Gliclazide 80mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Gliclazide 80mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 80 mg gliclazide
Excipient with known effect Each tablet contains 43 mg of lactose.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
White, round tablet, scored on one side and embossed MP90 on the reverse side.
The tablet can be divided into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the treatment of maturity onset diabetes mellitus
4.2 Posology and method of administration
Posology
Adults:
The total daily dose may vary from 40 to 320 mg taken orally. The dose should be adjusted according to the individual patient’s response, commencing with 40 - 80 mg daily ('A - 1 tablets) and increasing until adequate control is achieved.
A single dose should not exceed 160 mg (2 tablets). When higher dose are required, Gliclazide 80 mg Tablets should be taken twice daily and according to the main meals of the day.
In obese patients or those not showing adequate response to Gliclazide 80 mg Tablets alone, additional therapy may be required.
Elderly:
Plasma clearance of gliclazide is not altered in the elderly and steady state plasma levels can therefore be expected to be similar to those in adults under 65 years. Clinical experience in the elderly to date shows that gliclazide is effective and well tolerated. Care should be exercised, however, when prescribing sulfonylureas in the elderly due to a possible age-related increased risk of hypoglycaemia.
Paediatric population:
Gliclazide 80 mg Tablets, as with other sulfonylureas, is not indicated for the treatment of juvenile onset diabetes mellitus.
Method of administration For oral use.
4.3 Contraindications
Gliclazide 80 mg Tablets is contraindicated in:
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, other sulfonylureas or sulfonamides
- Juvenile onset diabetes
- Diabetes complicated by ketosis and acidosis
- Lactation (see section 4.6)
- Diabetics undergoing surgery after severe trauma or during infections
- Diabetic pre-coma and coma
- Severe renal or hepatic insufficiency
- Treatment with miconazole (see section 4.5)
- Gliclazide should, where possible, be avoided in porphyria.
4.4 Special warnings and precautions for use
Hypoglycaemia
This treatment should be prescribed only if the patient is likely to have a regular food intake (including breakfast). It is important to have a regular carbohydrate intake due to the increased risk of hypoglycaemia if a meal is taken late, if an inadequate amount of food is consumed or if the food is low in carbohydrate. Hypoglycaemia is more likely to occur during low-calorie diets, following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycaemic agents is being used.
Hypoglycaemia may occur following administration of sulfonylureas (see section 4.8). Some cases may be severe and prolonged. Hospitalisation may be necessary
and glucose administration may need to be continued for several days.
Careful selection of patients, of the dose used, and clear patient directions are necessary in order to reduce the risk of hypoglycaemic episodes.
Factors which increase the risk of hypoglycaemia:
- overdose of Gliclazide;
- malnutrition, irregular mealtimes, skipping meals, periods of fasting or dietary changes;
- severe hepatic insufficiency
- renal insufficiency
- imbalance between physical exercise and carbohydrate intake
- patient refuses or (particularly in elderly subjects) is unable to co-operate
- certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency
- concomitant administration of alcohol or certain other medicines (see section 4.5).
Renal and hepatic insufficiency
The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic insufficiency or severe renal failure. A hypoglycaemic episode occurring in these patients may be prolonged, so appropriate management should be initiated.
Patient information
The risks of hypoglycaemia, together with its symptoms, treatment and conditions that predispose to its development, should be explained to the patient and to family members.
The patient should be informed of the importance of following dietary advice, of taking regular exercise, and of regular monitoring of blood glucose levels.
Poor blood glucose control
Blood glucose control in a patient receiving antidiabetic treatment may be affected by any of the following: fever, trauma, infection or surgical intervention. In some cases, it may be necessary to administer insulin.
The hypoglycaemic efficacy of any oral antidiabetic agent, including gliclazide, is attenuated over time in many patients. This may be due to progression in the severity of the diabetes, or to a reduced response to treatment. This phenomenon is known as secondary failure which is distinct from primary failure, when an active substance is ineffective as first-line treatment. Adequate dose adjustment and dietary compliance should be considered before classifying the patient as secondary failure.
Laboratory tests
Measurement of glycated haemoglobin levels (or fasting venous plasma glucose) is recommended in assessing blood glucose control. Blood glucose selfmonitoring may also be useful.
Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
1) The following products are likely to increase the risk of hypoglycaemia: Contraindicated combination:
Miconazole (systemic route, oromucosal gel): increases the hypoglycaemic effect with possible onset of hypoglycaemic symptoms, or even coma.
Combinations which are not recommended:
Phenylbutazone (systemic route): increases the hypoglycaemic effect of sulfonylureas (displaces their binding to plasma proteins and/or reduces their elimination). It is preferable to use a different anti-inflammatory agent, or else to warn the patient and emphasise the importance of self-monitoring. Where necessary, adjust the dose during and after treatment with the anti-inflammatory agent.
Alcohol: increases the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Avoid alcohol or medicines containing alcohol.
Combinations requiring precautions for use:
Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur when one of the following drugs is taken, for example:
Other antidiabetic agents (insulins, acarbose, biguanides), beta-blockers, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H2-receptor antagonists, MAOIs, sulfonamides, and non-steroidal anti-inflammatory agents.
2) The following products may cause an increase in blood glucose levels:
Combination which is not recommended:
Danazol: diabetogenic effect of danazol.
If the use of this active substance cannot be avoided, warn the patient and emphasise the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic agent during and after treatment with danazol.
Combinations requiring precautions during use:
Chlorpromazine (neuroleptic agent): high doses (> 100 mg per day of chlorpromazine) increase blood glucose levels (reduced insulin release).
Warn the patient and emphasise the importance of blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with the neuroleptic agent.
Glucocorticoids (systemic and local route: intra-articular, cutaneous and rectal preparations) and tetracosactrin: increase in blood glucose levels with possible ketosis (reduced tolerance to carbohydrates due to glucocorticoids).
Warn the patient and emphasise the importance of blood glucose monitoring, particularly at the start of treatment. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with glucocorticoids.
Ritodrine, salbutamol, terbutaline - I.V: Increased blood glucose levels due to beta-2 agonist effects. Emphasise the importance of monitoring blood glucose levels. If necessary, switch to insulin.
3) Combination which must be taken into account:
Anticoagulant therapy (e.g. warfarin): Sulfonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the anticoagulant may be necessary.
Care should be taken when giving Gliclazide 80 mg Tablets with drugs which are known to alter the diabetic state or potentate the drug's action.
The hypoglycaemic effect of Gliclazide 80 mg Tablets may be potentiated by salicylates, sulfonamides, octreotide, azapropazone, sulfinpyrazone, metabolism of gliclazide may be accelerated by aminoglutethimide, testosterone,
tetracycline compounds, chloramphenicol, clofibrate, disopyramide, and
cimetidine. Co-trimoxazole rarely enhances the effect of gliclazide.
Gliclazide may be diminished by rifamycins, oral contraceptives, thiazide diuretics, diazoxide, phenothiazine derivatives, thyroid hormones, loop diuretics, and abuse of laxatives.
Calcium channel blockers (nifedipine) may occasionally impair glucose tolerance as well as Lithium may occasionally impair glucose tolerance.
4.6 Fertility, pregnancy and lactation
Pregnancy:
There is no experience with the use of gliclazide during pregnancy in humans, even though there are few data with other sulfonylureas.
In animal studies, gliclazide is not teratogenic.
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 has not yet been established whether gliclazide or its metabolites are transferred to human milk. However, other sulfonylureas have been found in milk. Given the risk of neonatal hypoglycaemia, the product is contra-indicated in breastfeeding mothers.
4.7 Effects on ability to drive and use machines
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 (see other special warnings and precautions).
4.8 Undesirable effects
Based on the experience with gliclazide and with other sulfonylureas, the following undesirable effects have to be mentioned.
Hypoglycaemia (see special warnings and precautions)
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 are required.
Gastro-intestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation have been reported, but this type of adverse reaction can be avoided or minimized if Gliclazide 80 mg Tablets is taken during a meal.
The following undesirable effects have been more rarely reported:
Skin and subcutaneous tissue disorders:
Rash, pruritus, urticaria, erythema, maculopapular rashes, bullous reactions, photosensitivity skin reactions.
Blood and lymphatic system disorders:
Changes in haematology are rare. They may include anaemia, leucopenia, thrombocytopenia, and granulocytopenia. These are in general reversible upon discontinuation of gliclazide.
Hepatobiliary disorders:
Raised hepatic enzyme levels (ASAT, ALAT, 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
Cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia and allergic vasculitis have been described for other sulfonylureas.
With sulfonylureas cases were also observed of elevated liver enzyme levels and
even impairment of hepatic function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulfonylurea or led to life-threatening hepatic 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.
4.9 Overdose
The symptom to be expected with an overdose would be 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: sulphonamides, urea derivatives.
ATC code: A10BB09
Gliclazide is a sulphonylurea hypoglycaemic agent. Gliclazide stimulates the release of insulin from pancreatic P-cells, probably by facilitating Ca2+ transport across the P-cell membranes. Like other sulfonylureas, it exerts an important hypoglycaemic effect on the cell surface at one or more postbinding sites, although there is some evidence that there may sometimes be an increase in insulin receptors. The sulfonylureas also have an important hypoglycaemic action by decreasing hepatic glucose output, and it has recently been shown that the sulfonylureas, including gliclazide stimulate the most potent activator of liver phosphofructokinase at concentrations which are found in the blood of treated diabetic patients.
5.2 Pharmacokinetic properties
Absorption: The drug is readily absorbed from the gastrointestinal tract. It is extensively bound to plasma proteins. The half-life is about 10-12 hours.
Biotransformation: Gliclazide is extensively metabolised in the liver to metabolites without significant hypoglycaemic activity.
Elimination: Both unchanged drug and metabolites are excreted in the urine.
5.3 Preclinical safety data
No further relevant information.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Silicon dioxide Pregelatinized maize starch Talc
Magnesium stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C
6.5 Nature and contents of container
The tablets are packaged into polyvinyl chloride (PVC)/aluminium foil blister packs.
Boxes of 28 tablets or 60 tablets are available. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7 MARKETING AUTHORISATION HOLDER
Genethics Europe Limited 41 - 43 Klimentos Klimentos Tower Nicosia 1061 Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 42976/0057
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/03/2011
10 DATE OF REVISION OF THE TEXT
30/08/2016