Diaglycid® mr

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIAGLIZID® MR (DIAGLIZID MR)

Composition:

Active substance: gliclazide;

One tablet contains gliclazide 30 mg;

Excipients: hypromellose, lactose monohydrate, copovidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Modified-release tablets.

Main physicochemical properties: round-shaped tablets with flat surface, beveled edges, with or without a score line, white or white with a slightly yellowish tint. Marbling is acceptable.

Pharmacotherapeutic group.

Antidiabetic agents. Oral blood glucose-lowering agents, excluding insulins. Sulphonylureas, urea derivatives. Gliclazide. ATC code A10BB09.

Pharmacological Properties.

Pharmacodynamics. Gliclazide is a derivative of sulfonylurea, a synthetic oral hypoglycemic agent of the second generation, which reduces blood glucose levels by stimulating pancreatic β-cells. The drug restores the early peak of insulin secretion in response to glucose entry into the body and enhances the second phase of insulin secretion by β-cells. Gliclazide improves insulin effectiveness and reduces insulin resistance by increasing glucose uptake and accumulation in muscles and decreasing its production in the liver. The drug enhances insulin-stimulated glucose metabolism, accelerating glucose transport into tissues, and also activates muscle glycogen synthase.

Gliclazide counteracts the development of diabetic vascular complications, including microangiopathies and atherosclerotic macroangiopathies. This effect is achieved by reducing platelet adhesion and aggregation, normalizing prostaglandin metabolism (which is impaired in diabetes mellitus), and enhancing vascular fibrinolytic activity. In addition, the drug is a potent scavenger of free radicals (in diabetes mellitus, their production is significantly increased), normalizes vascular permeability, and prevents the development of microthrombosis and atherogenesis. Gliclazide slows lipid deposition. The drug promotes weight reduction and normalizes lipid metabolism (reduces plasma concentrations of cholesterol, triglycerides, and free fatty acids).

Pharmacokinetics. After oral administration, gliclazide is completely absorbed from the gastrointestinal tract. Food intake does not affect the rate or extent of its absorption. Following administration of modified-release tablets, gliclazide concentration progressively increases during the first 6 hours, then reaches a steady level maintained from 6 to 12 hours. Individual differences in pharmacokinetics among patients are insignificant. Protein binding of gliclazide to plasma proteins reaches 95%. Gliclazide is primarily metabolized in the liver and excreted by the kidneys as inactive metabolites. The elimination half-life of gliclazide is approximately 16 hours. In elderly individuals, no significant differences in pharmacokinetic parameters have been observed compared to younger subjects. A single daily dose of 30 mg gliclazide in modified-release tablets ensures maintenance of an effective drug concentration in plasma for 24 hours.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus in adults:

• reduction and control of blood glucose when glucose levels cannot be normalized by diet, physical exercise, or weight reduction alone;
• prevention of complications of type 2 diabetes: reduction in the risk of macro- and microvascular complications, including new onset or worsening of nephropathy in patients with type 2 diabetes managed according to an intensive glycemic control strategy.

Contraindications.

• Hypersensitivity to gliclazide, other sulfonylurea drugs, sulfonamides, or to any component of the medicinal product;
• insulin-dependent diabetes (type 1);
• diabetic precoma and coma, diabetic ketoacidosis (in such cases insulin therapy is recommended);
• severe hepatic or renal insufficiency;
• treatment with miconazole;
• breastfeeding period;
• treatment with quinolones.

Interaction with other medicinal products and other forms of interaction.

When using medicinal products that may cause hypoglycemia or hyperglycemia when co-administered, patients should be warned about the need for careful monitoring of blood glucose levels during treatment. Dose adjustment of the antidiabetic agent may be required during and after treatment with these medicinal products.

Medicinal products whose concomitant administration may increase the risk of hypoglycemia.

Concomitant use contraindicated with:

miconazole (for systemic use, oral gel), as it enhances the hypoglycemic effect, possibly leading to hypoglycemic symptoms and even coma.

Quinolones enhance the hypoglycemic effect, possibly resulting in severe, profound, persistent hypoglycemia that is difficult to control, or even coma, particularly in elderly patients with renal insufficiency.

Not recommended for concomitant use with:

phenylbutazone (for systemic use) due to enhanced hypoglycemic effect of sulfonylurea derivatives (by displacing their plasma protein binding and/or reducing their elimination);

alcohol due to increased risk of hypoglycemic reactions (as a result of inhibition of compensatory mechanisms), which may lead to hypoglycemic coma. Consumption of alcohol and medicinal products containing alcohol should be avoided.

Combinations requiring caution

Concomitant use with any of the following medicinal products may occasionally result in hypoglycemia due to enhanced hypoglycemic effect: other antidiabetic agents (insulin, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists), β-blockers, fluconazole, ACE inhibitors (captopril, enalapril), H2-receptor antagonists, MAO inhibitors, sulfonamides, clarithromycin, and nonsteroidal anti-inflammatory drugs.

Medicinal products whose concomitant administration may increase the risk of hyperglycemia.

Not recommended for concomitant use with:

danazol, as it exerts a diabetogenic effect.

Combinations requiring caution:

chlorpromazine (neuroleptic) when used in high doses (over 100 mg daily) increases blood glucose levels (due to reduced insulin release);

glucocorticoids (for systemic and local use: intra-articular, topical, and rectal preparations) and tetracosactide increase blood glucose levels, possibly leading to ketoacidosis (by reducing carbohydrate tolerance);

ritodrine, salbutamol, terbutaline (intravenous) may increase blood glucose levels due to β2-agonist effects.

Combinations to be considered:

anticoagulants (e.g., warfarin, etc.) — when co-administered with anticoagulants, sulfonylurea derivatives may potentiate the anticoagulant effect. If necessary, the dose of anticoagulants may be adjusted.

St. John’s wort (Hypericum perforatum) preparations reduce gliclazide concentrations. Emphasis should be placed on the importance of blood glucose monitoring.

Special precautions for use.

Hypoglycemia. This medication should only be prescribed to patients who are able to eat regularly (including breakfast). It is important to consume carbohydrates regularly, as the risk of hypoglycemia increases when meals are delayed, inadequate in quantity, or low in carbohydrates.

Hypoglycemia is more likely to occur with low-calorie diets, prolonged or intense physical exertion, alcohol consumption, or concomitant use of hypoglycemic agents.

Hypoglycemia may occur during treatment with sulfonylurea drugs (see section "Adverse reactions"). Sometimes hypoglycemia can be severe and prolonged. In such cases, hospitalization and administration of glucose for several days may be required.

To reduce the risk of hypoglycemic episodes, individual patient characteristics must be considered, clear instructions provided, and the dose carefully adjusted.

Factors that increase the risk of hypoglycemia:

• patient noncompliance or inability to follow medical advice (particularly in elderly patients);
• poor or irregular nutrition, periods of fasting, or dietary changes;
• imbalance between physical activity and carbohydrate intake;
• alcohol consumption;
• renal impairment;
• severe hepatic impairment;
• drug overdose;
• certain endocrine disorders: thyroid dysfunction, hypopituitarism, and adrenal insufficiency;
• concomitant use of certain medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Renal and hepatic impairment: The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic impairment or severe renal impairment. Hypoglycemic episodes in such patients may be prolonged and therefore require appropriate treatment.

Patients and their family members should be informed about risk factors and conditions that may predispose to hypoglycemia, symptoms of hypoglycemia (see section "Adverse reactions"), and methods for their management.

Patients should be informed about the importance of adhering to dietary recommendations, the importance of regular physical activity, and regular monitoring of blood glucose.

Worsening glycemic control in patients receiving antidiabetic medications may be caused by St. John's wort (Hypericum perforatum) or any concomitant therapy that may affect gliclazide metabolism, infection, fever, trauma, or surgery. In some cases, insulin therapy may be necessary.

The hypoglycemic efficacy of any oral antidiabetic agent, including gliclazide, may change over time. This may result from progression of disease severity or reduced response to treatment. This phenomenon is known as secondary failure, which differs from primary failure, where the drugs are ineffective from the beginning of treatment. Before concluding that secondary failure has developed in a patient, the appropriateness of the prescribed dose and the patient's adherence to dietary recommendations should be verified.

Alterations in blood glucose concentration, including hypoglycemia and hyperglycemia, have been observed in patients with diabetes mellitus, particularly in the elderly, who are receiving concomitant treatment with fluoroquinolones. Careful monitoring of blood glucose levels is recommended in all patients receiving Diaglyzid® MR and fluoroquinolones simultaneously.

Laboratory tests. Measurement of glycated hemoglobin (or fasting blood glucose levels) is recommended to assess blood glucose control.

In patients with glucose-6-phosphate dehydrogenase deficiency, treatment with sulfonylurea agents may induce hemolytic anemia. Gliclazide should be used with caution in such patients, and alternative therapy without sulfonylurea agents should be considered.

The product contains lactose; therefore, it should not be administered to patients with rare hereditary forms of galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy. Oral antidiabetic agents (including Diaglyzid® MR) should not be used during pregnancy. Experience with gliclazide use during pregnancy is limited (fewer than 300 cases in pregnant women), and data on the use of other sulfonylurea agents are also limited. Animal studies have shown that gliclazide has no teratogenic effects.

Gliclazide use during pregnancy should be avoided whenever possible.

Glycemic control should be achieved before planning pregnancy to reduce the risk of abnormalities associated with uncontrolled diabetes. Upon planning or immediately after confirmation of pregnancy, women should be switched from oral antidiabetic agents to insulin therapy.

Breastfeeding. There are no data on the passage of gliclazide or its metabolites into breast milk. Diaglyzid® MR is contraindicated during breastfeeding due to the potential risk of neonatal hypoglycemia. Risk to newborns and infants cannot be excluded.

Fertility. In preclinical studies, no effects on fertility or reproductive capacity in male or female rats were observed.

Ability to affect reaction speed when driving or operating machinery.

Diaglyzid® MR may have a minor influence on the ability to drive or operate machinery. Patients should be aware of the symptoms of hypoglycemia, know how to recognize them, and exercise caution when driving or operating machinery, especially at the beginning of treatment.

Dosage and Administration

For oral use.

Prescribed only for adults.

The daily dose may vary from 1 to 4 tablets (from 30 to 120 mg per day).

The daily dose should be taken once daily with breakfast.

Tablets should be swallowed whole (do not crush or chew).

If a patient forgets to take the tablets, the dose should not be doubled the next day.

Like all antidiabetic agents, Diaglizide® MR requires individual dose adjustment based on the patient's individual response to treatment (blood glucose levels, glycated hemoglobin HbA1c).

Initial dose and dose titration. The recommended initial dose is 30 mg (1 tablet) per day. If adequate glucose control is achieved, treatment may continue at this dose. If enhanced glucose control is needed, the daily dose may be gradually increased to 60 mg (2 tablets), 90 mg (3 tablets), or 120 mg (4 tablets). Dose increases should be performed gradually, with intervals of 1 month, except when no reduction in blood glucose levels is observed within 2 weeks of treatment. In such cases, the dose may be increased at the end of the second week of treatment.

Maximum recommended daily dose – 120 mg (4 tablets).

Switching patients from formulations containing glipizide 80 mg to Diaglizide® MR 30 mg modified-release tablets: 1 tablet containing glipizide 80 mg corresponds to 1 tablet of Diaglizide® MR 30 mg. Blood parameters must be closely monitored during the switch to Diaglizide® MR 30 mg.

Switching patients from other oral antidiabetic agents to Diaglizide® MR 30 mg: Diaglizide® MR 30 mg may be prescribed instead of another oral antidiabetic agent. The dosage and elimination half-life of the previous agent should be taken into account. A transition period is usually not required. Treatment should start at a dose of 30 mg, followed by dose adjustment (see "Initial dose and dose titration").

When switching from hypoglycemic sulfonylurea agents with a longer elimination half-life than Diaglizide® MR 30 mg, a treatment-free interval of several days may be necessary to avoid the cumulative effect of both agents and prevent hypoglycemia. Treatment with Diaglizide® MR 30 mg should be initiated at a dose of 30 mg per day (1 tablet), followed by dose adjustment according to the principles described for initiation and dose titration (see above).

Concomitant use with other antidiabetic agents: Diaglizide® MR 30 mg may be used in combination with biguanides, alpha-glucosidase inhibitors, and insulin. If adequate blood glucose control is not achieved in patients taking Diaglizide® MR 30 mg, insulin therapy may be initiated concomitantly under strict medical supervision.

For elderly patients (over 65 years), the dosing regimen for Diaglizide® MR 30 mg is the same as for patients under 65 years of age.

For patients with mild to moderate renal impairment, the dosing regimen for Diaglizide® MR 30 mg is the same as for patients with normal renal function; however, such patients should be under close medical supervision.

For patients at risk of hypoglycemia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"), a minimal initial dose of 30 mg per day is recommended.

For patients with severe vascular diseases (ischemic heart disease, severe carotid artery disease, diffuse vascular disease), a minimal initial dose of 30 mg per day is recommended.

Prevention of complications in type 2 diabetes mellitus. According to the ADVANCE study, an intensive glycemic control strategy (HbA1c ≤ 6.5%) should be followed. The intensive glycemic control strategy involves gradual dose escalation of Diaglizide® MR 30 mg up to 120 mg per day. Dose escalation should be performed under HbA1c monitoring, strict adherence to dietary and physical activity recommendations, and careful monitoring of hypoglycemia risk. Additional antidiabetic agents such as metformin, acarbose, thiazolidinediones, or insulin may also be added.

Children. Safety and efficacy of glipizide in children and adolescents (under 18 years of age) have not been established. Data on use of the drug in children are lacking.

Overdose

Overdose with sulfonylurea derivatives may lead to hypoglycemia.

Mild hypoglycemic symptoms without loss of consciousness or neurological signs should be corrected by carbohydrate intake, dose adjustment, and/or dietary changes. Close monitoring should continue until the physician is certain that the patient is no longer at risk. Severe hypoglycemic reactions, such as coma, seizures, or other neurological disturbances, are possible and must be treated as medical emergencies requiring immediate hospitalization.

In cases of diagnosed hypoglycemic coma or suspected development of coma, the patient should receive a rapid intravenous injection of 50 mL of concentrated glucose solution (20% or 30%). This should be followed by a continuous infusion of a less concentrated glucose solution (10%) at a rate sufficient to maintain blood glucose levels above 1 g/L. Patients must remain under close medical supervision, and the physician will determine whether further monitoring is necessary. Since glipizide is highly protein-bound, hemodialysis is not beneficial.

Side effects

The following adverse reactions have been reported with the use of gliclazide.

Hypoglycemia. As with other sulfonylurea drugs, gliclazide may cause hypoglycemia, especially with irregular eating habits or when meals are skipped. Hypoglycemia may be accompanied by characteristic symptoms such as headache, intense hunger, nausea, vomiting, fatigue, sleep disturbances, restlessness, excitement, aggression, decreased concentration and attention, slowed reactions, depression, confusion, visual and speech disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, feelings of weakness, loss of self-control, delirium, seizures, shallow breathing, bradycardia, drowsiness, and loss of consciousness, which may progress to coma and potentially fatal outcomes.

In addition, adrenergic system-related symptoms may occur: sweating, clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, chest pain, and arrhythmia.

Symptoms of hypoglycemia usually resolve after carbohydrate intake (sugar). However, sugar substitutes are not effective in this case. Experience with other sulfonylurea drugs indicates that even if initial measures are effective, hypoglycemia may recur.

If a hypoglycemic episode is severe or prolonged and the patient's condition is only temporarily controlled by sugar intake, immediate medical attention or even hospitalization is required.

Gastrointestinal disorders: abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation. Adhering to recommendations to take the drug during breakfast may help prevent or minimize these effects.

Less frequently observed adverse effects:

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, angioedema, erythema, maculopapular eruptions, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis).

Blood and lymphatic system disorders (rare): anemia, leukopenia, thrombocytopenia, granulocytopenia. These effects usually resolve after discontinuation of the drug.

Hepatobiliary disorders: elevated liver enzymes (ALT, AST, alkaline phosphatase), hepatitis (isolated cases). If cholestatic jaundice occurs, treatment with the drug should be discontinued.

These adverse effects usually resolve after discontinuation of the drug.

Eye disorders: transient visual disturbances may occur due to changes in blood glucose levels, especially at the beginning of treatment.

Class-related sulfonylurea reactions: cases of erythropenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzymes, and even liver function impairment (e.g., with cholestasis and jaundice), hepatitis with regression after discontinuation of sulfonylurea drugs, or in isolated cases, progressive life-threatening hepatic failure.

In patients with type 2 diabetes treated according to an intensive glycemic control strategy, no previously unreported adverse reactions were identified. Some patients experienced severe hypoglycemia. Most episodes of hypoglycemia occurred in patients receiving concomitant insulin therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is very important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life.

3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in a place protected from light and inaccessible to children, at a temperature not exceeding 25 °C.

Packaging. 10 tablets per blister. 3 or 6 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.