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Information on the indications for using Gliclazide MR (gliclazide) in diabetes mellitus, its mechanisms of action, and results from clinical trials. the role of gliclazide in improving insulin secretion, insulin sensitivity, and peripheral glucose utilization. It also mentions the drug's anti-platelet and antioxidant properties. references to relevant studies.
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Pr GLICLAZIDE MR Gliclazide Modified Release Tablets 30 mg Hypoglycemic sulfonylurea - Oral antidiabetic agent AA PHARMA INC. 1165 Creditstone Road, Unit # Vaughan, ON L4K 4N Date of Preparation : June 25, 2010 Control No: 139545
See Toxicology Endocrine and Metabolism Hypoglycemic reactions As with other sulfonylurea drugs, manifestations of hypoglycemia including dizziness, lack of energy, drowsiness, headache and sweating have been observed and weakness, nervousness, shakiness and paresthesia have also been reported. All sulfonylurea drugs can induce severe hypoglycemia. Particularly susceptible are elderly subjects, patients with impaired hepatic or renal function, those who are debilitated or malnourished and patients with primary or secondary adrenal insufficiency. Some cases may be severe and prolonged. Hospitalisation may be necessary and glucose administration may need to be continued for several days. Hypoglycemia may be difficult to recognize in elderly patients and in patients receiving beta-blockers. Possible other symptoms of hypoglycemia are: 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, 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: clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia. This treatment should only be prescribed 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 periods of low- calorie diet, following prolonged or strenuous exercise, following alcohol intake or during the administration of a combination of hypoglycemic agents. Usually, hypoglycemic symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners have no effect. Experience with other sulphonylureas shows that hypoglycemia can recur even when measures prove effective initially.
prolonged and appropriate management should be instituted (See Monitoring and Laboratory Tests). Special Populations Pregnant Women: 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. Nursing Women: The product is contraindicated in breast-feeding mothers because the potential for hypoglycemia in nursing infants may exist. Some sulfonylurea drugs are excreted in human milk although it is not known whether gliclazide is one of them (See CONTRAINDICATIONS). Pediatrics (< 18 years of age): Safety and effectiveness of GLICLAZIDE MR in children have not been established. GLICLAZIDE MR is therefore not recommended for use in children and adolescents. Geriatrics (> 65 years of age) : Efficacy and tolerance of GLICLAZIDE MR, 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. Monitoring and Laboratory Tests 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. ADVERSE REACTIONS Adverse Drug Reaction Overview Gliclazide modified release tablets 30 mg have been evaluated for safety in controlled clinical trials in 955 patients, of which 728 were treated in long-term studies for up to 10 months, in comparison with gliclazide 80 mg tablets. The percentage of patients discontinuing treatment due to adverse events was lower in the gliclazide modified release tablets 30 mg group (2.9%) than in the gliclazide 80 mg tablets group (4.5%). The most frequently reported serious adverse events during clinical trials were coronary heart disease, cerebrovascular accidents, carcinoma, and gastrointestinal events (diarrhea, constipation, nausea, vomiting, gastritis, flatulence, dyspepsia). The most frequent adverse event is hypoglycemia. Serious adverse drug reactions that resulted in hospitalization during clinical trials were malaise, acute renal failure, and thrombophlebitis.
Gliclazide Modified Release Tablets 30 mg (n= 728) % Gliclazide 80 mg tablets (n= 734) % Resistance mechanism Infection viral 7.7 5. 6 Otitis media 1.1 0. Respiratory Rhinitis 4.4 4. Bronchitis 4.4 4. Pharyngitis 4.3 3. Upper respiratory infection 3.3 3. Coughing 2.1 2. Pneumonia 1.5 1. Sinusitis 1.5 1. Musculo-skeletal Back pain 5.2 4. Arthralgia 3.0 3. Arthrosis 2.2 2. Arthritis 1.4 2. Tendinitis 1.1 1. Myalgia 2.3 1. Secondary term Inflicted injury 4.3 4. Body as a whole Headache 3.8 4. Asthenia 2.2 2. Cardiovascular
Hypertension 3.2 3. Angina pectoris 2.1 2. Oedema legs 1.2 1. Urinary Urinary tract infections 2.6 3. Gastrointestinal Diarrhea 2.5 2. Constipation 1.6 1. Gastritis 1.2 0. Gastroenteritis 1.1 1. Nausea 1.1 0. Abdominal pain 1.1 1. Central, periph. nervous system Dizziness 2.2 2. Neuralgia 1.2 0. Metabolism and nutrition Hyperglycemia 1.9 2. Lipid metabolism disorder 1.4 0. Hyperlipaemia 1.0 0. Skin and appendages disorders Dermatitis 1.6 1. Rash 1.0 1. Skin disorder 1.9 2. Pruritus 1.0 0. Vision disorders
Gastro-intestinal: abdominal pain, anal fissure, appetite increased, colitis, duodenal ulcer, epigastric fullness, faecal incontinence, flatulence, gastric irritation, gastroesophageal reflux, GI neoplasm benign, hemorrhoids, melena, dry mouth, oesophagitis, saliva increased, tooth ache, tooth disorder, vomiting. These reactions are generally dose-related and may disappear when the dose is reduced. Hearing and vestibular: hearing decreased, tinnitus. Liver and biliary: increased liver enzymes, hepatitis, hepatomegaly. Metabolic and nutritional: gout, glycosuria, hypercholesterolemia, hypertriglyceridemia, thirst. Cases of hepatic porphyria and disulfiram-like reactions have been described with sulfonylurea drugs. Clinical experience to date has shown that gliclazide 80 mg tablets has a low incidence of disulfiram type reactions. Musculo-skeletal: arthropathy, bursitis, hernia congenital, skeletal pain, spine malformation. Reproductive: balanoposthitis, benign female breast neoplasm, impotence, mastitis, menstrual disorder, prostatic disorder, vaginitis. Respiratory: asthma, dyspnea, tracheitis. Skin and appendages: fungal dermatitis, eczema, erythema, hyperkeratosis, maculopapular or morbiliform rash, nail disorder, onychomycosis, pruritus, dry skin, skin ulceration, urticaria. These reactions may persist during treatment, which must be then interrupted. Cases of porphyria tarda and of photosensitivity have also been described with sulfonylurea drugs. Urinary: albuminuria, cystitis, nocturia, polyuria, renal calculus, renal cyst.
Vision: cataract, conjunctival haemorrhage, diplopia, glaucoma, abnormal lacrimation, retinal disorder, abnormal vision, vitreous disorder, xerophthalmia. Abnormal Hematologic and Clinical Chemistry Findings The pattern of laboratory tests abnormalities previously observed with gliclazide 80 mg tablets was similar to that for other sulfonylureas. Occasional mild to moderate elevations of hepatic enzymes, 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. As with all hypoglycemic sulfonylurea drugs, a few rare cases of leukopenia, agranulocytosis, thrombocytopenia and anemia have been reported with gliclazide 80 mg tablets. No laboratory tests abnormalities other than those already reported with gliclazide 80 mg tablets have been observed during controlled clinical trials performed on gliclazide modified release tablets 30 mg Post-Market Adverse Drug Reactions In post-marketing experience with gliclazide modified release tablets 30 mg, gastrointestinal disturbance, 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 serious adverse drug reactions reported with gliclazide are hypoglycaemic coma, pancytopenia, thrombocytopenia, hepatitis, cholestatic jaundice, pyrexia, pancreatitis acute and skin reactions (pruritus and rash). Class attribution effects : 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.
Phenylbutazone (systemic route) C Increases the risk of hypoglycemia Combination is not recommended. 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. Where necessary, adjust the dose during and after treatment with the anti- inflammatory agent. Other antidiabetic agents (insulins, acarbose, biguanides) C Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. Beta-blockers C Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. Fluconazole C^ Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. Angiotensin converting enzyme inhibitors C (^) Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. H2-receptor antagonists C (^) Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur.
MAOIs C^ Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. Sulfonamides C^ Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. Nonsteroidal anti- inflammatory agents C (^) Increases the risk of hypoglycemia Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycemia may occur. Danazol C^ Causes an increase in blood glucose levels Combination is not recommended because of diabetogenic effect of danazol. If the use of this active substance cannot be avoided, warn the patient and emphasise 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. Chlorpromazine (neuroleptic agent) C (^) Causes an increase in blood glucose levels Combination requiring precautions during use. High doses (>100 mg per day of chlorpromazine) increase blood glucose levels (reduced insulin release). Warn the patient and emphasise 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.
Drug-Lifestyle Interactions This treatment should only be prescribed 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 periods of low- calorie diet and following prolonged or strenuous exercise. Intolerance to alcohol (disulfiram- like reaction: flushing, sensation of warmth, giddiness, nausea and occasionally tachycardia) may occur in patients treated with sulfonylurea. Alcohol increases the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Avoid alcohol or medicines containing alcohol. Treatment with GLICLAZIDE MR can have effects on ability to drive and use machines. 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. DOSAGE AND ADMINISTRATION Dosing Considerations Determination of the proper dosage for GLICLAZIDE MR for each patient should be made on the basis of frequent determinations of blood glucose during dose titration and throughout maintenance. The daily dose of GLICLAZIDE MR may vary from 30 to 120 mg (1 to 4 tablets) once daily. Recommended Dose and Dosage Adjustment The recommended starting dose of GLICLAZIDE MR is 1 tablet per day (30 mg), even in elderly patients (over 65 years old). A single daily dose provides effective blood glucose control. The single daily dose may be between one and three, or even four, tablets. The daily dose should not exceed 120 mg.
Dose adjustment should be carried out in steps of 30 mg, according to the blood glucose response. Each step should last for at least two weeks. Administration It is recommended that the medication be taken at breakfast time. The tablets should be swallowed whole and must not be chewed or crushed.
