Diamicron/Diamicron MR 60

Gliclazide.

Diamicron: Each tablet contains Gliclazide 80 mg.
Diamicron MR: One modified release tablet contains gliclazide 60 mg.
Excipient with known effect: Lactose monohydrate.

Pharmacology: Pharmacodynamics: Gliclazide reduces blood glucose by stimulating insulin secretion from the β-cells in the islets of Langerhans.
Pharmacodynamic effects: 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.
Hemo-vascular 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.
Diamicron MR 60: Mechanism of action: Gliclazide is a hypoglycemic sulfonylurea oral antidiabetic active substance differing from other related compounds by an N-containing heterocyclic ring with an endocyclic bond.
Increase in postprandial insulin and C-peptide secretion persists after two years of treatment.
In addition to these metabolic properties, gliclazide has hemovascular properties.
Pharmacokinetics: Diamicron: Gliclazide is rapidly absorbed from the gastrointestinal tract, and the concentration in the blood reaches a maximum 11-14 hours after administration.
In humans, binding to proteins is 94.2%.
As the apparent terminal elimination half-life for gliclazide is 20 hours in humans, the drug can be administered in two daily doses.
Elimination is mainly in the urine: less than 1% of the dose ingested is found unchanged in the urine.
Diamicron MR 60: Absorption: Plasma 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.
Distribution: Plasma protein binding is approximately 95%. The volume of distribution is around 30 liters.
A single daily intake of GLICLAZIDE (DIAMICRON MR) 60 mg maintains effective gliclazide plasma concentrations over 24 hours.
Biotransformation: Gliclazide is mainly metabolized 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.
Elimination: The elimination half-life of gliclazide varies between 12 and 20 hours.
Linearity/non-linearity: The relationship between the dose administered ranging up to 120 mg and the area under the concentration time curve is linear.
Special populations: Elderly: No clinically significant changes in pharmacokinetic parameters have been observed in elderly patients.

For non-insulin-dependent diabetes (type 2) in adults, in association with dietary measures and with exercise, when these measures alone are not sufficient.

Diamicron: Restricted to adults.
As with any hypoglycemic agent, the dosages should be adjusted to the particular circumstances.
In the event of a transitory loss of blood glucose control in a patient where good control is usually achieved by diet, it may be sufficient to administer this product for a short period.
Patients under the age of 65: Initial dose: The recommended initial dose is one tablet per day.
Dosage steps: Adjustments in posology are usually made in steps of one tablet at a time, depending on the response in blood glucose. At least 14 days should separate successive steps in the dose.
Maintenance treatment: The posology can vary from 1 to 3, or rarely 4, tablets per day.
The usual posology is 2 tablets a day, as 2 daily doses.
Patients at particular risk: Patients over the age of 65: Begin the treatment with a half-tablet once a day.
The dose can be progressively increased until the patient's blood glucose is satisfactorily controlled, while keeping to steps of at least 14 days between successive levels, and with close monitoring of blood glucose.
Other patients at particular risk: In patients who are malnourished or showing markedly poor general state of health, or whose calorie intake is irregular, or whose kidney or liver function is impaired, treatment should be begun at the lowest dose. The stepwise increases in dosage must be scrupulously adhered to in order to avoid a hypoglycemic reaction.
Patients treated with other oral hypoglycemic agents: As with any sulfonylurea, this medicinal product can be used as follow-on from another antidiabetic drug, without any transitional period being needed. When patients change to this medication from a sulfonylurea with a longer half-life (such as chlorpropamide), they must be closely monitored (for several weeks). This is to avoid the possible occurrence of hypoglycemia due to an overlapping of effects from the two treatments.
Pediatric population: The safety and efficacy of Gliclazide (Diamicron) 80 mg in children and adolescents have not been established. No data are available.
Method of administration: Oral route.
Missed Dose: Take one tablet with the next meal. Do not take a double dose to compensate the single dose the patient has forgotten to take.
Diamicron MR 60: The daily dose of GLICLAZIDE (DIAMICRON MR) 60 mg may vary from one half to 2 tablets per day, i.e. from 30 to 120 mg taken orally in a single intake at breakfast time.
It is recommended to swallow the dose without crushing or chewing.
If a dose is forgotten, there must be no increase in the dose taken the next day.
As with any hypoglycemic 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 [half a tablet of GLICLAZIDE (DIAMICRON MR) 60 mg. 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 GLICLAZIDE (DIAMICRON MR) 60 mg modified-release tablet is equivalent to two Gliclazide (Diamicron MR) 30 mg modified-release tablets. The breakability of the GLICLAZIDE (DIAMICRON MR) 60 mg modified-release tablet enables flexibility of dosing to be achieved.
Switching from Gliclazide (Diamicron) 80 mg tablets to GLICLAZIDE (DIAMICRON MR) 60 mg modified-release tablets: One tablet of Gliclazide (Diamicron) 80 mg tablet is comparable to 30 mg of the modified release formulation (i.e. half a tablet of DIAMICRON 60 mg.) Consequently, the switch can be performed with careful blood monitoring.
Switching from another oral antidiabetic agent to GLICLAZIDE (DIAMICRON MR) 60 mg: GLICLAZIDE (DIAMICRON MR) 60 mg 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 GLICLAZIDE (DIAMICRON MR) 60 mg.
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 hypoglycemic sulfonylurea 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 hypoglycemia. The procedure described for initiating treatment should also be used when switching to treatment with GLICLAZIDE (DIAMICRON MR) 60 mg, i.e. 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: GLICLAZIDE (DIAMICRON MR) 60 mg can be given in combination with biguanides, alpha glucosidase inhibitors or insulin.
In patients not adequately controlled with GLICLAZIDE (DIAMICRON MR) 60 mg, concomitant insulin therapy can be initiated under close medical supervision.
Special Populations: Elderly: GLICLAZIDE (DIAMICRON MR) 60 mg should be prescribed using the same dosing regimen recommended for patients under 65 years of age.
Renal impairment: In patients with mild to moderate renal insufficiency, 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 hypoglycemia: 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.
Pediatric population: The safety and efficacy of GLICLAZIDE (DIAMICRON MR) 60 mg in children and adolescents have not been established. No data are available.
Missed Dose: It is important to take the medicine everyday as regular treatment works better.
However, if the patient forgets to take a dose of GLICLAZIDE (DIAMICRON MR) 60 mg, take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose.
Discontinuation of Treatment: As the treatment for diabetes is usually life long, the patient should discuss with the doctor before stopping this medicinal product.
Stopping could cause high blood sugar (hyperglycemia) which increases the risk of developing complications of diabetes. If the patient has any further questions on the use of this product, ask the doctor or pharmacist.

An overdose of sulfonylurea drugs may cause hypoglycemia.
Moderate symptoms of hypoglycemia, 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 hypoglycemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as a medical emergency, requiring immediate hospitalization.
If hypoglycemic 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.

This medicinal product is contraindicated in cases of: Hypersensitivity to gliclazide or to any of the excipients, other sulfonylureas, sulfonamides; type 1 diabetes; diabetic pre-coma and coma, diabetic keto-acidosis; severe renal or hepatic insufficiency: in these cases the use of insulin is recommended; treatment with miconazole; lactation.

Hypoglycemia: 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 hypoglycemia if a meal is taken late, if an inadequate amount of food is consumed or if the food is low in carbohydrate. Hypoglycemia is more likely to occur during low-calorie diets, following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycemic agents is being used.
Hypoglycemia may occur following administration of sulfonylurea. Some cases may be severe and prolonged. Hospitalization 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 hypoglycemic episodes.
Factors which increase the risk of hypoglycemia: patient refuses or is unable to co-operate (particularly in elderly subjects); 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 (Diamicron/Diamicron MR 60); certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency; concomitant administration of other medicinal products.
Renal and hepatic insufficiency: The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic insufficiency or severe renal failure. If hypoglycemia occurs in such patients, it can be prolonged, and appropriate management must be initiated.
Information for the patient: The risks of hypoglycemia, together with its symptoms, treatment, and conditions that predispose to its development, should be explained to patients 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.
Blood sugar imbalance: Blood glucose control in a patient receiving oral antidiabetic treatment may be affected by any of the following: St. John's Wort (Hypericum perforatum) preparations, fever, injury, infection or surgery.
In some cases, it may be necessary to administer insulin.
The hypoglycemic 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.
Dysglycemia: Disturbances in blood glucose, including hypoglycemia and hyperglycemia have been reported in diabetic patients receiving concomitant treatment with fluoroquinolones, especially in elderly patients. Indeed, careful monitoring of blood glucose is recommended in all patients receiving at the same time Gliclazide (Diamicron/Diamicron MR 60) and a fluoroquinolone.
Laboratory tests: Measurement of glycated hemoglobin 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 (glucose-6-phosphate dehydrogenase deficiency) with sulfonylurea agents can lead to hemolytic anemia. 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.
Porphyric patients: Cases of acute porphyria have been described with some other sulfonylurea drugs, in patients who have porphyria.
Excipients: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Driving and using machines: Gliclazide (Diamicron/Diamicron MR 60) has no or negligible influence on the ability to drive and use machines. However, patients should be made aware of the symptoms of hypoglycemia and should be careful if driving or operating machinery, especially at the beginning of treatment.

Pregnancy: There is no or limited amount of data (less than 300 pregnancy outcomes) from the use of gliclazide in pregnant women, even though there are few data with other sulfonylurea.
In animal studies, gliclazide is not teratogenic.
As a precautionary measure, it is preferable to avoid the use of Gliclazide during pregnancy.
Control of diabetes should be obtained before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes.
Oral hypoglycemic agents are not suitable, insulin is the drug of first choice for treatment of diabetes during pregnancy. It is recommended that oral hypoglycemic therapy is changed to insulin before a pregnancy is attempted, or as soon as pregnancy is discovered.
Breastfeeding: It is not known whether gliclazide or its metabolites are excreted in breast milk. Given the risk of neonatal hypoglycemia, the product is therefore contraindicated in breastfeeding mother.
A risk to the newborns/infants cannot be excluded.
Diamicron: Fertility: No effect on fertility or reproductive performance was noted in male and female rats.

Based on the experience with gliclazide, the following undesirable effects have been reported.
Hypoglycemia: The most frequent adverse reaction with gliclazide is hypoglycemia.
As for other sulfonylureas, treatment with Gliclazide (Diamicron) can cause hypoglycemia, in particular if mealtimes are irregular and if meals are skipped.
Possible symptoms of hypoglycemia 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 hypoglycemia can recur even when measures prove effective initially.
If a hypoglycemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalization are required.
Other undesirable effects: Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation have been reported: if these should occur they can be avoided or minimized if gliclazide is taken with a meal or by splitting the doses.
The following undesirable effects have been more rarely reported: Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis), and exceptionally, drug rash with eosinophilia and systemic symptoms (DRESS).
Blood and lymphatic system disorders: changes in hematology are rare. They may include anemia, leucopenia, thrombocytopenia, granulocytopenia. 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: As for other sulfonylureas, the following adverse events have been observed: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, 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 sulfonylurea or led to life-threatening liver failure in isolated cases.
Diamicron MR 60: Skin and subcutaneous tissue disorders: autoimmune bullous disorders.
Reporting of Adverse Drug Reaction: Seek medical attention immediately at the first sign of any adverse drug reaction.

The following substances can increase hypoglycemia: Combination contraindicated: Miconazole (systemic route, oromucosal gel): Increases the hypoglycemic effect with possible onset of hypoglycemic symptoms, or even coma.
Combinations which are not recommended: Phenylbutazone (systemic route): Increases the hypoglycemic 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 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: Consumption of alcoholic drinks and of medicinal products containing alcohol should be avoided.
Increases hypoglycemic reaction (due to inhibition of compensating reactions), that can lead to the onset of hypoglycemic coma.
Diamicron:"Antabuse effect", in particular with chlorpropamide, glibenclamide, glipizide and tolbutamine.
Combinations requiring precautions for use: Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur when one of the following drugs is taken: Other antidiabetic agents (insulin, acarbose, metformin, thiazolidinediones, dipeptidylpeptidase-4 inhibitors, GLP-1 receptor agonists), beta-blockers, fluconazole, angiotensin converting enzyme inhibitor (captopril, enalapril), H2-receptor antagonists, MAOIs, sulfonamides, clarythromycin and non-steroidal 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 per 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 route and local route: intraarticular use, cutaneous or rectal preparations) and tetracosactide: 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 (I.V.): Increased blood glucose levels due to beta-2 agonist effects. Emphasize the importance of monitoring blood glucose levels. If necessary, switch to insulin.
Saint John's Wort (Hypericum perforatum) preparations: Gliclazide exposure is decreased by Saint John's Wort (Hypericum perforatum). Emphasize the importance of blood glucose levels monitoring.
The following products may cause dysglycemia: Combinations requiring precautions during use: Fluoroquinolones: In case of concomitant use of Gliclazide (Diamicron/Diamicron MR 60) and a fluoroquinolone, the patient should be warned of the risk of dysglycemia, and the importance of blood glucose monitoring should be emphasized.
Combinations which must be taken into account: Anticoagulant therapy (warfarin): Sulfonylureas may lead to potentiation of anticoagulation during treatment.
Adjustment of the anticoagulant posology may be necessary.

Diamicron MR 60: Special Precautions for Disposal: No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store at temperature not exceeding 30°C.
Diamicron: Do not use Gliclazide (Diamicron) 80 mg if the patient notes signs of deterioration on the packaging or on blisters.

Antidiabetic Agents

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

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