Oziclid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OZIKLIDE (OZIKLIDE)

Composition:

Active substance: gliclazide;

One modified-release tablet contains 30 mg of gliclazide;

Excipients: povidone, calcium hydrogen phosphate, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Modified-release tablets.

Main physicochemical properties: white or almost white, biconvex, film-coated tablets without coating, marked with "G30" on one side and smooth on the other.

Pharmacotherapeutic group.

Antidiabetic agents. Blood-glucose-lowering agents, excluding insulin. Sulphonylureas, urea derivatives. Gliclazide. ATC code A10BB09.

Pharmacological Properties

Pharmacodynamics

Gliclazide is an oral hypoglycemic agent, a derivative of sulfonylurea, distinguished from other agents by the presence of a heterocyclic ring containing nitrogen and endocyclic bonds.

Gliclazide reduces plasma glucose levels by stimulating insulin secretion from pancreatic β-cells of the islets of Langerhans. Elevated postprandial insulin levels and C-peptide secretion are maintained even after 2 years of treatment. Gliclazide also possesses hemovascular properties.

Effect on insulin secretion. In patients with type 2 diabetes, gliclazide restores the early peak of insulin secretion in response to glucose intake and enhances the second phase of insulin secretion. A significant increase in insulin release occurs in proportion to food intake or glucose load.

Hemovascular properties. Gliclazide reduces microthrombosis through two mechanisms potentially involved in the development of diabetic complications:

• Partially inhibits platelet aggregation and adhesion, reducing levels of platelet activation markers (β-thromboglobulin, thromboxane B2);
• Enhances endothelial fibrinolytic activity (increases tPA activity).

Pharmacokinetics

Plasma concentration of gliclazide progressively increases during the first 6 hours after administration, then reaches a steady level (plateau) maintained from the 6th to the 12th hour after dosing.

A single daily dose of Oziclíd provides effective plasma concentrations of gliclazide for 24 hours.

Individual variations are minor.

Gliclazide is completely absorbed from the gastrointestinal tract. Food intake does not affect the rate or extent of absorption.

A linear relationship exists between administered doses up to 120 mg and plasma concentrations. Plasma protein binding of gliclazide is approximately 95%.

Gliclazide is primarily metabolized in the liver and excreted in urine; less than 1% of the active substance is excreted unchanged in urine. Active metabolites are absent in plasma.

The elimination half-life of gliclazide is approximately 12–20 hours.

The volume of distribution is approximately 30 L.

In elderly patients, no clinically significant changes in pharmacokinetics have been observed.

Clinical characteristics.

Indications.

Type 2 diabetes:

• Reduction and control of blood glucose when it is not possible to normalize glucose levels 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.

Contraindications.

• Hypersensitivity to gliclazide or to other sulfonylurea drugs, sulfonamides, or to any component of the drug;
• Type 1 diabetes;
• Diabetic precoma or coma, diabetic ketoacidosis (insulin therapy is recommended in these cases);
• Severe hepatic or renal insufficiency;
• Concomitant treatment with miconazole;
• Concomitant treatment with quinolones;
• Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

When using drugs that, when administered concomitantly, may cause hypoglycemia or hyperglycemia, patients should be warned about the necessity of careful monitoring of blood glucose levels during treatment. Dose adjustment of the antidiabetic drug may be required during and after treatment with these agents.

Drugs whose concomitant administration may increase the risk of hypoglycemia

Contraindicated concomitant use:

Miconazole (for systemic use, oral gel) enhances the hypoglycemic effect, possibly leading to symptoms of hypoglycemia and even coma.

Quinolones enhance the hypoglycemic effect, possibly causing severe, profound, and persistent hypoglycemia, which may be difficult to control, or even leading to coma, particularly in elderly patients with renal insufficiency.

Not recommended concomitant use

Phenylbutazone (for systemic use) enhances the hypoglycemic effect of sulfonylurea derivatives (by displacing their plasma protein binding and/or reducing their excretion).

Alcohol increases the risk of hypoglycemic reactions (due to inhibition of compensatory mechanisms), which may lead to hypoglycemic coma. Consumption of alcohol and alcohol-containing medications should be avoided.

Combinations requiring caution

Concomitant use with any of the following drugs may in some cases lead to hypoglycemia due to enhanced hypoglycemic effect: other antidiabetic drugs (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, nonsteroidal anti-inflammatory drugs.

Drugs whose concomitant administration may increase the risk of hyperglycemia

Concomitant use not recommended

Danazol 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 formulations) 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 and others): when used concomitantly with anticoagulants, sulfonylurea derivatives may potentiate their anticoagulant effect. If necessary, the dose of anticoagulants may require adjustment.

Special precautions for use.

Hypoglycaemia. This medicinal product should only be prescribed to patients who are able to eat regular meals (including breakfast). It is important to regularly consume carbohydrates, as the risk of hypoglycaemia increases if meals are delayed, insufficient, or low in carbohydrates. Hypoglycaemia is more likely to occur during low-calorie diets, prolonged or intense physical exertion, alcohol consumption, or when combining hypoglycaemic agents.

Hypoglycaemia may occur during treatment with sulphonylurea drugs (see section "Adverse reactions"). Occasionally, hypoglycaemia can be severe and prolonged. In such cases, hospitalization and administration of glucose for several days may be required.

To reduce the risk of hypoglycaemic episodes, individual patient characteristics should be taken into account, clear instructions provided, and the dose carefully adjusted.

Factors increasing the risk of hypoglycaemia:

• Patient refuses or is unable to follow medical advice (particularly relevant for elderly patients);
• Inadequate, irregular food intake, periods of fasting, or dietary changes;
• Imbalance between physical exertion and carbohydrate intake;
• Alcohol consumption;
• Renal impairment;
• Severe hepatic impairment;
• Overdose of the drug;
• 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. Hypoglycaemic 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 hypoglycaemia, symptoms of hypoglycaemia (see section "Adverse reactions"), and methods for their management.

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

Worsening glycaemic 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 surgical intervention. In some cases, insulin therapy may become necessary.

The hypoglycaemic efficacy of any oral antidiabetic agent, including gliclazide, may change over time. This may be due to progression of disease severity or reduced response to treatment. This phenomenon is known as secondary failure, which differs from primary failure, where the drug is ineffective from the beginning of treatment. Before concluding that secondary failure has occurred, the appropriateness of the prescribed dose and the patient’s adherence to diet should be verified.

Laboratory tests: Assessment of blood glucose control is recommended through measurement of glycated haemoglobin (HbA1c) or fasting blood glucose levels.

In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, sulphonylurea agents may induce haemolytic anaemia. Gliclazide should be used with caution in such patients, and consideration should be given to alternative therapies not involving sulphonylurea agents.

Use during pregnancy or breastfeeding.

Pregnancy. Oral antidiabetic agents should not be used during pregnancy.

Experience with gliclazide use during pregnancy is limited (fewer than 300 cases of use in pregnant women), as are data on other sulphonylurea agents. Animal studies have shown that gliclazide has no teratogenic effect.

It is advisable to avoid using gliclazide during pregnancy.

When pregnancy is planned or confirmed, women should be switched from oral hypoglycaemic agents to insulin therapy.

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

Fertility. Preclinical studies revealed no effects of gliclazide on fertility or reproductive performance in male or female rats.

Ability to affect reaction speed when driving or operating machinery.

Oziclíd may have a negligible influence on the ability to drive or operate machinery. Patients should be aware of the symptoms of hypoglycaemia, be able to recognize them, and exercise caution when driving or operating machinery, especially at the beginning of treatment.

Dosage and Administration

For oral use only.

Prescribe only to adult patients.

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

The daily dose should be taken once daily with breakfast.

Half a tablet or a whole tablet(s) should be swallowed whole (do not crush or chew).

If a patient forgets to take a dose, they should not double the dose the next day.

As with all antidiabetic agents, Oziklid 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) daily. 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 made gradually, at intervals of 1 month, except in cases where 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 from glipizide 80 mg formulations to Oziklid modified-release tablets: 1 tablet containing 80 mg glipizide corresponds to 1 tablet of Oziklid. Blood parameters should be closely monitored during the switch to Oziklid.

Switching from other oral antidiabetic agents to Oziklid: Oziklid may be prescribed as a replacement for another oral antidiabetic agent. The dosage and half-life of the previous agent should be taken into account. A transition period is usually not required. Treatment should begin with a 30 mg dose, followed by dose adjustment (see "Initial dose and dose titration").

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

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

In elderly patients (aged 65 years and older): The dosing regimen for Oziklid is the same as for patients under 65 years of age.

In patients with mild to moderate renal impairment: The dosing regimen for Oziklid is the same as for patients with normal renal function; however, such patients should be closely monitored.

Hypoglycemia risk factors:

• inadequate or irregular food intake;
• severe or poorly compensated endocrine disorders
  (hypothyroidism, hypopituitarism, and adrenocorticotropic insufficiency);
• discontinuation of long-term corticosteroid therapy and/or therapy with high-dose
  corticosteroids;
• severe vascular diseases (severe ischemic heart disease, severe carotid artery pathology,
  diffuse vascular disease).

A minimal initial dose of 30 mg daily is recommended.

For prevention of complications of type 2 diabetes: An intensive glycemic control strategy should be followed (HbA1c level ≤ 6.5%). The intensive glycemic control strategy involves gradual dose escalation of Oziklid up to 120 mg daily. Dose increases should be performed under HbA1c monitoring, strict dietary and physical exercise recommendations, and with careful assessment of hypoglycemia risk. Additional antidiabetic agents such as metformin, acarbose, thiazolidinediones, or insulin may also be considered.

Children.

Glipizide is not recommended for use in children due to lack of data on safety and efficacy in this patient population.

Overdose

Overdose of sulfonylurea agents may cause hypoglycemia.

Symptoms of moderate hypoglycemia (without loss of consciousness or neurological symptoms) should be corrected by carbohydrate intake (sugar), adjustment of the antidiabetic agent dose, and/or dietary changes. Close monitoring of the patient should continue until the physician is confident the patient is safe.

Severe hypoglycemia leading to coma, seizures, or other neurological disturbances requires emergency medical care and immediate hospitalization.

In cases of diagnosed hypoglycemic coma or suspected coma development, the patient should receive an immediate intravenous injection of 50 mL of concentrated glucose solution (20–30%), followed by continuous infusion of a less concentrated glucose solution (10%) at a rate sufficient to maintain blood glucose levels above 1 g/L. Continuous patient monitoring is required. The physician will determine further management based on the patient’s condition.

Glipizide is highly protein-bound; therefore, dialysis is ineffective.

Adverse Reactions

Based on experience with gliclazide and other sulfonylurea derivatives, the following undesirable effects may occur.

Hypoglycemia. As with other sulfonylurea drugs, gliclazide may cause hypoglycemia, particularly in cases of irregular eating habits or when a meal has been skipped. Hypoglycemia may be accompanied by characteristic symptoms such as headache, intense hunger, nausea, vomiting, fatigue, sleep disturbances, excitement, aggression, impaired concentration and reaction, depression, confusion, visual and speech disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, weakness, loss of self-control, delirium, seizures, shallow breathing, bradycardia, drowsiness, and loss of consciousness, which may progress to coma and potentially fatal outcomes.

Additionally, symptoms related to the adrenergic system may occur: sweating, cold clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, chest pain, and arrhythmia.

Typically, symptoms of hypoglycemia resolve after carbohydrate intake (sugar). However, sugar substitutes are ineffective in such cases. Experience with other sulfonylurea drugs indicates that even when initial measures are effective, hypoglycemia may recur.

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

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

The following adverse effects are observed less frequently:

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, erythema, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis), and very rarely drug reaction with eosinophilia and systemic symptoms (DRESS).

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

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

The aforementioned adverse effects usually resolve after discontinuation of the drug.

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

Class-specific reactions of sulfonylurea drugs: cases of erythropenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, and hyponatremia have been reported. During treatment with sulfonylurea drugs, increased levels of liver enzymes and even liver function impairment (e.g., with cholestasis and jaundice), as well as hepatitis, have also been described. These abnormalities generally improved after discontinuation of the drugs, but in isolated cases led to life-threatening liver failure.

During the ADVANCE study, serious adverse reactions were monitored. No previously unreported adverse reactions were identified in the group of patients with type 2 diabetes treated according to an intensive glycemic control strategy. Several patients experienced severe hypoglycemia. Most episodes of hypoglycemia occurred in patients receiving concomitant insulin therapy.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

10 tablets per blister; 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.