Gliclazide 40mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Gliclazide 40mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Gliclazide 40mg
Also Contains Lactose Monohydrate Ph. Eur 55 mg For Excipients, see 6.1
3 PHARMACEUTICAL FORM
Tablet
White to off-white, circular, flat, bevelled edged, uncoated tablets with “40” on one side, plain on reverse.
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 320 mg taken orally. The dose should be adjusted according to the individual patient’s response, commencing with 40-80 mg daily (1 - 2 tablets) and increasing until adequate control is achieved. A single dose should not exceed 160 mg (4 tablets). When higher doses are required, Gliclazide 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 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 Tablet is effective and well tolerated. Care should be exercised, however, when prescribing sulphonylureas in the elderly due to a possible age-related increased risk of hypoglycaemia.
Children:
Gliclazide Tablet as with other sulphonylureas, is not indicated for the treatment of juvenile onset diabetes mellitus.
4.3 Contraindications
Gliclazide Tablets should not be used in:
• Juvenile onset diabetes
• Diabetes complicated by ketosis and acidosis.
• Pregnancy
• Diabetes undergoing surgery, after severe trauma or during infections.
• Patients known to have hypersensitivity other sulphonylureas and related drugs.
• Diabetic pre-coma and coma.
• Severe renal or hepatic insufficiency: in these cases the use of insulin is recommended.
• Lactation
• Treatment with Miconazole (see section “Interactions with other medicinal products and other forms of Interaction”)
4.4 Special warnings and precautions for use
Hypoglycaemia: All sulphonylurea drugs are capable of producing moderate or severe hypoglycaemia. Hypoglycaemia is more likely to occur following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycaemic agents is being used.
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 to reduce the risk of hypoglycaemic episodes.
Factors which increase the risk of hypoglycaemia:
patient refuses or (particularly in elderly subjects) is unable to cooperate,
malnutrition, irregular mealtimes, skipping meals, periods of fasting or dietary changes,
imbalance between physical exercise and carbohydrate intake,
renal insufficiency,
severe hepatic insufficiency,
overdose of Gliclazide Tablets,
certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency,
concomitant administration of certain other medicines (see Interactions).
In order to reduce the risk of hypoglycaemia it is therefore recommended:
to initiate treatment for non-insulin dependant diabetes by diet alone, if this is possible,
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.
Dosage adjustments 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 adjustments made in drug dosage and/or meal patterns,
on the occurrence of severe hypoglycaemic reactions (coma or neurological impairment, see overdose),
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 times, it may be necessary to increase progressively the dosage of Gliclazide Tablets and if this is insufficient, to discontinue the treatment with Gliclazide Tablets and to administer insulin. As with other sulphonylureas, hypoglycaemia will occur if the patient’s dietary intake is reduced or of they are receiving a larger dose of Gliclazide Tablets than required.
Care should be exercised in patients with hepatic and/or renal impairment and a small starting dose should be used with careful patient monitoring.
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.
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.
This medicinal product contains Lactose Monohydrate. 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
Care should be taken when giving Gliclazide Tablets with drugs which are known to alter the diabetic state or potentiate the drug’s action.
The hypoglycaemic effect of gliclazide may be potentiated by phenylbutazone, salicylates, sulphonamides, coumarin derivatives, MAOIs, beta adrenergic blocking agents, tetracycline compounds, chloramphenicol, clofibrate, disopyramide, miconazole (oral forms) and cimetidine.
It may be diminished by corticosteroids, oral contraceptives, thiazide diuretics, Phenothiazine derivatives, thyroid hormones and abuse of laxatives.
1) The following products are likely to increase the risk of hypoglycaemia
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 sulphonylureas (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), betablockers, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H2-receptor antagonists, MAOIs, sulfonamides and nonsteroidal 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: (IV.)
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): Sulphonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the anticoagulant may be necessary.
4.6 Fertility, Pregnancy and lactation
Pregnancy:
Gliclazide is contraindicated during pregnancy (see section 4.3 contra-indications).
There is no experience with the use of gliclazide during pregnancy in humans, even though there are few data with other sulphonylureas. 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.
Lactation:
It has not been established whether gliclazide is transferred to human milk. However, other sulphonylureas have been found in milk and there is no evidence to suggest that gliclazide differs from the group in this respect. Gliclazide should, therefore, not be taken while the mother is breast-feeding.
4.7 Effects on ability to drive and use machines
Patients should be informed that their concentration may be affected if their diabetes is not satisfactorily controlled, especially at the beginning of treatment (see special warnings and precautions).
4.8 Undesirable effects
Based on the experience with gliclazide and with other sulphonylureas, the following undesirable effects have to be mentioned.
Hypoglycaemia
As for other sulphonylureas, treatment with gliclazide 40mg tablets 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 sulphonylureas 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, erythema, maculopapular rashes, bullous reactions.
Blood and lymphatic system disorders: Changes in haematology are rare. They may include anaemia, leucopoenia, thrombocytopenia, granulocytopoenia. 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: Cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopoenia and allergic vasculitis, have been described for other sulphonylureas.
With other sulphonylureas cases were also observed of elevated liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulphonylurea or led to life-threatening liver failure in isolated cases.
4.9 Overdose
The symptoms to be expected of overdose would be hypoglycaemia. The treatment is gastric lavage and correction of the hypoglycaemia by appropriate means with continual monitoring of the patient’s blood sugar until the effect of the drug has ceased.
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
A10B B09 Oral Blood Glucose Lowering Drugs
Gliclazide is a hypoglycaemic sulphonylurea differing from other related compounds by the addition of an azabicyclo-octane ring.
In man, apart from having similar hypoglycaemic effect to the other sulphonylureas, gliclazide has been shown to reduce platelet adhesiveness and aggregation and increase fibrinolytic activity. These factors are thought to be implicated in the pathogenesis of long-term complications of diabetes mellitus.
Gliclazide primarily enhances the first phase of insulin secretion, but also to a lesser degree its second phase. Both phases are diminished in non-insulin dependent diabetes mellitus.
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 than 5% of the dose is excreted unchanged in the urine.
5.3 Preclinical safety data
No data of relevance which is additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Lactose monohydrate Microcrystalline cellulose Magnesium stearate Purified talc Croscarmellose sodium Povidone
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Blisters: Do not store above 25°C. Store in the original package.
Tablet containers: Do not store above 25°C. Keep the container tightly closed.
6.5 Nature and contents of container
Al / PVC/PVDC blister, pack sizes of 20, 28, 56, 60, 84, 100 tablets.
HDPE tablet containers, pack sizes of 100, 250, 500 or 1000 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Brill Pharma Limited Unit 3, Canalside
Northbridge Road
Berkhamsted
Hertfordshire HP4 lEG, UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 40496/0040
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
08/11/2012
10 DATE OF REVISION OF THE TEXT
10/06/2014