Gliclazide Tablets 80mg Bp
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Gliclazide Tablets 80mg BP
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Gliclazide 80mg For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Gliclazide Tablets are white, round, flat, uncoated, with bevelled edges debossed 'GZ/80' with break line on one side and plain on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Non insulin-dependent diabetes mellitus.
4.2 Posology and method of administration
For oral administration
Adults
The total daily dose may vary from 40 to 320mg taken orally. The dose should be adjusted according to the individual patient’s response, commencing with 40-80mg daily (1/2 - 1 tablet) and increasing until adequate control is achieved. A single dose should not exceed 160mg (two tablets). When higher doses are required, gliclazide tablets should be taken twice daily according to the main meals of the day.
In obese patients or those not showing adequate response to gliclazide alone, additional therapy may be required.
Elderly
Plasma clearance of gliclazide in 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 show that gliclazide is effective and well tolerated. However, care should be exercised when prescribing sulphonylureas in the elderly due to a possible age-related increased risk of hypoglycaemia.
Renal and hepatic impairment.
The starting dose should be 40mg daily (1/2 tablet) increasing until adequate control is achieved.
Children
As with other sulphonylureas, gliclazide is not indicated for the treatment of juvenile onset diabetes mellitus.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients, other sulphonylureas, sulphonamides,
• Type I diabetes,
• Diabetic coma and pre-coma, diabetic keto-acidosis,
• Severe infection, stress, trauma, surgical procedures or other severe conditions where the drug is unlikely to control the hyperglycaemia.
• Severe renal or hepatic insufficiency: in these cases the use of insulin is recommended,
• Lactation (see section 4.6),
• Treatment with Miconazole (see section 4.5)
• Gliclazide should, where possible, be avoided in porphyria.
• Patients with rare hereditory problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.4 Special warnings and precautions for use
Hypoglycaemia: 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.
Factors which increase the risk of hypoglycaemia:
• In patients controlled by diet alone. patient refuses or (particularly in elderly subjects) is unable to co-operate
• malnutrition, irregular mealtimes, skipping meals, periods of fasting or dietary changes
• imbalance between physical exercise and carbohydrate intake
• certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency
• concomitant administration of alcohol or certain other medicines (see section 4.5).
• In cases of Gliclazide tablets overdose.
• When calorie or glucose intake is insufficient
• In patients with hepatic and/or renal impairment. However, in long-term clinical trials patients with renal insufficiency have been treated satisfactorily using gliclazide at reduced doses with careful patient monitoring.
In order to reduce the risk of hypoglycaemia it is therefore recommended:
• To initiate treatment for non-insulin dependent diabetics by diet alone, if this is possible. 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.
• To take into account the age of the patient: blood sugar levels not strictly controlled by diet alone might be acceptable in the elderly.
• To adjust the dose of gliclazide according to the blood glucose response and to the 24 hour urinary glucose during the first days of treatment
• Careful selection of patients, of the dose used, and clear patient directions are necessary to reduce the risk of hypoglycaemic episodes.
Dosage adjustment may be necessary:
• On the occurrence of mild symptoms of hypoglycaemia (sweating, pallor, hunger pangs, tachycardia, sensation of malaise). Such findings should be treated with oral glucose and adjustment made in drug dosage and/or meal patterns.
• On the occurrence of severe hypoglycaemic reactions (coma or neurological impairment, (see overdose).
• On loss of control of blood glucose (hyperglycaemia). When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such time, it may be necessary to increase progressively the dosage of gliclazide and if this is insufficient, to discontinue treatment with gliclazide and to administer insulin. As with other sulphonylureas, hypoglycaemia will occur if the patients’ dietary intake is reduced or if they are receiving a larger dose of gliclazide than required
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 (see section 4.8), 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 self-monitoring may also be useful.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since gliclazide belongs to the class of sulphonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.
4.5
Interaction with other medicinal products and other forms of interaction
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 antiinflammatory 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 (e.g. metformin), thiazolidinediones, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists), ACE inhibitors (e.g. captopril, enalapril), testosterone, anabolic steroids, beta-blockers, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H2-receptor antagonists, MAOIs, trimethoprim, sulfonamides, clarithromycin and nonsteroidal anti-inflammatory agents.
The warning signs of hypoglycaemia (such as tremor) may also be masked by beta-blockers.
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.
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.
The hypoglycaemic effect of gliclazide may be potentiated by salicylates, sulphonamides, octreotide, azapropazone, sulfinpyrazone, metabolism of gliclazide may be accelerated by aminoglutethimide, testosterone, tetracycline compounds, chloramphenicol, clofibrate, disopyramide, cimetidine. Co-trimoxazole rarely enhances the effect of gliclazide.
Clofibrate group drugs may improve glucose tolerance and have an additive effect. Octreotide possibly reduces antidiabetic drug requirements in diabetes mellitus. Fluconazole and miconazole increase plasma concentrations of sulphonylureas. Rifamycins, phenothiazines, corticosteroids, loop and thiazide diuretics, diazoxide, oestrogens, progesterones, oral contraceptives, aminoglutethimide, thyroid hormones and abuse of laxatives may reduce the effect of sulphonylureas.
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 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. Studies in animal have shown reproductive toxicity (see section 5.3).
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.
Lactation
It has not been established whether gliclazide or its metabolites are excreted in the breast milk. However, some sulphonylureas are excreted in breast milk. Given the risk of neonatal hypoglycaemia, the product is contra-indicated in breast-feeding mothers.
4.7 Effects on ability to drive and use machines
Gliclazide has no known influence on the ability to drive and use machines.
However, patients should be informed that their concentration may be affected if their diabetes is not satisfactorily controlled, especially at the beginning of treatment. (see section 4.4)
4.8 Undesirable effects
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 are required.
Gastrointestinal disturbances including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation have been reported, but this type of adverse reaction can be avoided if gliclazide is taken with a meal.
Hypersensitivity reactions can occur, usually in the first 6-8 weeks of therapy, and they consist mainly of allergic skin reactions including pruritis, erythema and bullous eruption.
The following undesirable effects have been more rarely reported:
- Blood and lymphatic system disorders: anaemia, leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia and aplastic anaemia and granulocytopenia have been observed during treatment with gliclazide but are not known to be directly attributable to the drug.
- Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis), photosensitivity skin reactions.
- Hepatobiliary disorders: Raised hepatic enzyme levels (ASAT, ALAT, alkaline phosphatase), hepatic failure, 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 sulphonylureas, the following adverse events have been observed: cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatraemia, 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.
4.9 Overdose
An 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.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Sulfonamides, urea derivatives ATC code: A10BB09
Gliclazide is a hypoglycaemic sulphonylurea 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.
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
The drug is well absorbed and its half-life in man is approximately 10-12 hours. Gliclazide is metabolised in the liver; less that 5% of the dose is excreted unchanged in the urine.
5.3 Preclinical safety data
Preclinical 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 fetal body weight was observed in animals receiving doses 9.4 fold higher than the maximum recommended dose in humans.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate colloidal anhydrous silica Pregelatinised maize starch purified talc Magnesium Stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
36 months
6.4 Special precautions for storage
Do not store above 25oC. Store in the original package.
6.5 Nature and contents of container
Blister composed of opaque white PVC 250 micron with aluminium foil 20 microns containing packs of 28, 30, 56 or 60 tablets in cartons.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited
Sage House
319 Pinner Road
Harrow
Middlesex
HA1 4HG
8 MARKETING AUTHORISATION NUMBER(S)
PL 20075/0114
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12/04/2006
10 DATE OF REVISION OF THE TEXT
10/06/2016