GLICLAZIDE ZYDUS FRANCE 60 mg Tab LM Plq/30

Modified-release tablet.

Elongated tablet, white to cream-white, engraved with "60" on one side.

Gliclazide ....................................................................................................................................... 60 mg

For a modified-release tablet.

Excipient(s) with known effect: Lactose monohydrate (118,80 mg/tablet).

Excipients:

Non-insulin-dependent diabetes (type 2) in adults, when diet, physical exercise and weight reduction alone are not sufficient to achieve glycaemic control.

Dosage

The daily dose of GLICLAZIDE ZYDUS FRANCE 60 mg may vary from 30 to 120 mg as a single oral dose taken at breakfast.

It is recommended to swallow the tablet(s) whole, without crushing or chewing them.

In case of a missed dose, the next day's dose must not be increased.

As with any hypoglycaemic agent, the dose must be adjusted according to each patient's individual metabolic response (blood glucose, HbA1c).

Method of administration

Initial dose

The recommended initial dose is 30 mg per day.

• if glycaemic control is satisfactory, this dose may be maintained as maintenance treatment,

• if glycaemic control is not satisfactory, the dose may be increased to 60, 90 or 120 mg per day, in successive steps, respecting an interval of at least 1 month between each step, except in patients whose blood glucose does not decrease after two weeks of treatment. In this case, a dose increase may be proposed at the end of the second week of treatment.

The maximum recommended dose is 120 mg per day.

One modified-release tablet of GLICLAZIDE ZYDUS FRANCE 60 mg is equivalent to two modified-release tablets of GLICLAZIDE ZYDUS FRANCE 30 mg.

Other specialties presented as scored modified-release tablets allowing administration of a fraction of the dose are available.

Switch from gliclazide 80 mg tablets to GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet:

One gliclazide tablet dosed at 80 mg is comparable to 30 mg of the modified-release formulation. Therefore, the switch may be made provided that blood glucose changes are closely monitored.

Switch from another oral antidiabetic by GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet :

GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet may take over from another oral antidiabetic treatment.

In this case, the dose and half-life of the previous antidiabetic must be taken into account.

The switch will generally be made without a transition period, preferably starting with a dose of 30 mg. The dose will then be adjusted as indicated above, depending on each patient's glycaemic response.

When switching from a sulfonylurea with a prolonged half-life, a therapeutic window of a few days may be necessary to avoid an additive effect of the two products, which risks causing hypoglycaemia.

During this switch, it is recommended to follow the same procedure as when initiating treatment with gliclazide 60 mg, i.e. to start at a dose of 30 mg per day, then to increase the dose in successive steps, depending on the metabolic results.

Combination with other antidiabetics:

GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet may be combined with biguanides, alpha-glucosidase inhibitors or insulin.

In patients insufficiently controlled with GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet, combined treatment with insulin may be initiated under strict medical supervision.

Special populations

Elderly patients

GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet will be prescribed according to the same dosage regimen as in subjects under 65 years of age.

Renal impairment

In patients with mild to moderate renal impairment, the dosage regimen will be the same as in subjects with normal renal function, but with careful monitoring.

These data have been confirmed in clinical trials.

Patients at risk of hypoglycaemia

• States of undernutrition or malnutrition,

• Severe or poorly compensated endocrine disorders (anterior pituitary insufficiency, hypothyroidism, adrenal insufficiency),

• Withdrawal from prolonged and/or high-dose corticosteroid therapy,

• Severe vascular disease (severe coronary artery disease, severe carotid involvement, diffuse vascular disease).

It is recommended to systematically start treatment at the minimum dose of 30 mg/day.

Paediatric population

The safety and efficacy of gliclazide have not been established in children and adolescents.

There is no data in children.

This medicine is contraindicated in cases of:

• hypersensitivity to the active substance or to any of the excipients listed in section Composition, other sulfonylureas, sulfonamides;

• type 1 diabetes;

• diabetic pre-coma and coma, diabetic ketoacidosis;

• severe renal or hepatic insufficiency: in these situations, it is recommended to use insulin;

• treatment with miconazole (see section Interactions) ;

• breastfeeding (see section Fertility, pregnancy and breastfeeding).

Hypoglycaemia :

This treatment will only be prescribed if the patient is likely to eat regularly (including having breakfast). It is important to take carbohydrates regularly, as the risk of hypoglycaemia is increased in cases of late meals, insufficient food intake or food low in carbohydrates. Hypoglycaemia may occur particularly during a low-calorie diet, after strenuous or prolonged exercise, after alcohol intake, or when an association of hypoglycaemic agents is administered.

Hypoglycaemia may occur after administration of hypoglycaemic sulfonamides (see section Adverse effects). Some episodes may be severe and prolonged. Hospitalisation may then prove necessary, and glucose intake may need to be continued over several days.

Careful selection of patients, the dose used and adequate patient information are necessary to reduce the risk of hypoglycaemia.

Factors favouring the risk of hypoglycaemia:

• Refusal or inability of the patient to cooperate (particularly in elderly subjects);

• Malnutrition, irregular meal times, skipped meals, fasting periods or change in diet;

• Imbalance between physical exercise and carbohydrate intake;

• Renal impairment;

• Severe hepatic impairment;

• Overdose of gliclazide;

• Certain endocrine disorders: thyroid disorders, pituitary and adrenal insufficiency and adrenal insufficiency;

• Concomitant administration of other medicinal products (see section Interactions).

Renal and hepatic impairment: the pharmacokinetics and/or pharmacodynamics of gliclazide may be modified in patients with hepatic impairment or severe renal impairment. In these patients, hypoglycaemia may be prolonged, and appropriate management must be instituted.

Patient information:

The risks of hypoglycaemia, its symptoms (see section Adverse effects), its treatment, and the conditions predisposing to it must be explained to the patient and their family.

The patient must be informed in particular of the importance of adhering to the diet, the need to perform regular physical exercise, and of regularly monitoring blood glucose.

Glycaemic imbalance:

The glycaemic balance of a patient treated with an oral antidiabetic may be modified if the following events occur: concomitant administration of preparations based on St John's Wort (Hypericum perforatum) (see section Interactions), fever, trauma, infection or surgical intervention.

In certain cases, it may be necessary to resort to insulin.

The hypoglycaemic efficacy of any oral antidiabetic agent, including gliclazide, may diminish over time in many patients: this may be related to worsening of diabetes or to a decrease in response to treatment. This phenomenon is called secondary failure to distinguish it from primary failure, in which the medicine is ineffective from the first use. Before classifying a patient as a secondary failure, possibilities of adjusting the dose and monitoring the diet should be evaluated.

Dysglycaemia:

Disturbances of blood glucose, including hypoglycaemia and hyperglycaemia, have been reported in diabetic patients receiving concomitant treatment with fluoroquinolones, particularly in elderly patients. Therefore, careful monitoring of blood glucose is recommended in all patients receiving GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet concomitantly with a fluoroquinolone.

Laboratory tests:

Measurement of glycated haemoglobin (or fasting blood glucose) is recommended to assess glycaemic control. Self-monitoring of blood glucose may also be performed.

Medicinal products of the sulfonylurea class may cause haemolytic anaemia in subjects with an enzymatic deficiency in G6PD (glucose-6-phosphate dehydrogenase). As gliclazide belongs to this class, precautions must be taken in patients deficient in G6PD and a treatment belonging to a therapeutic class other than sulfonylureas should be considered.

Excipients:

This medicine contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

The following products are likely to increase hypoglycaemia

Contraindicated combinations

• Miconazole (general route, buccal gel).

Increased hypoglycaemic effect with possible occurrence of hypoglycaemic manifestations, even coma.

Combinations not recommended

• Phenylbutazone (general route).

Increase in the hypoglycaemic effect of sulfonylureas (displacement of their binding to plasma proteins and/or reduction of their elimination).

Preferably use another anti-inflammatory; otherwise warn the patient and reinforce self-monitoring: adjust the dosage if necessary during treatment with the anti-inflammatory and after its discontinuation.

• Alcohol.

Increase in the hypoglycaemic reaction (inhibition of compensatory reactions), which may facilitate the occurrence of hypoglycaemic coma.

Avoid taking alcoholic beverages and medicines containing alcohol.

Associations requiring precautions for use

• Due to the increased hypoglycaemic effect, in some cases hypoglycaemia may occur during concomitant treatment with the following medicinal products:

Other antidiabetic agents (insulin, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists), beta-blockers, fluconazole, angiotensin-converting enzyme inhibitors (captopril, enalapril), H2-receptor antagonists, MAOIs, sulfonamides, clarithromycin and non-steroidal anti-inflammatory drugs.

The following products may lead to an increase in blood glucose.

Combinations not recommended

• Danazol.

Diabetogenic effect of danazol.

If the combination cannot be avoided, inform the patient and reinforce glycaemic and urinary monitoring.

Possibly adjust the dose of the antidiabetic agent during treatment with danazol and after its discontinuation.

Associations requiring precautions for use

• Chlorpromazine (neuroleptics).

At high dosages (> 100 mg per day of chlorpromazine), elevation of blood glucose (decreased insulin release).

Inform the patient and reinforce blood glucose monitoring. Possibly adjust the dose of the antidiabetic during treatment with the neuroleptic and after its discontinuation.

• Glucocorticoids (general and local routes: intra-articular, cutaneous and rectal enema) and tetracosactide.

Elevation of blood glucose, sometimes with ketosis (decreased glucose tolerance caused by corticosteroids).

Inform the patient and reinforce blood glucose monitoring, especially at the start of treatment. Possibly adjust the dose of the antidiabetic during treatment with corticosteroids and after their discontinuation.

• Ritodrine, salbutamol, terbutaline.

(IV route)

Elevation of blood glucose by beta-2 stimulants.

Reinforce blood glucose monitoring. Consider switching to insulin if necessary.

• Preparations based on St John's Wort (Hypericum perforatum)

Exposure to gliclazide is decreased by St John's Wort (Hypericum perforatum), hence the importance of monitoring blood glucose.

The following products may cause dysglycaemia.

Associations requiring precautions for use

• Fluoroquinolones.

In case of concomitant use of GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet with a fluoroquinolone, the patient must be warned of the risk of dysglycaemia and blood glucose monitoring must be reinforced.

Associations to be taken into account

• Anticoagulants (warfarin….).

Sulfonylurea hypoglycaemic agents may lead to an increase in the anticoagulant effect during treatment.

An adjustment of the anticoagulant dose may be necessary.

Pregnancy

There are no data or limited data (fewer than 300 pregnancies) on the use of gliclazide in pregnant women; few data exist with other sulfonylureas.

In animals, gliclazide is not teratogenic (see section Preclinical safety).

As a precaution, it is preferable to avoid using gliclazide during pregnancy.

Diabetes control should be achieved before conception in order to reduce the risk of congenital malformations due to poorly controlled diabetes.

During pregnancy, oral antidiabetics are not appropriate; insulin is then the treatment of choice for diabetes. It is recommended to switch from oral antidiabetics to insulin when pregnancy is planned or as soon as it is discovered.

Breast-feeding

The excretion of gliclazide or its metabolites in breast milk is not known. Given the risk of neonatal hypoglycaemia, gliclazide is therefore contraindicated in women who are breastfeeding.

A risk in the newborn/infant cannot be excluded.

Fertility

No effect on fertility or reproduction has been observed in male and female rats (see section Preclinical safety).

GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet has no effect or negligible effect on the ability to drive vehicles and use machines. However, patients should be made aware of the symptoms of hypoglycaemia and should be careful when driving and/or using machines, especially at the start of treatment.

Based on clinical experience with gliclazide, the following adverse effects have been reported:

Hypoglycaemia

The most frequent adverse effect with gliclazide is hypoglycaemia.

As with other hypoglycaemic sulfonylureas, treatment with GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet may cause hypoglycaemia, particularly in cases of meals taken at irregular intervals or when a meal is skipped.

Possible symptoms are: headache, intense hunger, nausea, vomiting, fatigue, sleep disturbances, agitation, aggressiveness, decreased concentration, alertness and reactions, depression, confusion, visual disturbances and speech disturbances, aphasia, tremors, paresis, sensory disturbances, dizziness, feeling of helplessness, loss of self-control, delirium, convulsions, shallow breathing, bradycardia, drowsiness, loss of consciousness or even coma, which may lead to a fatal outcome.

On the other hand, signs of adrenergic counter-regulation may be observed: hyperhidrosis, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina and cardiac arrhythmia.

Symptoms generally disappear after taking carbohydrates (sugars). In contrast, artificial sweeteners have no effect. Experience with other hypoglycaemic sulfonylureas shows that, despite initially effective measures, hypoglycaemia may recur.

In case of severe or prolonged hypoglycaemia, even if temporarily controlled by sugar intake, immediate medical treatment or even hospitalisation may be necessary.

Other adverse effects

Gastrointestinal disorders such as abdominal pain, nausea, vomiting, dyspepsia, diarrhoea, constipation have been reported; they may be avoided or reduced if the treatment is taken during breakfast.

The following adverse effects have been reported less frequently:

• Mucocutaneous eruptions : rash, pruritus, urticaria, angioedema, erythema, maculopapular eruptions, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis), and exceptionally, DRESS syndrome (drug rash with eosinophilia and systemic symptoms).

• Haematological disorders : these are rare and include anaemia, leukopenia, thrombocytopenia, granulocytopenia. These abnormalities are generally reversible upon discontinuation of treatment.

• Hepatobiliary disorders : elevation of liver enzymes (AST, ALT, alkaline phosphatases), hepatitis (isolated cases). Discontinue treatment if cholestatic jaundice occurs. As a general rule, these symptoms regress upon discontinuation of treatment.

• Visual disorders : transient visual disturbances due to variations in blood glucose may occur, particularly at the initiation of treatment.

Class effects:

As with other hypoglycaemic sulfonylureas, the following adverse effects have been observed: erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatraemia, increased liver enzyme levels, hepatic insufficiency (cholestasis and jaundice) or even hepatitis, which regressed upon discontinuation of treatment; only a few cases led to hepatic insufficiency with life-threatening prognosis.

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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/ .

An overdose of sulfonylureas can cause hypoglycaemia.

Moderate symptoms of hypoglycaemia, without loss of consciousness or neurological signs, must absolutely be corrected by carbohydrate intake, an adjustment of the dosage and/or a change in diet. Close monitoring must be continued by the physician until the patient is out of danger.

Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and constitute a medical emergency requiring immediate hospitalisation of the patient.

If hypoglycaemic coma is diagnosed or suspected, the patient must receive a rapid intravenous injection of 50 mL of a concentrated glucose solution (20 to 30%), followed by a continuous infusion of more dilute glucose solution (at 10%) at the rate necessary to maintain blood glucose above 1 g/L.

Close monitoring of the patient will be instituted and reinforced if necessary by the physician according to the patient's condition.

Due to the strong protein binding of gliclazide, dialysis is not necessary.

Pharmacotherapeutic class: hypoglycaemic sulfonylurea – urea derivative, ATC code: A10BB09

Mechanism of action

Gliclazide is a hypoglycaemic sulfonylurea, an oral antidiabetic agent, possessing a nitrogen-containing heterocycle with endocyclic linkage, which distinguishes it from other sulfonylureas. Gliclazide lowers blood glucose by stimulating insulin secretion from the beta cells of the islets of Langerhans. The increase in insulin and C-peptide secretion that follows a meal persists after 2 years of treatment.

In addition to these metabolic properties, gliclazide has haemovascular properties.

Clinical efficacy and safety

Effects on insulin release

In type 2 diabetics, in the presence of glucose, gliclazide restores the early peak of insulin secretion and increases the second phase of insulin secretion. A significant increase in the insulin response is observed in response to a meal or glucose intake.

Haemovascular properties

Gliclazide reduces the microthrombosis process through two mechanisms that may be involved in the complications of diabetes:

• a partial inhibition of platelet aggregation and adhesiveness as well as a decrease in platelet activation markers (beta-thromboglobulin, thromboxane B2);

• an action on the fibrinolytic activity of the vascular endothelium with an increase in t-PA activity.

Absorption

After oral administration, the plasma concentration increases progressively until the 6th hour to reach a plateau between the 6th and the 12th hour.

Intra-individual variations are small.

Absorption of gliclazide is complete. Food intake changes neither the rate nor the extent of absorption.

Distribution

Plasma protein binding is approximately 95 %. The volume of distribution is approximately 30 litres. A single daily dose of GLICLAZIDE ZYDUS FRANCE 60 mg, modified-release tablet, maintains an effective plasma concentration of gliclazide for 24 hours.

Biotransformation

Gliclazide is mainly metabolised in the liver. Excretion is essentially urinary; less than 1% is found unchanged in the urine. No circulating active metabolite has been detected.

Elimination

The elimination half-life of gliclazide is 12 to 20 hours.

Linearity/non-linearity

Up to the dose of 120 mg, there is a linear relationship between the administered dose and the area under the concentration curve (AUC).

Special populations

Elderly patients

In elderly subjects, no clinically significant change in pharmacokinetic parameters has been observed.

Pre-clinical data, based on chronic toxicity and genotoxicity studies, revealed no risk for humans. No long-term carcinogenicity study has been carried out.

No teratogenic effect has been reported in animals; only a decrease in foetal weight was observed in animals given doses 25 times higher than the maximum recommended dose in humans. In studies carried out in animals, administration of gliclazide had no impact on fertility and reproduction.

2 years.

This medicine does not require any particular storage precautions.

No special requirements for disposal.

List I

Marketing authorisation (AMM)

CIP 3400930178669 (Plq/30). CIP 3400930178676 (Plq/90).

Price:

2,92 euros (Plq/30). 8,22 euros (Plq/90).

Social Security reimbursement at 65% based on the TFR: 2.92 euros (Plq/30), 8.22 euros (Plq/90) in the indications:

• Indication(s) listed in the marketing authorisation (AMM) on the date of publication of this decree (Plq/30, Plq/90)

Collection.