Information for the Patient
Diamicron
Pharmacology
DIAMICRON (gliclazide) is an hypoglycemic agent of the sulfonylurea group.
The hypoglycemic action of DIAMICRON (gliclazide) is related to an improvement in insulin secretion from the functioning beta cells of the pancreas. It potentiates the insulin release, improves the dynamics of insulin.
Hemobiological properties of DIAMICRON (gliclazide) have been observed in pharmacology studies. These are attributed to gliclazide action on the platelet behaviour, prostaglandin equilibrium and fibrinolysis.
Gliclazide is rapidly absorbed from the gastro-intestinal tract and the plasma peak of gliclazide occurs between 4 and 6 hours. In man it is highly bound to plasma proteins, about 94%. The mean elimination half-life in man approximates 10.4 hours.
Following oral administration the unchanged gliclazide in plasma is extensively metabolized with little of the unchanged compound (<1%) appearing in the urine.
Gliclazide metabolites and conjugates are primarily eliminated via kidneys: 60 to 70%, and about 10 to 20% via faeces.
Some five principal metabolites have been identified in urine, essentially oxidized and hydroxylated derivatives, some as glucuronic acid conjugates.
Indications
Control of hyperglycemia in gliclazide responsive diabetes mellitus of stable, mild, non-ketosis prone, maturity onset or adult type which cannot be controlled by proper dietary management and exercise, or when insulin therapy is not appropriate.
Precautions
Efficacy and tolerance of DIAMICRON, prescribed using the same therapeutic regimen in subjects over 65 years, has been confirmed in clinical trials. Severe hypoglycemia can be induced by all sulfonylurea drugs, particularly susceptible are elderly subjects.
As a result of drug interaction, hypoglycemia may be potentiated when a sulfonylurea is used concurrently with agents such as: long-acting sulfonamides, tuberculostatics, clarithromycin, phenylbutazone, clofibrate, monoamine oxidase inhibitors, coumarin derivatives, salicylates, non-steroidal anti-inflammatory agents, probenecid, beta-blockers, miconazole (see Contraindications), azole antifungal agents (oral and parenteral preparations), H2-receptor antagonists, disopyramide and angiotensin converting enzyme inhibitors. In addition, hypoglycaemia is potentiated when gliclazide is used in combination with other antidiabetic agents (insulin, alpha gluclosidase inhibitors, biguanides) which is not indicated.
Certain drugs tend to induce hyperglycemia and may lead to loss of control of blood sugar control. These include diuretics (thiazides, furosemide), corticosteroids and tetracosactrin, danazol, chlorpromazine, ritodrine/ salbutamol/ terbutaline (IV), oral contraceptives (estrogen plus progestogen) and nicotinic acid in pharmacologic doses.
Barbiturates should be used with caution in patients receiving an oral hypoglycemic agent since they may reduce the hypoglycemic effect.
Combination with anticoagulant therapy (warfarin and other) must be taken into account because sulfonulureas may lead to potentiation of anticoagulation during concomitant treatment. Adjustment of the anticoagulant dosage may be necessary.
Intolerance to alcohol (disulfiram-like reaction: flushing, sensation of warmth, giddiness, nausea and occasionally tachycardia) may occur in patients treated with sulfonylurea. This reaction can be prevented by avoiding the use of alcohol. Alcohol increases the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Avoid alcohol or medicines containing alcohol.
The product is contra-indicated in breast-feeding mothers. Some sulfonylurea drugs are excreted in human milk although it is not known whether DIAMICRON (gliclazide) is one of them. Because the potential for hypoglycemia in nursing infants may exist, the product is contra-indicated in breast-feeding mothers (see Contraindications).
Safety and effectiveness in children have not been established. DIAMICRON is therefore not recommended for use in children and adolescents.
Gliclazide is contraindicated in pregnancy. It is recommended that insulin be used during pregnancy in diabetic women (see Contraindications).
Uncontrolled diabetes (gestational or not) is associated with a higher incidence of congenital abnormalities and perinatal mortality. Blood glucose control should be optimal around the time of conception to reduce the risk of congenital malformations.
Measurement of glycated haemoglobin levels (or fasting venous plasma glucose) is recommended in assessing blood glucose control. Blood glucose self-monitoring is also recommended.
Blood glucose control in a patient receiving antidiabetic treatment may be affected by fever and infection or surgical intervention. Closed monitoring is required in these patients. In some cases, it may be necessary to administer insulin.
Hepatic function should be assessed before initiating therapy and the liver function should be assessed periodically in patients with impaired hepatic function.
In patients with impaired renal function, blood and urine glucose should be regularly monitored. Measurements of glycated hemoglobin levels are recommended.
Elderly patients (malnourished, with impaired hepatic, renal, or adrenal function) will require periodic monitoring and special care.
Supplied
Each scored, white tablet, breakable into four, contains: gliclazide 80 mg. Nonmedicinal ingredients: corn starch, lactose, magnesium stearate, pregelatinized corn starch and talc. Blister packs, boxes of 60.
Contraindications
Known hypersensitivity or allergy to gliclazide, other sulfonylureas, sulfonamides, or to any of the excipients of this product (for a complete listing, see Supplied). Unstable and/or insulin dependent diabetes mellitus, particularly juvenile diabetes, diabetic ketoacidosis, diabetic pre-coma and coma. During stress conditions such as serious infection, trauma or surgery. In the presence of liver disease or renal impairment. Treatment with miconazole via systemic route or oromucosal gel (see Drug Interactions). Pregnancy and lactation (see Precautions, Pregnancy and Lactation).
Warnings
The use of DIAMICRON (gliclazide) will not prevent the development of complications peculiar to diabetes mellitus.
Use of DIAMICRON (gliclazide) must be considered as treatment in addition to proper dietary regimen and not as substitute for diet.
The efficacy of gliclazide, in reducing glucose to the desired level decreases over a long period of time in many patients: this may be due to progression in the severity of the diabetes, or to a reduced response to treatment. If a loss of adequate blood glucose-lowering response to DIAMICRON (gliclazide) is detected, the drug should be discontinued.
Adverse Effects
Nausea, vomiting, diarrhea, epigastric fullness and gastric irritation can be observed. These reactions are generally dose-related and may disappear when the dose is reduced.
In post-marketing experience with gliclazide, the most frequently reported adverse drug reaction is hypoglycaemia.
The most serious adverse drug reactions reported with gliclazide are hypoglycaemic coma, pancytopenia, thrombocytopenia, hepatitis, cholestatic jaundice, pyrexia, and skin reactions (pruritus and rash).
Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea and constipation have been reported.
Skin and subcutaneous tissue disorders, rash, pruritus, urticaria, erythema, maculopapular rashes and bullous reactions have been more rarely reported.
The most frequently reported adverse drug reactions during long-term studies and post-market experience are hypoglycaemia (see Warnings and Precautions) and gastrointestinal disturbances (including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation).
A decrease in the uptake of radioactive iodine by the thyroid gland has been reported with other sulfonylurea drugs. This has not been shown with DIAMICRON (gliclazide) during a study involving 15 patients.
Cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia and allergic vasculitis, have been described for other sulphonylureas. With other sulfonylureas cases were also observed of elevated liver enzyme levels (AST, ALT, alkaline phosphatise) 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. Discontinue treatment if cholestatic jaundice appears.
The pattern of laboratory tests abnormalities observed with DIAMICRON (gliclazide) was similar to that for other sulfonylureas. Occasional mild to moderate elevations of AST, LDH and creatinine and decrease in natremia have been observed. These abnormalities frequently encountered with treated or untreated diabetic patients are rarely associated with clinical symptoms and generally not considered to be drug related.
(See Precautions.) Weakness, nervousness, shakiness and paresthesia have been reported. Severe hypoglycemia which mimics acute CNS disorders may occur. Hepatic and/or renal disease, malnutrition, debility, advanced age, alcoholism, adrenal or pituitary insufficiency may be predisposing factors.
Allergic reactions such as pruritus, erythema, urticaria and morbiliform or maculopapular rash have been reported. These reactions may persist during treatment, which must then be interrupted. Cases of cutanea porphyria tarda and of photosensitivity have also been described with sulfonylurea drugs.
As with all hypoglycemic sulfonylurea drugs, a few rare cases have been reported of leukopenia, erythrocytopenia agranulocytosis, thrombocytopenia, haemolytic anemia, pancytopenia and allergic vasculitis.
Cases of hepatic porphyria and disulfiram-like reactions have been described with sulfonylurea drugs. Clinical experience to date has shown that DIAMICRON (gliclazide) has a low incidence of disulfiram type reactions.
With other sulfonylureas cases were also observed of elevated liver enzyme levels (AST, ALT, alkaline phosphatise) 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. Rare cases of jaundice have been reported. Discontinue treatment if cholestatic jaundice appears.
arteritis, cardiac failure, cerebrovascular disorder, coronary artery disorder, epistaxis, hypotension, myocardial infarction, oedema legs, palpitation, tachycardia, thrombophlebitis, vein disorder.
Overdose
Overdosage with sulfonylureas may result in hypoglycemia but it should be noted that the dosage which causes such hypoglycemia varies widely and may be within the accepted therapeutic range in sensitive individuals.
The manifestations of hypoglycemia include sweating, flushing or pallor, numbness, chilliness, hunger, trembling, headache, dizziness, increased pulse rate, palpitations, increased blood pressure and apprehensiveness in mild cases. In more severe cases, coma appears.
However, symptoms of hypoglycemia are not necessarily as typical as those described above and sulfonylureas may cause insidious development of symptoms mimicking cerebrovascular insufficiency.
Discontinue medication and treat hypoglycemia by giving dextrose promptly and in sufficient quantity.
Some sulfonylurea-induced hypoglycemias may be refractory to treatment and susceptible to relapse especially in elderly or malnourished patients. Continuous dextrose infusions for hours or days have been necessary.
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.
Dosage
Determination of the proper dosage for DIAMICRON (gliclazide) for each patient should be made on the basis of frequent determinations of blood glucose during dose titration and throughout maintenance.
The recommended daily dosage of DIAMICRON (gliclazide) is 80 to 320 mg (1 to 4 tablets). Dosage of 160 mg and above should be divided into two equal parts for twice a day administration. DIAMICRON should be taken preferentially with meals.
The recommended starting dose of DIAMICRON (gliclazide) is 2 tablets per day (160 mg) taken as one tablet twice a day with meals. The total daily dose should not exceed 320 milligrams.
In patients where on initial trial the maximal recommended dose fails to lower blood glucose adequately, the drug should be discontinued. During the course of therapy a loss of effectiveness may occur.
It is advisable to ascertain the contribution of the drug in control of the blood glucose by discontinuing the medication semi-annually or at least annually with careful monitoring of the patient. If the need for the drug is not evident, the drug should not be resumed. In some diabetic subjects, short-term administration periods of the drug may be sufficient during periods of transient loss of blood sugar controls.
Patients Receiving Insulin: Maturity onset diabetics with no ketoacidosis or history of metabolic decompensation and whose insulin requirements are less than 40 units per day may be considered for DIAMICRON (gliclazide) therapy after cessation of insulin. If a change from insulin to DIAMICRON (gliclazide) is contemplated in such a patient, discontinue insulin for a period of 2 or 3 days to determine whether any therapy other than dietary regulation and exercise is needed. During this insulin free interval, test the patient's urine at least 3 times daily for glucose and ketone bodies and monitor the results carefully. The appearance of significant ketonuria accompanied by glucosuria within 12 to 24 hours after the withdrawal of insulin, strongly suggests that the patient is ketosis prone, and precludes the change from insulin to sulfonylurea therapy.
