INSTRUCTIONS for medical use of the medicinal product Glipida (Gliclada®)

Composition:

active substance: gliclazide;

1 modified-release tablet contains 30 mg of gliclazide;

excipients: hypromellose, calcium carbonate, lactose monohydrate, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Modified-release tablets.

Main physicochemical characteristics: oval, slightly biconvex tablets of white to almost white color.

Pharmacotherapeutic group. Antidiabetic agents. Blood glucose-lowering agents, excluding insulin. Sulfonamides, 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 having endocyclic bonds.

Gliclazide reduces glucose levels in blood plasma by stimulating insulin secretion from pancreatic β-cells of the islets of Langerhans. Enhanced postprandial insulin levels and C-peptide secretion are maintained even after 2 years of treatment.

Gliclazide also has 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 accordance with food intake or glucose load.

Hemovascular properties.

Gliclazide reduces microthrombosis through two mechanisms that may contribute to the development of complications in diabetes mellitus:

partially inhibits platelet aggregation and adhesion, reduces levels of platelet activation markers (β-thromboglobulin, thromboxane B2);
affects endothelial fibrinolytic activity (increases tPA activity).

Prevention of complications in type 2 diabetes.

ADVANCE – an international, multicenter, randomized trial with a bifactorial design, aimed at evaluating the benefits of an intensive glycemic control strategy (HbA1c ≤ 6.5%) based on modified-release gliclazide tablets (Gliclazide MR), compared to standard glycemic control, and the benefits of blood pressure reduction using a fixed-dose combination of perindopril/indapamide compared to placebo, on top of standard therapy (double-blind comparison), regarding the impact on major macro- and microvascular events in patients with type 2 diabetes.

The primary endpoint consisted of major macrovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular (new onset or worsening of nephropathy, retinopathy) events.

A total of 11,140 patients with type 2 diabetes were included in the study (mean values: age 66 years, BMI (body mass index) 28 kg/m², duration of diabetes 8 years, HbA1c level 7.5%, and systolic/diastolic blood pressure (SBP/DBP) 145/81 mm Hg). Among these patients, 83% had hypertension, 325 patients and 10% had a history of macro- and microvascular disease, respectively, and 27% had microalbuminuria (MAU). The majority of patients had previously received treatment for type 2 diabetes: 90% via oral agents (47% monotherapy, 46% dual therapy, and 7% triple therapy), and 1% with insulin, while 9% were on diet alone. Initially, sulfonylureas (72%) and metformin (61%) were predominantly prescribed. Concomitant therapy included antihypertensive agents (75%), lipid-lowering drugs (35%, mainly statins – 28%), aspirin and other antiplatelet agents (47%). During a 6-week run-in period with perindopril/indapamide combination and standard glucose-lowering therapy, patients were randomly assigned to either a standard glycemic control regimen (n = 5,569) or an intensive glycemic control strategy based on Gliclazide MR (n = 5,571). The intensive glycemic control strategy was based on initiating Gliclazide MR at the beginning of treatment or switching to Gliclazide MR from standard therapy (the therapy the patient was receiving at enrollment), with possible dose escalation to the maximum, followed by addition of other glucose-lowering agents such as metformin, acarbose, thiazolidinediones, or insulin if needed. Patients were under close medical supervision and strictly adhered to dietary recommendations.

The follow-up period lasted 4.8 years. Treatment with Gliclazide MR, as part of the intensive glycemic control strategy (mean achieved HbA1c level – 6.5%), compared to standard glycemic control (mean achieved HbA1c level – 7.3%), resulted in a significant 10% relative risk reduction in the combined incidence of major macro- and microvascular complications ((HR) 0.90, 95% CI [0.82; 0.98], p = 0.013; 18.1% of patients in the intensive control group vs. 20% in the standard control group). The benefits of the intensive glycemic control strategy with Gliclazide MR as the cornerstone of therapy were due to:

a significant 14% relative risk reduction in major microvascular events (HR 0.86, 95% CI [0.77; 0.97], p = 0.014; 9.4% vs. 10.9%);
a significant 21% relative risk reduction in new cases or progression of nephropathy (HR 0.79, 95% CI [0.66–0.93], p = 0.006; 4.1% vs. 5.2%);
a significant 8% relative risk reduction in new-onset microalbuminuria (HR 0.92, 95% CI [0.85–0.99], p = 0.030; 34.9% vs. 37.9%);
a significant 11% relative risk reduction in renal events (HR 0.89, 95% CI [0.83; 0.96], p = 0.001; 26.5% vs. 29.4%).

At the end of the study, 65% and 81.1% of patients in the intensive control group (vs. 28.8% and 50.2% in the standard control group) achieved HbA1c targets of ≤ 6.5% and ≤ 7%, respectively.

90% of patients in the intensive control group received Gliclazide MR (mean daily dose was 103 mg), with 70% of them receiving the maximum daily dose of 120 mg. In the Gliclazide MR-based intensive glycemic control group, patient body weight remained stable.

The benefits of the Gliclazide MR-based intensive glycemic control strategy were independent of blood pressure reduction.

Pharmacokinetics.

Plasma levels of gliclazide increase within the first 6 hours, reaching a plateau maintained for 6–12 hours after administration. Gliclazide is completely absorbed in the gastrointestinal tract. Food intake does not affect the rate or extent of absorption.

The relationship between dose (up to 120 mg) and the area under the concentration-time curve (AUC) is linear. Plasma protein binding is 95%.

Gliclazide is almost completely metabolized in the liver and is primarily excreted in urine. Less than 1% of unchanged gliclazide is excreted in urine. No active metabolites are present in plasma.

The elimination half-life of gliclazide ranges from 12 to 20 hours. The volume of distribution is approximately 30 liters.

After a single dose, gliclazide plasma concentrations are maintained for 24 hours.

Pharmacokinetic parameters are not significantly altered in elderly patients.

Intra-individual variability is low.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus in adults:

Reduction and control of blood glucose when it is impossible to normalize glucose levels by diet, physical exercise, and weight reduction alone.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

When using drugs that may cause hypoglycemia or hyperglycemia when used concomitantly, patients must 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.

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

Contraindicated concomitant use with:

Miconazole (for systemic use, oral gel) because it enhances the hypoglycemic effect, possibly leading to hypoglycemic symptoms or even coma.

Not recommended concomitant use with:

Phenylbutazone (for systemic use) – it enhances the hypoglycemic effect of sulfonylurea derivatives (by displacing their binding to plasma proteins and/or reducing their elimination).

An alternative anti-inflammatory agent should preferably be used, and the patient should be warned and advised about the importance of self-monitoring. If necessary, the dose of the antidiabetic drug should be adjusted during and after anti-inflammatory therapy.

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 products should be avoided.

Combinations requiring caution due to enhanced hypoglycemic effect:

Concomitant use with any of the following drugs may in some cases lead to hypoglycemia due to potentiation of the hypoglycemic effect: other antidiabetic agents (insulin, acarbose, biguanides, 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.

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

Not recommended concomitant use:

With danazol – because it exerts a diabetogenic effect.

If use of this agent cannot be avoided, the patient must be warned and the importance of monitoring urine glucose and blood glucose levels emphasized. This is necessary to adjust the dose of the antidiabetic agent during and after danazol therapy.

Combinations requiring caution:

Chlorpromazine (neuroleptic) – when used in high doses (over 100 mg daily), increases blood glucose levels (due to reduced insulin release); the patient should be warned and the importance of monitoring blood glucose levels emphasized. This is necessary to adjust the dose of the antidiabetic agent during and after neuroleptic therapy.

Glucocorticoids (for systemic and local use: intra-articular, topical, rectal preparations) and tetracosactide increase blood glucose levels, possibly leading to ketoacidosis (by reducing carbohydrate tolerance); the patient should be warned and the importance of monitoring blood glucose levels emphasized, especially at the beginning of treatment. This is necessary to adjust the dose of the antidiabetic agent during and after glucocorticoid therapy.

Ritodrine, salbutamol, terbutaline (intravenous) may increase blood glucose levels due to β2-agonist effects; blood glucose levels should be monitored, and if necessary, treatment should be switched to insulin.

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

Medicinal products that may cause dysglycemia.

Combinations requiring caution.

Fluoroquinolones: when used concomitantly with gliclazide, patients should be warned about the risk of dysglycemia and the importance of monitoring blood glucose levels.

Combinations with warnings:

Anticoagulants (e.g., warfarin, etc.): sulfonylurea derivatives may potentiate the anticoagulant effect of anticoagulants when used concomitantly. If necessary, the dose of anticoagulants may need to be adjusted.

Special precautions.

Hypoglycemia.

This medication should be prescribed only to patients who are able to eat regularly (including breakfast). Regular intake of carbohydrates is important, as the risk of hypoglycemia increases when meals are delayed, inadequate in quantity, or low in carbohydrates. The risk of hypoglycemia is further increased by low-calorie diets, prolonged or intense physical exertion, alcohol consumption, or concomitant use of hypoglycemic agents.

Hypoglycemia may occur with concomitant use of sulfonylureas. In some cases, it may be severe and prolonged. In such cases, hospitalization and administration of glucose for several days may be required.

Careful patient evaluation, appropriate dosing, and strict adherence to the prescribed dosing regimen are essential measures to reduce the risk of hypoglycemia.

Factors that increase the risk of hypoglycemia:

Patient refusal or inability to follow medical advice (particularly in elderly patients);
Inadequate or irregular nutrition, missed meals, fasting periods, 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").

Patients and their family members should be informed about the risk of hypoglycemia, its symptoms, treatment, and factors that increase its likelihood.

Patients must understand the importance of diet, regular physical activity, and regular monitoring of blood glucose levels.

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.

Worsening glycemic control in patients receiving antidiabetic medications may be triggered by St. John's wort (Hypericum perforatum), infection, fever, trauma, or surgery. In some cases, insulin therapy may become 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 drug is ineffective from the start of treatment. Before concluding secondary failure, the appropriateness of the prescribed dose and the patient's adherence to diet should be verified.

Disglycemia.

Alterations in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported in diabetic patients receiving concomitant therapy with fluoroquinolones, particularly in elderly patients. Therefore, close monitoring of blood glucose levels is recommended in all patients receiving gliclazide and fluoroquinolones simultaneously.

Laboratory parameters: Glycated hemoglobin (HbA1c) levels (or fasting blood glucose) are recommended for assessing long-term glycemic control.

Patients with glucose-6-phosphate dehydrogenase deficiency: Sulfonylurea agents may induce hemolytic anemia in such patients. Gliclazide should be used with caution in these individuals, and alternative non-sulfonylurea therapy should be considered.

Patients with porphyria: Cases of acute porphyria have been reported with the use of certain other sulfonylurea agents in patients with porphyria.

Information on excipients in the medicinal product.

Gliclada contains lactose; therefore, it is contraindicated in patients with hereditary galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of gliclazide during pregnancy are lacking or limited (fewer than 300 pregnancy exposures reported), and data on other sulfonylureas are also limited. Animal studies have not shown teratogenic effects of gliclazide.

As a precautionary measure, gliclazide use during pregnancy should be avoided.

Glycemic control should be achieved before pregnancy is planned to reduce the risk of abnormalities associated with uncontrolled diabetes. Insulin is the treatment of choice for diabetes during pregnancy; oral hypoglycemic agents are not considered acceptable.

Women should be switched from oral antidiabetic agents to insulin when pregnancy is planned or immediately after pregnancy is confirmed.

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

Fertility. No effects on fertility or reproductive performance in male or female rats were observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

For oral use.

To be prescribed only to 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, during breakfast.

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

If a patient forgets to take the tablets, the dose should not be increased the following day.

Like all antidiabetic agents, Gliclada requires individual dose adjustment depending 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 be continued at this dose.

If enhanced glucose control is required, 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 patients from formulations containing gliclazide 80 mg to Gliclada modified-release tablets 30 mg: 1 tablet containing gliclazide 80 mg corresponds to 1 tablet of Gliclada modified-release 30 mg. Blood parameters must be carefully monitored during the switch to modified-release tablets.

Switching patients from other oral antidiabetic drugs to Gliclada modified-release tablets 30 mg: Gliclada may be prescribed instead of another oral antidiabetic agent. The dosage and half-life of the previous drug should be taken into account. A transition period is usually not required. Treatment should start with a dose of 30 mg, followed by dose adjustment (see "Initial dose and dose titration").

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

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

Elderly patients (aged ≥65 years): The dosing regimen for Gliclada is the same as for patients under 65 years of age.

Patients with mild to moderate renal impairment: The dosing regimen for Gliclada is the same as for patients with normal renal function; however, such patients should be under close medical supervision.

Patients at risk of hypoglycemia:

patients suffering from undernutrition or inadequate nutrition;
patients with severe endocrine disorders or endocrine dysfunction (hypopituitarism, hypothyroidism, adrenocorticotropic insufficiency);
patients after discontinuation of prolonged and/or high-dose corticosteroid therapy;
patients with severe vascular diseases (severe ischemic heart disease, severe carotid insufficiency, diffuse vascular disease).

A minimum initial daily dose of 30 mg is recommended.

Patients with severe vascular diseases (ischemic heart disease, severe carotid artery disease, diffuse vascular disease) should be started on a minimum initial dose of 30 mg per day.

Prevention of complications in type 2 diabetes. According to the ADVANCE study, an intensive glycemic control strategy should be followed (HbA1c level ≤ 6.5%). The intensive glycemic control strategy involves gradual dose escalation of Gliclada from 60 mg to 120 mg per day. Dose increases should be performed under monitoring of HbA1c levels, strict adherence to dietary and physical activity recommendations, and careful monitoring of the risk of hypoglycemia. Addition of other antidiabetic agents such as metformin, acarbose, thiazolidinediones, or insulin may also be considered.

Children

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

Overdose

Overdose with sulfonylurea derivatives may lead to the development of hypoglycemia.

Mild to moderate hypoglycemic symptoms without loss of consciousness or neurological signs can be managed by carbohydrate intake, dose adjustment, and/or dietary changes. Close monitoring of the patient is required until the condition normalizes.

In cases of severe hypoglycemia with coma, seizures, or other neurological disorders, the patient must be immediately hospitalized and emergency medical measures initiated.

In cases of diagnosed or suspected hypoglycemia, the patient should receive an intravenous injection of 50 mL of concentrated glucose solution (20–30%), followed by infusion of a less concentrated glucose solution (10%) to achieve and maintain blood glucose levels above 1 g/L. The physician must ensure close monitoring of the patient and decide, based on the patient's condition, whether further observation is necessary.

Due to the strong protein binding of gliclazide to plasma proteins, dialysis is not effective in these patients.

Adverse Reactions

When using gliclazide and other sulfonylurea derivatives, the undesirable effects listed below may occur.

The most common adverse reaction associated with gliclazide is hypoglycemia.

As with other sulfonylurea drugs, gliclazide may cause hypoglycemia, particularly in cases of irregular eating habits or when a meal is missed. Hypoglycemia may be accompanied by characteristic symptoms such as headache, intense hunger, nausea, vomiting, increased fatigue, sleep disturbances, agitation, aggression, impaired concentration and reaction time, depression, confusion, visual and speech disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, weakness, loss of self-control, delirium, seizures, shallow breathing, bradycardia, somnolence, 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 (sugar) intake. However, sugar substitutes are ineffective in such cases. Clinical experience with other sulfonylurea agents 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 temporarily controlled by sugar intake, immediate medical attention or even hospitalization is required.

Other adverse reactions.

Gastrointestinal disorders: abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation. Adherence to the recommendation to take the medication 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, angioedema, maculopapular rash, bullous reactions (such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and autoimmune bullous disorders), 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 upon discontinuation of treatment.
Hepatobiliary disorders: elevated liver enzymes (ALT, AST, alkaline phosphatase), hepatitis (isolated cases). If cholestatic jaundice occurs, treatment should be discontinued. These adverse effects typically resolve after stopping the drug.
Eye disorders: transient visual disturbances may occur, particularly at the beginning of treatment, due to changes in blood glucose levels.

Reactions that may occur with any sulfonylurea agent: cases of erythropenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzymes, and even liver dysfunction (e.g., with cholestasis and jaundice), hepatitis with regression after discontinuation of sulfonylurea drugs, or in isolated cases, progressive liver failure with life-threatening consequences.

Clinical studies.

During the multicenter ADVANCE study, serious adverse reactions were monitored. Overall, serious adverse reactions occurred in 59.3% of 5571 patients in the intensive glycemic control group (vs. 58.1% of 5569 patients in the standard glycemic control group), with minimal intergroup differences in the frequency of individual adverse reaction types. In patients with type 2 diabetes treated according to an intensive glycemic control strategy, no previously unreported adverse reactions were identified. A number of patients experienced severe hypoglycemia. The overall frequency of adverse reactions was low and, as expected, higher in the intensive glycemic control group compared to the standard control group (2.7% vs. 1.5%; risk ratio 1.86; p<0.001). Most episodes of hypoglycemia occurred in patients receiving concomitant insulin therapy.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is highly important. It enables continuous monitoring of the benefit-risk balance associated with drug use. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 30°C. Keep out of reach of children.

Packaging.

10 tablets per blister; 3, 6, or 9 blisters per cardboard box.

15 tablets per blister; 2, 4, or 6 blisters per cardboard box.

Prescription status. By prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Glilada