Gliclazide

Gliclazide is a sulfonylurea hypoglycaemic agent for oral use. Its SmPC notes that it differs from related compounds by a nitrogen-containing heterocyclic ring with an endocyclic bond. It lowers blood glucose by stimulating insulin secretion from the beta cells of the islets of Langerhans and, besides this metabolic action, has haemovascular properties.

Mechanism of Action

• Insulin release: gliclazide binds to the sulfonylurea receptor (SUR1) of the beta cell and closes ATP-sensitive potassium channels. The cell depolarises, voltage-dependent calcium channels open, and the calcium that enters triggers exocytosis of insulin granules.
• Effect in type 2 diabetes: it restores the first peak of insulin secretion in response to glucose and increases the second phase. The insulin response to a meal or to glucose rises significantly, and the increase in post-meal insulin and C-peptide secretion persists after two years of treatment.
• Haemovascular properties: gliclazide reduces microthrombosis through two mechanisms that may be involved in diabetic complications: partial inhibition of platelet aggregation and adhesion, with lower platelet activation markers (beta-thromboglobulin and thromboxane B2), and an effect on the fibrinolytic activity of the vascular endothelium, with increased tPA activity.

Pharmacokinetics

• Absorption (30 mg modified-release tablet): plasma levels rise progressively over the first 6 hours and reach a plateau between 6 and 12 hours after the dose. Intra-individual variability is low. Gliclazide is completely absorbed, and food does not affect the rate or extent of absorption.
• Distribution: plasma protein binding is about 95% and the volume of distribution is about 30 litres. A single daily dose of the 30 mg tablet maintains effective plasma concentrations over 24 hours.
• Metabolism: mainly hepatic. Less than 1% of the drug appears unchanged in urine, and no active metabolites have been detected in plasma.
• Elimination: excreted mainly in urine as metabolites, with an elimination half-life of 12 to 20 hours.
• Linearity: the area under the concentration-time curve is linearly related to the dose up to 120 mg.
• Special populations: no clinically significant changes in pharmacokinetics were seen in elderly patients.

• Type 2 diabetes mellitus (non-insulin-dependent) in adults, when dietary measures, physical exercise and weight loss alone are not enough to control blood glucose.

This page follows the Spanish (AEMPS) SmPC of the 30 mg modified-release tablet. Other nationally authorised gliclazide products, such as the 80 mg tablets the SmPC mentions when describing a switch, have their own SmPCs, and strengths, doses and wording can differ.

• Hypersensitivity to gliclazide, to any of the excipients, or to other sulfonylureas or sulfonamides.
• Type 1 diabetes.
• Diabetic pre-coma and coma, and diabetic ketoacidosis.
• Severe renal or hepatic insufficiency; insulin is recommended in these cases.
• Treatment with miconazole.
• Breastfeeding.

The SmPC describes the reactions by type and does not assign frequency bands. The most frequent reaction is hypoglycaemia.

• Hypoglycaemia: as with other sulfonylureas, it can occur when meals are irregular and especially when meals are skipped. Symptoms include headache, intense hunger, nausea, vomiting, lassitude, sleep disturbances, nervousness, aggression, poor concentration, reduced alertness and slowed reactions, depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, convulsions, shallow breathing, bradycardia, drowsiness and loss of consciousness, which may end in coma and death. Signs of adrenergic counter-regulation may also appear: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias. Symptoms usually resolve after carbohydrate (sugar) is taken; artificial sweeteners have no effect. Hypoglycaemia can return even after initial relief, and a severe or prolonged episode needs immediate medical treatment or hospitalisation.
• Gastrointestinal disorders: abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation. They can be avoided or minimised by taking gliclazide with breakfast.
• Skin and subcutaneous reactions (reported less often): rash, pruritus, urticaria, angioedema, erythema, maculopapular rash, blistering reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis and autoimmune bullous disorders) and, exceptionally, drug rash with eosinophilia and systemic symptoms (DRESS).
• Blood and lymphatic disorders (rare): anaemia, leucopenia, thrombocytopenia and granulocytopenia, which generally reverse when treatment stops.
• Hepatobiliary disorders: raised liver enzymes (AST, ALT, alkaline phosphatase) or hepatitis, in isolated cases. Treatment should be stopped if cholestatic jaundice appears; these findings usually resolve after stopping.
• Eye disorders: transient visual disturbances, especially at the start of treatment, due to changes in blood glucose.
• Class effects (seen with other sulfonylureas): erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatraemia, raised liver enzymes and even impaired liver function (with cholestasis and jaundice) and hepatitis, which regressed after withdrawal or in isolated cases progressed to life-threatening liver failure.

Contraindicated combination

• Miconazole (systemic, oral gel): increases the hypoglycaemic effect, with possible hypoglycaemic symptoms or even coma.

Combinations that are not recommended

• Phenylbutazone (systemic): increases the hypoglycaemic effect of sulfonylureas (displaces them from plasma proteins and/or reduces their elimination). Another anti-inflammatory medicine is preferable; otherwise warn the patient, stress self-monitoring of blood glucose and adjust the dose during and after the anti-inflammatory treatment if needed.
• Alcohol: increases the hypoglycaemic reaction (by inhibiting compensatory reactions) and may lead to hypoglycaemic coma. Avoid alcohol and medicines containing alcohol.
• Danazol: has a diabetogenic effect. If it cannot be avoided, warn the patient, monitor blood and urine glucose, and adjust the antidiabetic dose during and after danazol.

Combinations needing precautions (hypoglycaemia may occur)

• Other antidiabetic agents (insulins, acarbose, metformin, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists), beta-blockers, fluconazole, ACE inhibitors (captopril, enalapril), H2-receptor antagonists, MAO inhibitors, sulfonamides, clarithromycin and non-steroidal anti-inflammatory medicines.

Combinations needing precautions (blood glucose may rise)

• Chlorpromazine (high doses, above 100 mg a day): raises blood glucose by reducing insulin release.
• Glucocorticoids (systemic and local: intra-articular, skin, rectal) and tetracosactide: raise blood glucose, with possible ketosis. Stress glucose monitoring, particularly at the start.
• Ritodrine, salbutamol and terbutaline (intravenous): raise blood glucose through beta-2 agonist effects; insulin may be needed.
• St John’s wort (Hypericum perforatum): lowers gliclazide exposure. Stress blood glucose monitoring.

Other

• Fluoroquinolones: blood glucose disturbances, both hypoglycaemia and hyperglycaemia, have been reported, especially in elderly patients. Monitor blood glucose carefully when used together.
• Anticoagulants (warfarin and others): sulfonylureas may potentiate the anticoagulant effect, so the anticoagulant dose may need adjusting.
• Food: consistent food intake reduces the risk of hypoglycaemia.

Gliclazide 30 mg modified-release tablets are taken by mouth as a single daily dose with breakfast. The tablet or tablets should be swallowed whole. As with all hypoglycaemic medicines, the prescriber adjusts the dose to the metabolic response (blood glucose and HbA1c).

Recommended Dose

• Range: 1 to 4 tablets a day, that is 30 to 120 mg, in a single oral dose with breakfast.
• Starting dose: 30 mg a day. If blood glucose is adequately controlled, this dose can be used for maintenance.
• Titration: if control is inadequate, the dose can be raised stepwise to 60, 90 or 120 mg a day. Leave at least 1 month between increases, except in patients whose blood glucose has not fallen after two weeks of treatment; the dose can then be raised at the end of the second week.
• Maximum: 120 mg a day.

Switching and Combination

• From 80 mg gliclazide tablets: one 80 mg tablet is comparable to one 30 mg modified-release tablet, so the change can be made with careful blood monitoring.
• From another oral antidiabetic: the dose and half-life of the previous medicine are taken into account, and a transition period is generally not needed. Start with 30 mg and adjust as above. When replacing a long half-life sulfonylurea, several treatment-free days may be needed to avoid an additive effect that could cause hypoglycaemia.
• Combination treatment: gliclazide can be combined with biguanides, alpha-glucosidase inhibitors or insulin. If blood glucose is not adequately controlled on gliclazide 30 mg, insulin can be added under close medical supervision.

Special Populations

• Elderly: same dosing as for patients under 65.
• Renal impairment: in mild to moderate impairment the usual dosing can be used with careful monitoring, as confirmed in clinical trials. Severe impairment is a contraindication.
• Patients at risk of hypoglycaemia: for undernourished or malnourished patients, those with severe or poorly compensated endocrine disorders (hypopituitarism, hypothyroidism, adrenocorticotropic insufficiency), those finishing prolonged and/or high-dose corticosteroid treatment, and those with severe vascular disease (severe coronary or carotid disease, diffuse vascular disease), start with the minimum daily dose of 30 mg.
• Children and adolescents: safety and efficacy have not been established; no data are available in children.

Missed Dose

If a dose is missed, do not increase the next day’s dose.

Hypoglycaemia

• Prescribe only to patients who eat regularly, including breakfast. Regular carbohydrate intake is important because hypoglycaemia is more likely if a meal is delayed, too little food is eaten or the food is low in carbohydrate. The risk is greater with low-calorie diets, after prolonged or strenuous exercise, after alcohol, or when several hypoglycaemic medicines are combined.
• Episodes can be severe and prolonged; hospitalisation and glucose for several days may be needed.
• Factors that raise the risk include a patient who refuses or cannot cooperate (particularly the elderly), malnutrition, irregular or skipped meals, fasting, a mismatch between exercise and carbohydrate intake, renal insufficiency, severe hepatic insufficiency, overdose, some endocrine disorders (thyroid disorders, hypopituitarism, adrenal insufficiency) and some co-medications.
• Patients and their families should be told about the risk, symptoms and treatment of hypoglycaemia, the predisposing situations, and the importance of diet, regular exercise and regular blood glucose monitoring.

Renal and Hepatic Impairment

The pharmacokinetics and/or pharmacodynamics of gliclazide may change in severe hepatic or renal insufficiency. Hypoglycaemia in these patients can be prolonged and needs appropriate treatment.

Poor Glycaemic Control and Secondary Failure

Glycaemic control may be affected by St John’s wort preparations, fever, trauma, infection or surgery; insulin may then be needed. The blood glucose-lowering effect of oral antidiabetic medicines, including gliclazide, falls over time in many patients, through progression of diabetes or a weaker response (secondary failure). Before concluding secondary failure, check that the dose and adherence to the diet are adequate.

Blood Glucose Disturbances with Fluoroquinolones

Hypoglycaemia and hyperglycaemia have been reported in diabetic patients taking fluoroquinolones, especially the elderly. Careful blood glucose monitoring is recommended when gliclazide and a fluoroquinolone are used together.

Laboratory Tests

Glycated haemoglobin (and fasting plasma glucose) is measured to assess glycaemic control, and self-monitoring of blood glucose can also help.

G6PD Deficiency and Porphyria

• Sulfonylureas can cause haemolytic anaemia in patients with G6PD deficiency. Take care in these patients and consider a treatment that is not a sulfonylurea.
• Cases of acute porphyria have been described with other sulfonylureas in patients with porphyria.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no or limited data (fewer than 300 pregnancies) on gliclazide. It was not teratogenic in animals. As a precaution, avoiding gliclazide in pregnancy is preferable. Diabetes should be controlled before conception to reduce the risk of birth defects linked to uncontrolled diabetes. Oral hypoglycaemic agents are not recommended; insulin is the first choice, and treatment should be changed to insulin before trying to conceive or as soon as pregnancy is discovered.
• Breastfeeding: it is not known whether gliclazide or its metabolites pass into breast milk. Because of the risk of neonatal hypoglycaemia, it is contraindicated in breastfeeding mothers.
• Fertility: no effect on fertility or reproductive function was seen in female and male rats.

Effect on Driving

Gliclazide has no or negligible influence on the ability to drive and use machines. Patients must be able to recognise the symptoms of hypoglycaemia and take care when driving or using machines, especially at the start of treatment.

The tablets need no special storage conditions. They are supplied in aluminium/PVC blisters in cartons; not all pack sizes may be marketed. Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the packaging.

Prescription only (Rx). Gliclazide modified-release tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.