Instructions for Glyklad modified-release tablets 60 mg blister No. 30
Composition
active ingredient: gliclazide;
1 modified-release tablet contains 60 mg of gliclazide;
Excipients: hypromellose, lactose monohydrate, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Modified-release tablets.
Main physicochemical properties: tablets from white to almost white, oval in shape, biconvex.
Pharmacotherapeutic group
. Oral hypoglycemic agents, sulfonamides, urea derivatives. ATX code A10B B09.
Pharmacological properties
Pharmacodynamics
Gliclazide is an oral hypoglycemic drug, a sulfonylurea derivative, which differs from other drugs in the presence of a heterocyclic ring containing nitrogen and having endocyclic bonds.
Gliclazide lowers blood glucose levels by stimulating insulin secretion by β cells of the islets of Langerhans of the pancreas. The increase in postprandial insulin levels and C-peptide secretion persist even after 2 years of use of the drug. 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 and increases the second phase of insulin secretion. A significant increase in insulin secretion occurs in response to food intake or glucose load.
Hemovascular properties.
Gliclazide reduces microthrombosis through two mechanisms that may be involved in the development of complications of diabetes:
• partially inhibits platelet aggregation and adhesion, reduces the number of platelet activation markers (β-thromboglobulin, thromboxane B2);
• affects the fibrinolytic activity of the vascular endothelium (increases the activity of tPA).
The primary endpoint consisted of major macrovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular (new cases or worsening of nephropathy, retinopathy) events.
11,140 patients were included in the clinical trials. During the 6-week lead-in period, patients continued to take their usual antidiabetic therapy. Patients were then randomly assigned to a standard glycemic control regimen (n = 5,569) or a regimen with gliclazide modified-release tablets as the basis of an intensive glycemic control strategy (n = 5,571). The intensive glycemic control strategy was based on the administration of gliclazide modified-release tablets from the beginning of treatment or on the administration of gliclazide modified-release tablets instead of standard therapy (the therapy the patient was receiving at the time of inclusion), with a possible increase in dose to the maximum and then the addition, if necessary, of other antidiabetic drugs such as metformin, acarbose, thiazolidinediones or insulin. The patients were under close medical supervision and strictly followed a diet.
The observation lasted 4.8 years. The result of treatment with gliclazide, modified-release tablets, which was the basis of the intensive glycemic control strategy (mean achieved HbA1c level – 6.5%) compared with standard glycemic control (mean achieved HbA1c level – 7.3%), was a significant overall reduction of 10% in the relative risk of major macro- and microvascular complications ((HR) 0.90, 95% Cl [0.82; 0.98] p = 0.013; 18.1% of patients in the intensive control group compared with 20% of patients in the standard control group). The advantages of the intensive glycemic control strategy with the appointment of gliclazide, modified-release tablets as the basis of therapy were due to:
− a significant reduction in the relative risk of major microvascular events by 14% (HR 0.86, 95% Cl [0.77; 0.97], p = 0.014; 9.4% vs. 10.9%);
− a significant reduction in the relative risk of new cases or progression of nephropathy by 21% (HR 0.79, 95% Cl [0.66 – 0.93], p = 0.006; 4.1% vs. 5.2%);
− a significant reduction of 8% in the relative risk of new-onset microalbuminuria (HR 0.92, 95% CI [0.85 – 0.99], p = 0.030; 34.9% vs. 37.9%);
− a significant reduction in the relative risk of renal events by 11% (HR 0.89, 95% Cl [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 (versus 28.8% and 50.2% in the standard control group) achieved the target HbA1c ≤ 6.5% and ≤ 7%, respectively. 90% of patients in the intensive control group were taking gliclazide modified-release tablets (mean daily dose 103 mg), 70% of whom were taking the maximum daily dose of 120 mg. In the intensive glycemic control group based on gliclazide modified-release tablets, the body weight of the patients remained stable.
The benefits of an intensive glycemic control strategy based on gliclazide, modified-release tablets, were independent of blood pressure reduction.
Pharmacokinetics
Absorption
The level of gliclazide in the blood plasma increases during the first 6 hours, reaching a plateau that is maintained from six to twelve hours after administration of the drug.
Individual fluctuations are insignificant.
Gliclazide is completely absorbed. Food intake does not affect the rate and extent of absorption.
Plasma protein binding is approximately 95%. The relationship between the administered dose in the range of up to 120 mg and the area under the concentration-time curve is linear. The volume of distribution is approximately 30 liters.
Metabolism
Gliclazide is metabolized mainly in the liver and excreted in the urine, less than 1% of the active substance is excreted in the urine unchanged. Active metabolites are absent in the blood plasma.
Breeding
The half-life of gliclazide is 12–20 hours.
In elderly patients, no clinically significant changes in the pharmacokinetics of the drug are noted.
A single dose of Gliclazide, modified-release tablets, maintains effective plasma concentrations of gliclazide for 24 hours.
Indication
Type II diabetes:
lowering and controlling blood glucose when glucose levels cannot be normalized by diet, exercise, or weight loss alone; preventing complications of type 2 diabetes: reducing the risk of macro- and microvascular complications, including new cases or worsening of nephropathy in patients with type 2 diabetes.
Contraindication
Hypersensitivity to gliclazide or to other sulfonylureas, sulfonamides or to any component of the drug; insulin-dependent diabetes mellitus (type I); diabetic precoma and coma, diabetic ketoacidosis; severe hepatic or renal failure (in which case the use of insulin is recommended); treatment with miconazole (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions
When using drugs that may cause hypo- or hyperglycemia, the patient should be warned about the need for careful monitoring of blood glucose levels during treatment. It may be necessary to adjust the dose of the hypoglycemic drug during and after treatment with these drugs.
Medications likely to increase the risk of hypoglycemia
Contraindicated combination
Miconazole (for systemic use, oromucosal gel) enhances the hypoglycemic effect with the possible development of symptoms of hypoglycemia or even coma.
Combinations that are not recommended
Phenylbutazone (for systemic use) enhances the hypoglycemic effect of sulfonylurea (replaces its binding to plasma proteins and/or reduces its excretion). It is advisable to use another anti-inflammatory agent and draw the patient's attention to the need and importance of self-monitoring. If necessary, the dosage of Gliclazide is adjusted during and after therapy with the anti-inflammatory agent.
Alcohol enhances the hypoglycemic reaction (by suppressing compensatory reactions), which can lead to the onset of hypoglycemic coma. The use of medications containing alcohol and the consumption of alcohol should be avoided.
Combinations requiring caution
Increased hypoglycemic effect of the drug and in some cases hypoglycemia may develop as a result of parallel use with the following medications: other antidiabetic drugs (insulin, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, glucose-1-phosphate receptor agonists), beta-blockers, fluconazole, angiotensin-converting enzyme inhibitors (captopril, enalapril), H2-receptor antagonists, MAO inhibitors, sulfonamides, clarithromycin and nonsteroidal anti-inflammatory drugs.
Medicines that may cause an increase in blood glucose levels
Combinations that are not recommended
Danazol: diabetogenic effect of danazol.
If the use of this active substance cannot be avoided, the patient should be warned about the need and importance of self-monitoring of glucose levels in the urine and blood. It may be necessary to adjust the dose of the antidiabetic agent during and after treatment with danazol.
Combinations requiring caution
Chlorpromazine (neuroleptic): high doses of chlorpromazine (>100 mg per day) increase blood glucose levels (due to decreased insulin secretion).
The patient should be advised of the need and importance of blood glucose monitoring. The dose of the antidiabetic active substance may need to be adjusted during and after treatment with the neuroleptic.
Glucocorticoids (for systemic and local use: intra-articular, cutaneous and rectal preparations) and tetracosactrin increase blood glucose levels with possible development of ketosis (due to reduced carbohydrate tolerance due to glucocorticoids).
The patient should be warned about the need and importance of monitoring blood glucose levels, especially at the beginning of treatment. It may be necessary to adjust the dose of the antidiabetic agent during and after treatment with glucocorticoids.
Ritodrine, salbutamol, terbutaline (intravenously) increase blood glucose levels due to the action of beta-2-agonists.
The patient should be advised to monitor blood glucose levels and, if necessary, switched to insulin.
Combinations to watch out for
Anticoagulant therapy (such as warfarin, etc.) Sulfonylureas may potentiate the anticoagulant effect during concomitant treatment. Dosage adjustment of the anticoagulant may be necessary.
Application features
Treatment is prescribed to patients who are able to maintain a full and regular diet (including breakfast). Regular carbohydrate intake is important because of the increased risk of hypoglycemia, which occurs when food is eaten late, in inadequate quantities, or if the food is low in carbohydrates. The risk of hypoglycemia increases with a low-calorie diet, prolonged and strenuous exercise, alcohol consumption, or when a combination of hypoglycemic agents is used.
Hypoglycemia may occur with concomitant use of sulfonylureas (see section 4.8) and may be severe and prolonged in some cases. Hospitalization and administration of glucose for several days may sometimes be required.
Careful examination of patients, use of a specific dose of the drug, and strict adherence to the dosage and administration regimen are necessary measures to reduce the risk of hypoglycemic episodes.
Factors that increase the risk of hypoglycemia:
– refusal or (especially in elderly patients) inability of the patient to cooperate;
– low-calorie or irregular eating, snacking, periods of fasting or changes in diet;
– imbalance between physical activity and carbohydrate consumption;
– renal failure;
– severe liver failure;
– overdose of Gliclazide;
– certain diseases of the endocrine system: thyroid disease, hypopituitarism and adrenal insufficiency;
– concomitant use of certain other medications (see section “Interaction with other medications and other types of interactions”).
Renal and hepatic failure
The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic or severe renal impairment. Hypoglycaemic episodes occurring in such patients may be prolonged and require specific measures.
Information for patients
The patient and his family members should be warned about the risk of hypoglycemia, its symptoms (see section "Adverse reactions"), treatment, as well as factors that increase the risk of its development should be explained.
Patients should be aware of the importance of diet, regular exercise, and regular blood glucose testing.
Disruption of blood glucose regulation
Blood glucose control in patients taking antidiabetic drugs may be affected by factors such as fever, trauma, infection, or surgery. In some cases, insulin may be required.
The hypoglycaemic efficacy of any oral antidiabetic drug, including gliclazide, decreases over time in many patients: this may be due to progression of the severity of diabetes or a decrease in the response to treatment. This phenomenon is known as secondary failure, which is different from primary failure, when the active substance is ineffective in treatment with a first-line drug. Appropriate dose adjustment and dietary compliance are required before classifying the patient as a secondary failure.
Laboratory tests
It is recommended to measure glycosylated hemoglobin (or fasting venous plasma glucose). Self-monitoring of blood glucose may also be appropriate.
Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylureas may lead to hemolytic anemia. Since gliclazide belongs to the chemical class of sulfonylureas, caution should be exercised in patients with glucose-6-phosphate dehydrogenase deficiency, and alternative treatment with non-sulfonylurea drugs should be considered.
Special precautions for some components
Gliclazide contains lactose. Patients with rare hereditary problems of lactose intolerance, galactosemia or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy
There is no experience with the use of gliclazide during pregnancy, although there are some data on the use of other sulfonylureas.
Diabetes control should be achieved before pregnancy to reduce the risk of congenital anomalies associated with poor diabetes control.
Oral hypoglycemic agents are not recommended; insulin is the mainstay of diabetes treatment during pregnancy. It is recommended that the patient be switched to insulin if pregnancy is planned or occurs.
Breast-feeding
There is no data on the penetration of gliclazide or its metabolites into breast milk. Given the possible risk of hypoglycemia in the child, the use of the drug is contraindicated in women who are breastfeeding.
The ability to influence the reaction speed when driving or working with other mechanisms
Gliclazide has no known effect on the ability to drive or use machines. However, patients should be alert to the symptoms of hypoglycemia and exercise caution when driving or using machines, especially at the beginning of treatment.
Method of administration and doses
The daily dose can vary from 30 to 120 mg once a day during breakfast. It is recommended to take the tablet whole, without chewing.
If you miss a pill, do not increase the dose the next day.
As with any hypoglycemic agent, dosage should be adjusted based on the patient's individual response to treatment (blood glucose level, glycosylated hemoglobin HbAlc).
Starting dose and dose selection.
The recommended initial dose is 30 mg per day. If effective glucose control is achieved, treatment can be continued at this dose. If necessary, increased blood glucose control can be achieved by successive increases to 60 mg, 90 mg or 120 mg per day. Dose increases are recommended at 1-month intervals; this does not apply to patients who have not shown a reduction in blood glucose levels within 2 weeks of treatment. In such cases, the dose can be increased at the end of the second week of treatment.
The maximum recommended daily dose is 120 mg (2 tablets).
Transferring the patient from immediate-release preparations containing gliclazide at a dose of 80 mg to Gliclazide, modified-release tablets of 60 mg.
1 tablet containing 80 mg of gliclazide corresponds to 1 modified-release tablet of 30 mg. Blood counts should be carefully monitored when switching to Gliclazide, modified-release tablets of 60 mg.
Transferring a patient from other oral hypoglycemic drugs to Gliclazide, modified-release tablets.
Gliclazide can be prescribed instead of another oral hypoglycemic drug. The dosage and half-life of the latter should be taken into account. A transition period is usually not necessary. It should be started with a dose of 30 mg, with subsequent dose adjustment as described above ("Initial dose and dose selection").
When transferring from hypoglycemic sulfonylureas, which have a longer half-life than gliclazide, a break in treatment for several days may be necessary to avoid the cumulative effect of the two drugs and the development of hypoglycemia. When transferring a patient from other oral hypoglycemic drugs to gliclazide, modified-release tablets, treatment is initiated as described above ("Initial dose and dose selection").
Concomitant use with other antidiabetic drugs.
Gliclazide can be used in combination with biguanides, alpha-glucosidase inhibitors and insulin. If adequate blood glucose control is not achieved in patients taking gliclazide, concomitant insulin treatment can be initiated under close medical supervision.
Elderly patients.
No dose adjustment is required for patients over 65 years of age.
Patients with renal impairment.
No dose adjustment is required for patients with mild to moderate renal impairment. The patient should be under close medical supervision.
Patients at risk of hypoglycemia
– patients suffering from malnutrition or poor nutrition;
– patients with severe diseases of the endocrine system or its disorders (hypopituitarism, hypothyroidism, adrenocorticotrophic insufficiency);
– patients after discontinuation of long-term and/or high-dose corticosteroid therapy;
– patients with severe vascular diseases (severe ischemic heart disease, severe carotid insufficiency, diffuse vascular disease).
It is recommended to use a minimum initial daily dose of 30 mg.
Patients with severe vascular diseases (ischemic heart disease, severe carotid vascular pathology, diffuse vascular diseases).
A minimum starting dose of 30 mg per day is recommended.
To prevent complications of type 2 diabetes.
A strategy of intensive glycemic control (HbA1c ≤ 6.5%) should be followed. The strategy of intensive glycemic control involves a gradual increase in dose from 60 mg to 120 mg per day. The dose increase should be carried out under control of HbA1c with strict adherence to diet and exercise recommendations, preventing the risk of hypoglycemia. It is also possible to add other glucose-lowering drugs such as metformin, acarbose, thiazolidinediones or insulin.
Children.
Not used.
Overdose
Overdose of sulfonylurea derivatives can lead to the development of hypoglycemia.
Symptoms of moderate hypoglycemia without loss of consciousness or signs of neurological disorders should be eliminated by taking carbohydrates, adjusting the dose and/or changing the diet. The patient should be carefully monitored until the patient's condition normalizes.
In case of severe hypoglycemia with coma, seizures, or other neurological disorders, the patient should be immediately hospitalized and emergency medical care should be provided.
When diagnosing or suspecting the development of hypoglycemic coma, the patient should be given 50 ml of a concentrated glucose solution (20-30%) intravenously quickly. This should be followed by a continuous infusion of a less concentrated glucose solution (10%) at a rate that will maintain the blood glucose level above 1 g/l. The physician should ensure close monitoring of the patient and, depending on the patient's condition, decide on the need for further monitoring.
Due to the high binding of gliclazide to plasma proteins, dialysis is not effective for such patients.
Adverse reactions
Based on experience with gliclazide and sulfonylureas, the following side effects have been reported.
Hypoglycemia
Irregular meals and especially snacking during therapy with sulfonylureas, including Gliclazide, can lead to the development of hypoglycemia. Possible symptoms of hypoglycemia: headache, severe hunger, nausea, vomiting, fatigue, sleep disturbances, anxiety, irritability, impaired concentration, impaired consciousness and slowed reactions, depression, visual and speech disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, loss of self-control, delirium, convulsions, shallow breathing, bradycardia, drowsiness, loss of consciousness and even the development of coma with fatal outcome.
In addition, manifestations of adrenergic system disorders may occur: increased sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmia.
Symptoms usually resolve after ingestion of carbohydrates (sugar). However, artificial sweeteners do not have an effect. Experience with other sulfonylureas shows that hypoglycemia can recur even if effective measures are taken immediately.
If episodes of hypoglycemia are severe and prolonged, even if temporarily controlled by sugar intake, immediate hospitalization and emergency medical care are required.
Most cases of hypoglycemia occur in patients with concomitant insulin therapy.
Other side effects.
Gastrointestinal: abdominal pain, nausea, vomiting, dyspepsia, diarrhea and constipation. These symptoms can be eliminated or minimized if gliclazide is taken with breakfast.
The following are less common side effects.
Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, angioedema, flushing, maculopapular rash, bullous reactions (e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis).
Blood and lymphatic system disorders: changes in hematological parameters, including anemia, leukopenia, thrombocytopenia, granulocytopenia. These phenomena are rare and usually resolve after discontinuation of the drug.
Liver and biliary tract: increased liver enzymes (AST, ALT, alkaline phosphatase), hepatitis (isolated cases). In case of cholestatic jaundice, the drug should be discontinued.
On the part of the organs of vision: temporary visual impairment, due to changes in blood glucose levels, temporary visual impairment occurs, especially at the beginning of treatment.
Effects inherent to sulfonylurea drugs:
As with other sulfonylureas, cases of erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzymes and even liver dysfunction (e.g. with cholestasis and jaundice) and hepatitis have been observed, which resolve after discontinuation of the sulfonylurea or in some cases lead to life-threatening liver failure.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 30 °C in the original packaging to protect from moisture.
Keep out of reach of children.
Packaging
Modified-release tablets, 15 tablets per blister, 2, 4 or 6 blisters per box.
Vacation category
According to the recipe.
Producer
KRKA, dd, Novo mesto, Slovenia.
Location of the manufacturer and address of its place of business
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.
