- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe daily dose of Laaglyda MR may vary from 30 to 120 mg taken orally in a single intake at breakfast time. If a dose is forgotten, there must be no increase in the dose taken next day. As with any hypoglycaemic agent, the dose should be adjusted according to the individual patient's metabolic response (blood glucose, HbAlc).Initial doseThe recommended initial 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.One Laaglyda MR 60 mg modified-release tablet corresponds to two Laaglyda MR 30 mg modified-release tablets.
Switching from gliclazide (80 mg) tablets (immediate release formulation) to Laaglyda MR 60 mg tablets with modified releaseOne tablet of gliclazide (80 mg) is comparable to one modified-release tablet 30 mg. Consequently, the switch can be performed with careful blood monitoring.
Switchover from another oral antidiabetic medicinal product to Laaglyda MR 60 mg:Laaglyda MR modified-release tablets can be used to replace another oral antidiabetic medicinal product.The dosage and the half-life of the previous antidiabetic agent should be taken into account when switching to Laaglyda MR 60 mg modified 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 a hypoglycaemic sulphonylurea 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 Laaglyda MR modified release tablets, i.e. a starting dose of 30 mg/day, followed by a stepwise increase in dose, depending on the metabolic response.
Combination with other antidiabetic medicinesLaaglyda MR modified-release tablets can be given in combination with biguanides, alpha-glucosidase inhibitors or insulin. In patients not adequately controlled with Laaglyda MR 60 mg modified-release tablets, concomitant insulin therapy can be initiated under close medical supervision.Special populations
ElderlyLaaglyda MR modified-release tablets should be prescribed using the same dosing regimen recommended for patients under 65 years of age.
Patients with renal impairmentIn patients with mild to moderate renal impairment 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 undernourishment or malnourishment, severe or poorly compensated endocrine disorders (hypopituitarism, hypothyroidism, adrenocorticotrophic insufficiency), withdrawal of a prolonged and/or high-dose corticoid therapy, severe vascular disease (serious coronary heart disease, severe carotid impairment, diffuse vascular disease).It is recommended that the minimum daily dose of 30 mg is used.
Paediatric populationThe safety and efficacy of Laaglyda MR in children and adolescents have not been established.No data are available in children.
Method of administrationLaaglyda MR is to be taken as a single dose at breakfast time.It is recommended that the tablet(s) is swallowed whole.
Renal and hepatic insufficiencyThe 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 informationThe risk 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 sugar controlsThe 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 testsMeasurement of glycated haemoglobin levels (or fasting venous plasma glucose) is recommended in assessing blood glucose control. Blood-glucose self-monitoring may also be useful.Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since gliclazide belongs to the chemical class of sulfonylurea drugs, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.
Other ingredientsLaaglyda MR modified release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
1) The following medicines can increase the risk of hypoglycaemia:
Contraindicated combinationMiconazole (systemic route, oromucosal gel): increases the hypoglycaemic effect with possible onset of hypoglycaemic symptoms, or even coma.
Combinations which are not recommendedPhenylbutazone (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. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with the anti-inflammatory agent.Alcohol: increases in the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Alcohol and alcoholic medicinal products should be avoided.
Combinations requiring precautions for usePotentiation of the blood glucose lowering effect and thus in some instances hypoglycaemia may also occur when one of the following medicinal products is taken:other antidiabetics (insulins, acarbose, metformin, thiazolidinediones, dipeptidylpeptidase-4 inhibitors, GLP-1 receptor agonists), beta blockers, fluconazole, ACE inhibitors (captopril, enalapril), H2-receptor antagonists, MAO inhibitors, sulphonamides, clarithromycin and non-steroidal anti-inflammatory agents.2) The following medicinal products may cause an increase in blood glucose levels:
Combination which is not recommendedDanazol: diabetogenic effect of danazol.If the use of this active substance cannot be avoided the patient must be warned and informed of the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of the antidiabetic active substance during and after treatment with danazol.
Combinations requiring precautions during useChlorpromazine (neuroleptic agent): High doses (>100 mg per day of chlorpromazine) increase in blood glucose levels (reduction of insulin release).The patient must be warned and informed of 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 the glucocorticoids). The patient must be warned and informed of 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 sugar level due to beta-2-agonist effects. The patient must be informed of the importance of blood glucose monitoring. A switch to insulin treatment may be necessary.3) Combination which has to be taken into account:Anticoagulant therapy (e.g. warfarin, etc.):Sulphonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the dose of the anticoagulant may be necessary.
PregnancyThere 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.
Breast-feedingIt is not known whether gliclazide or its metabolites is excreted into breast milk. Given the risk of neonatal hypoglycaemia the product is contraindicated in breast-feeding mother.
HypoglycaemiaAs with other sulphonylureas, treatment with Laaglyda MR modified-release tablets can commonly cause hypoglycaemia if meals are taken irregularly, and, in particular, if they 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 the 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.
Other undesirable effects
Gastrointestinal disordersGastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation are uncommon; 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 disordersRash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis);
Blood and lymphatic system disordersChanges in haematology are rare. They may include anaemia, leucopenia, thrombocytopenia and granulocytopenia. These are generally reversible upon discontinuation of the medication.
Hepatobiliary disordersRaised hepatic enzyme levels (AST, ALT, alkaline phosphatase), hepatitis (isolated reports); Discontinuation of therapy if cholestatic jaundice appears.These undesirable effects normally disappear after discontinuation of treatment.
Eye disordersTransient visual disturbances may occur, especially on initiation of treatment, due to changes in blood glucose levels.
Class attribution effectsAs for other sulphonylureas, the following undesirable effects 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 sulphonylurea or led to life-threatening liver failure in isolated cases.
Effects on insulin releaseIn 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 propertiesGliclazide 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.
AbsorptionPlasma 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.
DistributionPlasma protein binding is approximately 95%. The volume of distribution is around 30 litres. A single daily intake of Laaglyda MR modified-release tablets maintains effective gliclazide plasma concentrations over 24 hours.
BiotransformationGliclazide 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.
EliminationThe elimination half-life of gliclazide is between 12 and 20 hours.
Linearity/non-linearityThe relationship between the dose administered ranging up to 120 mg and the area under the concentration-time curve is linear.Special populations
ElderlyNo clinically relevant changes in the pharmacokinetic parameters have been observed in elderly patients.
Consilient Health Ltd
No. 1 Church Road, Richmond upon Thames, Surrey, TW9 2QE, UK
+44(0)20 3751 1889
+44(0) 20 3751 1888