Diamicron MR 60 mg

Gliclazide.

Excipients/Inactive Ingredients: Lactose monohydrate, maltodextrin, hypromellose, magnesium stearate, anhydrous colloidal silica.

Pharmacotherapeutic Group: Sulfonamides, urea derivatives. ATC Code: A10BB09.
Pharmacology: Pharmacodynamics: Gliclazide is a hypoglycaemic sulfonylurea oral 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 β-cells of the islets of Langerhans. Increase in postprandial insulin and C-peptide secretion persists after 2 years of treatment.
In addition to these metabolic properties, gliclazide has haemovascular properties.
Effects on Insulin Release: In type 2 diabetics, gliclazide restores the 1st peak of insulin secretion in response to glucose and increases the 2nd 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 2 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 (β-thromboglobulin, thromboxane B₂); an action on the vascular endothelium fibrinolytic activity with an increase in t-PA activity.
Pharmacokinetics: Plasma levels increase progressively during the first 6 hrs, reaching a plateau which is maintained from the 6th-12th hr after administration.
Intra-individual variability is low.
Gliclazide is completely absorbed. Food intake does not affect the rate or degree of absorption.
The relationship between the dose administered ranging up to 120 mg and the area under the concentration time curve is linear.
Plasma protein-binding is approximately 95%.
Gliclazide 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.
The elimination half-life of gliclazide varies between 12 and 20 hrs.
The volume of distribution is around 30 L.
No clinically significant changes in pharmacokinetic parameters have been observed in elderly patients.
A single daily intake of Diamicron MR 60 mg scored tablet maintains effective gliclazide plasma concentrations over 24 hrs.
Toxicology: 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 foetal body weight was observed in animals receiving doses 25-fold higher than the maximum recommended dose in humans.

Non-insulin-dependent diabetes (type 2) in adults when dietary measures, physical exercise and weight loss are not sufficient to control blood glucose.

Diamicron: Standard Dosage: 2 tabs/day in 2 daily doses. As with all hypoglycaemic agents, the dosage must be adapted to suit each individual case. If the patient feels that the effect of Diamicron is too strong or too weak, consult the doctor or pharmacist.
Diamicron MR: 30 mg Tablet: Adults: Usual Daily Dose: 1-4 tabs/day as a single dose. It is recommended that the drug be taken at breakfast.
60 mg Scored Tablet: Adults: The daily dose of Diamicron MR 60 mg scored tablet may vary from ½-2 tabs/day ie, from 30-120 mg taken orally in a single intake at breakfast time.
As with any hypoglycaemic agent, the dose should be adjusted according to the individual patient's metabolic response (blood glucose, HbA1c).
Initial Dose: The recommended starting dose is 30 mg daily (½ tab Diamicron MR 60 mg scored tablet). 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 2 weeks of treatment. In such cases, the dose may be increased at the end of the 2nd week of treatment.
The maximum recommended daily dose is 120 mg.
One (1) Diamicron MR 60 mg modified-release scored tablet is equivalent to 2 Diamicron MR 30 mg modified-release tablets. The breakability of the Diamicron MR 60 mg modified-release scored tablet enables flexibility of dosing to be achieved.
Switching from Diamicron 80 mg Tablets to Diamicron MR 60 mg Modified-Release Scored Tablets: 1 tab Diamicron 80 mg is comparable to 30 mg of the modified-release formulation (ie, ½ tab Diamicron MR 60 mg scored tablet). Consequently, the switch can be performed with careful blood monitoring.
Switching from Another Oral Antidiabetic Agent to Diamicron MR 60 mg Score Tablet: Diamicron MR 60 mg Scored Tablet can be used to replace other oral antidiabetic agents. The dosage and the half-life of the previous antidiabetic agent should be taken into account when switching to Diamicron MR 60 mg scored tablet.
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 previously.
When switching from a hypoglycaemic sulfonylurea with a prolonged half-life, a treatment-free period of a few days may be necessary to avoid an additive effect of the 2 products, which might cause hypoglycaemia. The procedure described for initiating treatment should also be used when switching to treatment with Diamicron MR 60 mg scored tablet ie, a starting dose of 30 mg/day, followed by a stepwise increase in dose, depending on the metabolic response.
Combination Treatment with Other Antidiabetic Agents: Diamicron MR 60 mg scored tablet can be given in combination with biguanides, α-glucosidase inhibitors or insulin.
In patients not adequately controlled with Diamicron MR 60 mg scored tablet, concomitant insulin therapy can be initiated under close medical supervision.
In the elderly (>65 years), Diamicron MR 60 mg scored tablet should be prescribed using the same dosing regimen recommended for patients <65 years.
In patients with mild to moderate renal insufficiency (GFR=60-89 and 30-59 mL/min/1.73 m², respectively), 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, with treatment up to 10 months.
Patients at Risk of Hypoglycaemia: Undernourished or malnourished; severe or poorly compensated endocrine disorders (hypopituitarism, hypothyroidism, adrenocorticotrophic insufficiency); withdrawal of prolonged and/or high-dose corticosteroid therapy; severe vascular disease (severe coronary heart disease, severe carotid impairment, diffuse vascular disease).
It is recommended that the minimum daily starting dose of 30 mg is used.
There are no data and clinical studies available in children.
Administration: The tablets must be taken whole with half a glass of water just before breakfast.
It is recommended to swallow the dose of Diamicron MR without crushing or chewing.
It is preferable to take Diamicron MR before breakfast in order to avoid or to minimise the possible onset of digestive disorders.
Frequency of Administration: The once-daily administration of Diamicron MR must always be followed by a meal.
If a dose is forgotten, take 1 tab with the next meal. Do not take a double dose to compensate the single dose that has been forgotten. There must be no increase in the dose taken the next day.

An overdose of sulfonylurea 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 IV injection of 50 mL of concentrated glucose solution (50%). This should be followed by continuous infusion of a more dilute glucose solution (10%) at a rate that will maintain normal blood glucose levels. 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.

Known hypersensitivity to gliclazide or to any of the excipients of Diamicron MR, to other medicines of the same group (sulfonylureas) and sulfonamides; insulin-dependent diabetes (type 1); diabetic ketoacidosis, diabetic precoma and coma; severe renal or hepatic insufficiency (in these cases, the use of insulin is recommended); treatment with miconazole (see Interactions).
It is generally inadvisable to combine Diamicron MR with phenylbutazone, danazol and alcohol (see Interactions).
Use in Lactation: It is not known whether gliclazide or its metabolites are excreted in breast milk. Given the risk of neonatal hypoglycaemia, Diamicron MR is contraindicated in breastfeeding mother.

Hypoglycaemia: Diamicron/Diamicron MR is susceptible to cause episodes of hypoglycaemia. In the case of sweating, intense hunger, trembling, pallor, visual disturbances, feeling of malaise and abnormal behaviour, immediately eat sugar or something containing sugar and inform the doctor.
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 sulfonylurea (see Adverse Reactions). 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, dose used and clear patient directions are necessary to reduce the risk of hypoglycaemic episodes.
In consequence, treatment with a hypoglycaemic sulfonylurea requires: Regular Diet: It is important to eat regular meals, including breakfast, never to miss a meal, due to an increase in the risk of the onset of hypoglycaemia caused by an inadequate diet or a sugar imbalance.
Precise Regularity in the Administration of Treatment: It is important to take treatment regularly, once a day, preferably at breakfast (see Dosage & Administration).
Every administration of Diamicron MR must be followed by a meal.
Glycaemic Imbalance: In the case of surgery, trauma, fever or infection, the doctor may discontinue treatment with Diamicron/Diamicron MR and prescribe insulin.
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 Diamicron MR 60 mg scored tablet; certain endocrine disorders (thyroid disorders, hypopituitarism and adrenal insufficiency); concomitant administration of certain other medicinal products (see Interactions).
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 1st-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.
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 nonsulfonylurea alternative should be considered.
Excipients: Diamicron MR 60 mg scored tablet should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
If the treatment is discontinued, there is a risk of an imbalance in diabetes (hyperglycaemia).
In all cases, strictly comply with the doctor's prescription.
Follow as closely as possible the diet prescribed by the doctor.
Regularly carry out the laboratory tests as prescribed or recommended by the doctor.
Inform the doctor in the following cases: Surgery, trauma, fever or infection, difficulty in eating; planned pregnancy; administration of other drugs, in particular, anti-inflammatory agents, β-blockers, corticoids.
Also inform the dentist of treatment.
Avoid alcohol and alcoholic drinks.
Effects on the Ability to Drive or Operate Machinery: Patients should be made aware of the symptoms of hypoglycaemia and should be careful when driving or operating machinery, especially at the beginning of treatment.
Use in Pregnancy: There is no experience with the use of gliclazide during pregnancy in humans, even though there are few data with other sulfonylurea. 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 1st 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.

Use in Pregnancy: There is no experience with the use of gliclazide during pregnancy in humans, even though there are few data with other sulfonylurea. 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 1st 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.
Use in Lactation: It is not known whether gliclazide or its metabolites are excreted in breast milk. Given the risk of neonatal hypoglycaemia, Diamicron MR is contraindicated in breastfeeding mother.

Based on the experience with gliclazide and with other sulfonylurea, the following undesirable effects have to be mentioned.
Hypoglycaemia: As for other sulfonylureas, treatment with Diamicron/Diamicron MR 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 sulfonylurea 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 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, angioedema, erythema, maculopapular rashes, bullous reactions eg, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Blood and Lymphatic System Disorders: Changes in haematology are rare. They may include anaemia, leucopenia, thrombocytopenia, granulocytopenia. These are in general reversible upon discontinuation of medication.
Hepatobiliary 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, pancytopenia and allergic vasculitis, hyponatremia, elevated liver enzyme levels and even impairment of liver function (eg, with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulfonylurea or led to life-threatening liver failure in isolated cases.

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 hypoglycemic effect of sulfonylurea (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 emphasize 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.
Alcohol or medicinal products containing alcohol should be avoided.
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 eg: Other antidiabetic agents (insulins, acarbose, biguanides), β-blockers, fluconazole, angiotensin-converting enzyme inhibitors (captopril, enalapril), H₂-receptor antagonists, MAOIs, sulfonamides and nonsteroidal anti-inflammatory agents.
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 emphasize 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/day of chlorpromazine) increase blood glucose levels (reduced insulin release).
Warn the patient and emphasize 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 emphasize 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 β₂-agonist effects.
Emphasize the importance of monitoring blood glucose levels. If necessary, switch to insulin.
Combination Which Must be Taken Into Account: Anticoagulant Therapy (eg, Warfarin): Sulfonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the anticoagulant may be necessary.

Diamicron MR: Store below 30°C.
Shelf-Life: 3 years (Diamicron MR).

Antidiabetic Agents

A10BB09 - gliclazide ; Belongs to the class of sulfonylureas. Used in the treatment of diabetes.

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