily dose is 5 tablets.

Usually, the drug is taken 2 times/day (in the morning and in the evening).

Adverse Reactions

From the endocrine system: hypoglycemia (in case of dosage regimen violation and inadequate diet) – headache, feeling of fatigue, feeling of hunger, increased sweating, sharp weakness, palpitations, dizziness, impaired coordination of movements, temporary neurological disorders; with the progression of hypoglycemia, loss of self-control, loss of consciousness is possible.

From the metabolism: in some cases – lactic acidosis (weakness, myalgia, respiratory disorders, drowsiness, abdominal pain, hypothermia, decreased blood pressure, bradyarrhythmia).

From the digestive system: dyspepsia (nausea, diarrhea, feeling of heaviness in the epigastrium, “metallic” taste in the mouth), decreased appetite (the severity of these reactions decreases when the drug is taken with meals); rarely – hepatitis, cholestatic jaundice (drug withdrawal is required), increased activity of hepatic transaminases, alkaline phosphatase.

From the hematopoietic system: rarely – inhibition of bone marrow hematopoiesis (anemia, thrombocytopenia, leukopenia).

Allergic reactions: itching, urticaria, maculopapular rash.

Other: visual impairment.

In case of side effects, the dose should be reduced or the drug should be temporarily discontinued.

General side effects of sulfonylurea derivatives: erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, life-threatening liver failure.

Contraindications

• type 1 diabetes mellitus (insulin-dependent);
• Diabetic ketoacidosis;
• Diabetic precoma, diabetic coma;
• Hypoglycemia;
• Severe renal impairment;
• Acute conditions that may lead to changes in renal function: dehydration, severe infection, shock;
• Acute or chronic diseases accompanied by tissue hypoxia: heart failure, respiratory failure, recent myocardial infarction, shock;
• Hepatic failure;
• Porphyria;
• Pregnancy;
• Lactation period (breastfeeding);
• Concomitant use of miconazole;
• Conditions requiring insulin therapy, including infectious diseases, major surgical interventions, trauma, extensive burns;
• Chronic alcoholism;
• Acute alcohol intoxication;
• Lactic acidosis (including in history);
• Use for at least 48 hours before and within 48 hours after radioisotope or X-ray examinations with the administration of iodine-containing contrast agent;
• Adherence to a hypocaloric diet (less than 1000 cal/day);
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other sulfonylurea derivatives.

It is not recommended to use the drug in patients over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis.

With caution, the drug should be used in case of febrile syndrome, adrenal insufficiency, hypofunction of the anterior pituitary gland, thyroid diseases with impaired function.

Use in Pregnancy and Lactation

The use of Glimecomb is contraindicated during pregnancy. When planning pregnancy, as well as in case of pregnancy during the use of Glimecomb, it should be discontinued and insulin therapy should be prescribed.

Glimecomb is contraindicated during breastfeeding, since the active substances can be excreted in breast milk. In this case, it is necessary to switch to insulin therapy or stop breastfeeding.

Use in Hepatic Impairment

Contraindicated in hepatic failure.

Use in Renal Impairment

Contraindicated in severe renal impairment, acute conditions that may lead to changes in renal function: dehydration, severe infection, shock.

Geriatric Use

It is not recommended to use the drug in patients over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis.

Special Precautions

Treatment with Glimecomb is carried out only in combination with a low-calorie diet low in carbohydrates. It is necessary to regularly monitor blood glucose levels on an empty stomach and after meals, especially in the first days of treatment with the drug.

Glimecomb can only be prescribed to patients who have regular meals, necessarily including breakfast and ensuring sufficient carbohydrate intake.

When prescribing the drug, it should be taken into account that due to the intake of sulfonylurea derivatives, hypoglycemia may develop, and in some cases in a severe and prolonged form, requiring hospitalization and glucose administration for several days.

Hypoglycemia develops more often with a low-calorie diet, after prolonged or vigorous physical exercise, after alcohol consumption, or while taking several hypoglycemic drugs simultaneously.

To avoid the development of hypoglycemia, careful and individual dose selection is necessary, as well as providing the patient with complete information about the proposed treatment. During physical and emotional stress, when changing the diet, correction of the dose of Glimecomb is necessary.

Elderly individuals are especially sensitive to the action of hypoglycemic drugs; patients who do not receive balanced nutrition, with a general weakened condition; patients suffering from pituitary-adrenal insufficiency.

Beta-blockers, clonidine, reserpine, guanethidine can mask the clinical manifestations of hypoglycemia.

Patients should be warned about the increased risk of hypoglycemia in cases of ethanol intake, NSAIDs, during fasting.

In case of major surgical interventions and trauma, extensive burns, infectious diseases with febrile syndrome, it may be necessary to discontinue oral hypoglycemic drugs and prescribe insulin therapy.

During treatment, control of renal function is necessary. Determination of lactate in plasma should be carried out at least 2 times a year, as well as when myalgia appears. If lactic acidosis develops, treatment should be discontinued.

48 hours before surgical intervention or intravenous administration of iodine-containing X-ray contrast agent, the intake of Glimecomb should be discontinued. Treatment is recommended to be resumed after 48 hours.

During therapy with Glimecomb, the patient must refrain from consuming alcohol and/or preparations and food products containing ethanol.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms: lactic acidosis (since the drug contains metformin), hypoglycemia are possible.

Treatment: if symptoms of lactic acidosis appear, the drug should be discontinued. Lactic acidosis is a condition requiring emergency medical care; treatment is carried out in a hospital. The most effective method of treatment is hemodialysis.

In case of mild or moderate hypoglycemia, glucose (dextrose) or sugar solution is taken orally. In case of severe hypoglycemia (loss of consciousness), 40% dextrose (glucose) solution or glucagon is administered intravenously, intramuscularly or subcutaneously. After regaining consciousness, the patient should be given food rich in carbohydrates to avoid recurrent hypoglycemia.

Drug Interactions

Enhancement of the hypoglycemic effect of Glimecomb is observed with simultaneous use with ACE inhibitors (captopril, enalapril), histamine H₂-receptor blockers (cimetidine), antifungal drugs (miconazole, fluconazole), NSAIDs (phenylbutazone, azapropazone, oxyphenbutazone), with fibrates (clofibrate, bezafibrate), antituberculosis drugs (ethionamide), salicylates, coumarin anticoagulants, anabolic steroids, beta-blockers, MAO inhibitors, long-acting sulfonamides, with cyclophosphamide, chloramphenicol, fenfluramine, fluoxetine, guanethidine, pentoxifylline, tetracycline, theophylline, tubular secretion blockers, reserpine, bromocriptine, disopyramide, pyridoxine, with other hypoglycemic drugs (including acarbose, biguanides, insulin), allopurinol, oxytetracycline.

Reduction of the hypoglycemic effect of Glimecomb is observed with simultaneous use with barbiturates, corticosteroids, adrenomimetics (epinephrine, clonidine), antiepileptic drugs (phenytoin), with slow calcium channel blockers, carbonic anhydrase inhibitors (acetazolamide), thiazide diuretics, chlorthalidone, furosemide, triamterene, asparaginase, with baclofen, danazol, diazoxide, isoniazid, with morphine, ritodrine, salbutamol, terbutaline, with glucagon, rifampicin, with thyroid hormones, lithium salts, with high doses of nicotinic acid, chlorpromazine, oral contraceptives and estrogens.

Increases the risk of ventricular extrasystole against the background of cardiac glycosides.

Drugs that inhibit bone marrow hematopoiesis increase the risk of myelosuppression.

Ethanol increases the likelihood of developing lactic acidosis.

Pharmacokinetic interaction

Metformin reduces C_max in blood plasma and T_1/2 of furosemide by 31 and 42.3%, respectively.

Furosemide increases C_max of metformin by 22%.

Nifedipine increases absorption, increases C_max in blood plasma, and slows down the excretion of metformin.

Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene and vancomycin), secreted in the tubules, compete for tubular transport systems and, with long-term therapy, can increase C_max of metformin in blood plasma by 60%.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.