Summary of medicine characteristics - GLICLAZIDE 30 MG PROLONGED-RELEASE TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Gliclazide 30 mg prolonged-release tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 30 mg gliclazide.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release tablet
White to off-white, capsule shaped, biconvex tablets, debossed with ‘ML30’ on upper side and plain on lower side with approximate length 10.0 mm and width 4.50 mm.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Non insulin-dependent diabetes (type 2) in adults when dietary measures, physical exercise and weight loss alone are not sufficient to control blood glucose.
4.2 Posology and method of administration
Posology
The daily dose may vary from 1 to 4 tablets per day, i.e. from 30 to 120 mg taken orally in a single intake at breakfast time.
It is recommended that the tablet(s) be swallowed whole.
If a dose is forgotten, there must be no increase in the dose taken the next day. As with any hypoglycaemic agent, the dose should be adjusted according to the individual patient’s metabolic response (blood glucose, HbA1c).
Initial dose
The recommended starting dose is 30 mg daily.
If blood glucose is effectively controlled, this dose may be used for maintenance treatment.
If blood glucose is not adequately controlled, the dose may be increased to 60, 90 or 120 mg daily, in successive steps. The interval between each dose increment should be at least 1 month except in patients whose blood glucose has not reduced after two weeks of treatment. In such cases, the dose may be increased at the end of the second week of treatment.
The maximum recommended daily dose is 120 mg.
Switching from Gliclazide 80 mg tablets to Gliclazide 30 mg prolonged-release tablets
1 tablet of Gliclazide 80 mg is comparable to 1 tablet of Gliclazide 30 mg prolonged-release. Consequently the switch can be performed provided a careful blood monitoring.
Switching from another oral antidiabetic agent to Gliclazide 30 mg prolonged-release tablets
Gliclazide 30 mg prolonged-release tablets can be used to replace other oral antidiabetic agents.
The dosage and the half-life of the previous antidiabetic agent should be taken into account when switching to Gliclazide 30 mg prolonged-release tablets. A transitional period is not generally necessary. A starting dose of 30 mg should be used and this should be adjusted to suit the patient’s blood glucose response, as described above.
When switching from hypoglycaemic sulfonylurea with a prolonged half-life, a treatment free period of a few days may be necessary to avoid an additive effect of the two products, which might cause hypoglycaemia. The procedure described for initiating treatment should also be used when switching to treatment with Gliclazide 30 mg prolonged-release tablets, i.e. a starting dose of 30 mg/day, followed by a stepwise increase in dose, depending on the metabolic response.
Combination treatment with other antidiabetic agents
Gliclazide 30mg prolonged-release tablets can be given in combination with biguanides, alpha glucosidase inhibitors or insulin.
In patients not adequately controlled with Gliclazide 30 mg prolonged-release tablets, concomitant insulin therapy can be initiated under close medical supervision.
Special populations
Elderly
Gliclazide 30 mg prolonged-release tablets should be prescribed using the same dosing regimen recommended for patients under 65 years of age.
Renal impairment
In patients with mild to moderate renal insufficiency the same dosing regimen can be used as in patients with normal renal function with careful patient monitoring. These data have been confirmed in clinical trials.
Patients at risk of hypoglycaemia:
– Undernourished or malnourished,
– Severe or poorly compensated endocrine disorders (hypopituitarism,
hypothyroidism, adrenocorticotrophic insufficiency),
– Withdrawal of prolonged and/or high dose corticosteroid therapy,
– Severe vascular disease (severe coronary heart disease, severe carotid impairment, diffuse vascular disease);
It is recommended that the minimum daily starting dose of 30 mg is used.
Paediatric population
The safety and efficacy of Gliclazide 30 mg prolonged-release tablets in children and adolescents have not been established. No data are available in children.
Method of administration
Oral use.
It is recommended that the tablet(s) be swallowed whole without chewing or crushing.
4.3 Contraindications
This medicine is contra-indicated in case of:
Hypersensitivity to gliclazide or to any of the excipients listed in section 6.1, other sulfonylureas, sulfonamides,
Type 1 diabetes,
Diabetic pre-coma and coma, diabetic keto-acidosis,
Severe renal or hepatic insufficiency: in these cases the use of insulin is recommended,
Treatment with miconazole (see section 4.5),
Lactation (see section 4.6).
4.4 Special warnings and precautions for use
4.6 Fertility, pregnancy and lactation
Pregnancy
There is no or limited amount of data (less than 300 pregnancy outcomes) from the use of gliclazide in pregnant women, even though there are few data with other sulfonylureas.
In animal studies, gliclazide is not teratogenic (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Gliclazide during pregnancy.
Control of diabetes should be obtained before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes.
Oral hypoglycaemic agents are not suitable, insulin is the drug of first choice for treatment of diabetes during pregnancy. It is recommended that oral hypoglycaemic therapy is changed to insulin before a pregnancy is attempted, or as soon as pregnancy is discovered.
Breast-feeding
It is unknown whether gliclazide or its metabolites are excreted in human milk. Given the risk of neonatal hypoglycaemia, the product is therefore contra-indicated in breast-feeding mothers. A risk to the newborns/infants cannot be excluded.
Fertility
No effect on fertility or reproductive performance was noted in male and female rats (see section 5.3).
4.7 Effects on ability to drive and use machines
Gliclazide 30 mg prolonged-release tablets has no or negligible influence on the ability to drive and use machines. However, patients should be made aware of the symptoms of hypoglycaemia and should be careful if driving or operating machinery, especially at the beginning of treatment.
4.8 Undesirable effects
Based on the experience with gliclazide, the following undesirable effects have been reported.
The most frequent adverse reaction with gliclazide is hypoglycaemia.
As for other sulfonylureas, treatment with gliclazide can cause hypoglycaemia, if mealtimes are irregular and, in particular, if meals are skipped. Possible symptoms of hypoglycaemia are: headache, intense hunger, nausea, vomiting, lassitude, sleep disorders, agitation, aggression, poor concentration, reduced awareness and slowed reactions, depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disorders, dizziness, feeling of powerlessness, loss of self-control, delirium, convulsions, shallow respiration, bradycardia, drowsiness and loss of consciousness, possibly resulting in coma and lethal outcome.
In addition, signs of adrenergic counter-regulation may be observed: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.
Usually, symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners have no effect.
Experience with other sulfonylureas shows that hypoglycaemia can recur even when measures prove effective initially.
If a hypoglycaemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalisation is required.
Gastrointestinal disturbances, including abdominal pain, nausea, vomiting dyspepsia, diarrhoea, and constipation have been reported: if these should occur they can be avoided or minimised if gliclazide is taken with breakfast.
The following undesirable effects have been more rarely reported:
Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis and autoimmune bullous disorders), and exceptionally, drug rash with eosinophilia and systemic symptoms (DRESS).
Blood and lymphatic system disorders: Changes in haematology are rare. They may include anaemia, leucopenia, thrombocytopenia, granulocytopenia. These are in general reversible upon discontinuation of medication.
Hepato-biliary disorders: raised hepatic enzyme levels (AST, ALT, alkaline phosphatase), hepatitis (isolated reports). Discontinue treatment if cholestatic jaundice appears. These symptoms usually disappear after discontinuation of treatment.
Eye disorders
Transient visual disturbances may occur especially on initiation of treatment, due to changes in blood glucose levels.
Class attribution effects:
As for other sulfonylureas, the following adverse events have been observed: cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulfonylurea or led to life-threatening liver failure in isolated cases.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseAn overdose of sulfonylureas may cause hypoglycaemia.
Moderate symptoms of hypoglycaemia, without any loss of consciousness or neurological signs, must be corrected by carbohydrate intake, dose adjustment and/or change of diet. Strict monitoring should be continued until the doctor is sure that the patient is out of danger.
Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as a medical emergency, requiring immediate hospitalisation.
If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 mL of concentrated glucose solution (20 to 30 %). This should be followed by continuous infusion of a more dilute glucose solution (10 %) at a rate that will maintain blood glucose levels above 1 g/L. Patients should be monitored closely and, depending on the patient's condition after this time, the doctor will decide if further monitoring is necessary.
Dialysis is of no benefit to patients due to the strong binding of gliclazide to proteins.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: sulfonamides, urea derivative
ATC code: A10BB09
Mechanism of action
Gliclazide is a hypoglycaemic sulfonylurea oral antidiabetic active substance differing from other related compounds by an N-containing heterocyclic ring with an endocyclic bond.
Gliclazide reduces blood glucose levels by stimulating insulin secretion from the P-cells of the islets of Langerhans.
Increase in postprandial insulin and C-peptide secretion persists after two years of treatment.
In addition to these metabolic properties, gliclazide has haemovascular properties.
Pharmacodynamic effects
Effects on insulin release
In type 2 diabetics, gliclazide restores the first peak of insulin secretion in response to glucose and increases the second phase of insulin secretion. A significant increase in insulin response is seen in response to stimulation induced by a meal or glucose.
Haemovascular properties:
Gliclazide decreases microthrombosis by two mechanisms which may be involved in complications of diabetes:
A partial inhibition of platelet aggregation and adhesion, with a decrease in the markers of platelet activation (beta thromboglobulin, thromboxane B2).
An action on the vascular endothelium fibrinolytic activity with an increase in tPA activity.
5.2 Pharmacokinetic properties
Absorption
Plasma levels increase progressively during the first 6 hours, reaching a plateau which is maintained from the sixth to the twelfth hour after administration.
Intra-individual variability is low.
Gliclazide is completely absorbed. Food intake does not affect the rate or degree of absorption.
Distribution
Plasma protein binding is approximately 95%. The volume of distribution is around 30 litres.
A single daily intake of Gliclazide 30 mg prolonged-release tablets maintains effective gliclazide plasma concentrations over 24 hours.
Biotransformation
Gliclazide is mainly metabolised in the liver and excreted in the urine: less than 1% of the unchanged form is found in the urine. No active metabolites have been detected in plasma.
Elimination
The elimination half-life of gliclazide varies between 12 and 20 hours.
Linearity/non-linearity
The relationship between the dose administered ranging up to 120 mg and the area under the concentration time curve is linear.
Special populations
Elderly
No clinically significant changes in pharmacokinetic parameters have been observed in elderly patients.
5.3 Preclinical safety data
5.3 Preclinical safety dataPreclinical data reveal no special hazards for humans based on conventional studies of repeated dose toxicity and genotoxicity. Long term carcinogenicity studies have not been done. No teratogenic changes have been shown in animal studies, but lower foetal body weight was observed in animals receiving doses 25 fold higher than the maximum recommended dose in humans. Fertility and reproductive performance were unaffected after gliclazide administration in animal studies.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium Hydrogen Phosphate Dihydrate
Povidone K-30
Hypromellose K 100 LVCR
Silica, Colloidal anhydrous
Magnesium stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.