GLYADE MR gliclazide 30mg tablet blister pack
Chemical Name : 1-(3-azabicyclo[3.3.0]oct-3-yl)-3-p-tolylsulphonylurea CAS Registry Number : 21187-98-4 Molecular Formula : C15H21N3O3S Chemical Structure :
H3C
O O O
S N
N N
H H
GLYADE MR 30 mg
tablets are a modified release formulation.
Active Ingredient
Gliclazide is a white or almost white powder, practically insoluble in water, freely soluble in dichloromethane, sparingly soluble in acetone and slightly soluble in ethanol 96%. The melting point of gliclazide is approximately 168degC.
Excipients
Calcium hydrogen phosphate, maltodextrin, hypromellose, magnesium stearate and silica-colloidal anhydrous.
Gliclazide is an oral hypoglycaemic sulphonylurea which differs from other related compounds. It has an N-containing heterocyclic ring with an endocyclic bond. Gliclazide reduces blood glucose levels by stimulating insulin secretion from the -cells of the islets of Langerhans. Gliclazide shows high affinity, strong selectivity and reversible binding to the -cell KATP channels with a low affinity for cardiac and vascular KATP channels. Increased postprandial insulin and C-peptide secretion persists after two years of treatment. Gliclazide also has extra- pancreatic effects and haemovascular properties.
Effects on insulin release
In type II diabetes, 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 release is seen in response to stimulation induced by a meal or glucose.
Extra-pancreatic effects
Gliclazide has been shown to increase peripheral insulin sensitivity:
In muscle, euglycaemic hyperinsulinaemic clamp studies with gliclazide have demonstrated significantly increased (35%) insulin mediated glucose uptake which may improve diabetes control. Gliclazide potentiates insulin action on muscle glycogen synthase. These effects are consistent with a post-transcriptional action of gliclazide on GLUT4 glucose transporters.
Studies on glucose turnover have further shown that gliclazide decreases hepatic glucose production, leading to an improvement in fasting blood glucose levels.
Other actions
Gliclazide has been shown in some studies to have actions independent of that on glucose levels. These haemovascular effects of gliclazide include : Partial inhibition of platelet aggregation and adhesion with a decrease in markers of platelet activation (beta thromboglobulin, thromboxane B2) Increased vascular endothelial fibrinolytic activity (increased tPA activity) Anti-oxidant properties, notably a reduction in plasma lipid peroxides and increased erythrocyte superoxide dismutase activity Inhibition of the increased adhesiveness of type II diabetic patient's monocytes to endothelial cells in vitro. The anti-oxidant, platelet inhibiting and fibrinolytic actions of gliclazide involve processes which have been implicated in the pathogenesis of vascular complications of type II diabetes. There is no clinical evidence that the haemovascular effects of gliclazide are of therapeutic benefit in type II diabetes patients.
Hydration of the tablets induces formation of a gel to activate drug release. Plasma levels increase progressively, resulting in a plateau-shaped curve from the sixth to the twelfth hour after administration. Intra-individual variability is low. Gliclazide is completely absorbed and food intake does not affect the rate or degree of absorption. The relationship between the dose administered and the area under the concentration curve as a function of time is linear for doses of gliclazide up to 90mg/day. At the highest evaluated dose (135mg/day), the AUC increases slightly more than proportionally to the dose. Plasma protein binding is approximately 95%. Gliclazide is mainly metabolised in the liver, the products of which are extensively excreted in the urine. Less than 1% of unchanged drug is recovered in the urine. No active metabolites have been detected in plasma. The clearance of gliclazide has been found to be slightly reduced as a function of age. This reduction, however, is not considered to be clinically significant. The elimination half-life of gliclazide is approximately 16 hours. No clinically significant modifications in the pharmacokinetic parameters have been observed in elderly patients.
Type II diabetes in association with dietary measures when dietary measures alone are inadequate to control blood glucose. During controlled clinical trials in patients with type II diabetes, GLYADE MR, taken as a single daily dose, was shown to be effective long term in controlling blood glucose levels, based on monitoring of HbA1c.
This medication is contra-indicated in the following cases:
Hypersensitivity to gliclazide, other sulphonylureas, sulfonamides, or to any of the excipients;
Type I diabetes, diabetic keto-acidosis, diabetic pre-coma and coma;
Severe renal or hepatic insufficiency;
Treatment with miconazole (refer to Interactions with other medicines);
Pregnancy and lactation (refer to Use in pregnancy and Use in lactation).
It is generally not recommended to use this agent in combination with phenylbutazone or danazol (refer to Interactions).
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. Hypoglycaemia may occur following administration of sulphonylureas. Rarely cases may be severe and prolonged. This may involve hospitalisation and glucose infusion may need to be continued for several days. Careful selection of patients and of the dose used, as well as provision of adequate information to the patient are necessary to avoid hypoglycaemic episodes. The following factors may increase the risk of hypoglycaemia:
patient does not follow the doctor's treatment advice (particularly 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 anti-diabetic agents;
certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency, concomitant administration of certain other medicines (refer to Interactions with other medicines).
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 hypoglycaemia if a meal is delayed, an inadequate amount of food is consumed or the food is low in carbohydrate. Hypoglycaemia is more likely to occur during periods of low-calorie diet, following prolonged or strenuous exercise, following alcohol intake or during treatment with a combination of hypoglycaemic agents.
Poor blood glucose control
Blood glucose control in treated patients may be affected by: fever, trauma, infection or surgical intervention. It may be necessary to discontinue treatment and to administer insulin in these cases. The efficacy of oral antidiabetic agents often decreases in the long term. 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 and should be distinguished from primary failure, when the drug is ineffective as first-line treatment. However, before classifying the patient as a secondary failure, dose adjustment and reinforcement of dietary measures should be considered.
Renal and hepatic insufficiency
Severe renal or hepatic insufficiency may affect the distribution of gliclazide and hepatic insufficiency may also reduce the capacity for neoglucogenesis. These two effects increase the risk of severe hypoglycaemic reactions. A hypoglycaemic episode in these patients may be prolonged and appropriate management should be initiated.
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Treatment of patients with G6PD-deficiency with sulphonylurea agents can lead to haemolytic anaemia. Since gliclazide belongs to the chemical class of sulphonylurea drugs, caution should be used in patients with G6PD-deficiency and a non-sulphonylurea alternative should be considered.
Lactose intolerance
Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose galactose malabsorption, or the Lapp lactase deficiency should not take this medicinal product.
In animal studies embryo-toxicity and/or birth defects have been demonstrated with some sulfonylureas. Gliclazide should not be used in pregnant women. Animal studies of gliclazide have not shown any teratogenic effect. From a clinical point of view, there are no adequate data to allow evaluation of the possible malformative or foetotoxic effects of gliclazide, when administered during pregnancy.
GLYADE MR is contra-indicated during pregnancy and insulin is the drug of first choice for treatment of diabetes during pregnancy. Treatment should be changed from GLYADE MR to insulin therapy before pregnancy is attempted, or as soon as pregnancy is discovered. Control of diabetes should be achieved before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes.
It is not known whether gliclazide or its metabolites are excreted in breast milk. Given the risk of neonatal hypoglycaemia, GLYADE MR is contra-indicated in women who are breast feeding.
Blood glucose monitoring during and after treatment is necessary when GLYADE MR is used with medicines which can interact with gliclazide. It may also be necessary to adjust the dose of GLYADE MR during and after treatment withsuch medicines.
The following medications are likely to increase the risk of hypoglycaemia:
Concomitant use which is contraindicated:
Miconazole (systemic route, oromucosal gel):
Increases the hypoglycaemic effect with possible onset of hypoglycaemia symptoms, or even coma.
Concomitant use which is not recommended:
Phenylbutazone (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. Where necessary, adjust the dose during and after treatment with the anti-inflammatory agent.
Alcohol:
Acute alcohol intoxication potentiates the hypoglycaemic action of all sulphonylurea agents by inhibiting compensatory reactions. This can lead to the onset of hypoglycaemic coma. Ingestion of alcohol may also cause a disulfiram-like reaction with characteristic flushing of the face, throbbing headache, giddiness, tachypnoea, tachycardia or angina pectoris. Chronic alcohol abuse may, as a result of liver enzyme induction, increase the metabolism of sulphonylurea drugs, shortening the plasma half life and duration of action. Avoid alcohol or medicines containing alcohol.
Concomitant use which requires special care:
Potentiation of the blood glucose lowering effect and therefore in some instances, hypoglycaemia may occur when one of the following medications is taken: Other antidiabetic agents (insulins, acarbose, biguanides, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists), sulfonamides, clarithromycin, clofibrate, salicylates (high doses), chloramphenicol, MAOIs, -blockers, H2-receptor antagonists, ACE inhibitors, fluconazole and nonsteroidal anti-inflammatory agents.
The following medications may cause an increase in blood glucose levels:
Advise the patient and emphasise the importance of glucose monitoring.
Concomitant use which is not recommended:
Danazol:
If the use of danazol cannot be avoided, it may be necessary to adjust the dose of GLYADE MR during and after treatment with danazol.
Concomitant use which requires special care:
Chlorpromazine:
High doses (>100 mg per day of chlorpromazine) can increase blood glucose levels (reduced insulin release). Advise the patient and emphasise the importance of glucose monitoring. It may be necessary to adjust the dose of GLYADE MR during and after treatment with chlorpromazine.
Glucocorticoids (systemic and local route: intra-articular, cutaneous and rectal preparations) and tetracosactrin: Concomittant use may increase blood glucose levels with possible ketosis (glucocorticoids cause reduced tolerance to carbohydrates).
Salbutamol, terbutaline (intravenous):
May cause increased blood glucose levels due to beta-2 agonist effects. If necessary, switch to insulin.
Barbiturates, Oestrogens and progestogens:
May adversely affect blood sugar control with hypoglycaemic agents in some patients by causing increased blood glucose levels.
Concomitant use to be taken into consideration:
Anticoagulant therapy (Warfarin):
Sulphonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of warfarin may be necessary.
Patients should be made aware of the symptoms of hypoglycaemia and should be careful if driving or operating machinery, especially at the beginning of treatment
Glycated haemoglobin should be monitored regularly. Blood glucose measurement may also be useful.
Good clinical acceptability of gliclazide, has been established in many studies as well as in medical practice. The safety of GLYADE MR has been evaluated in controlled clinical trials in 955 patients, of which 728 patients were treated in long-term comparative trials, against gliclazide 80mg tablets, for up to 10 months. In these comparative trials, the overall incidence and type of adverse events were similar in both GLYADE MR and gliclazide 80mg groups. Adverse events were generally mild and transient, not requiring discontinuation of therapy. However, where patients did discontinue due to adverse events, the percentage was lower in the
GLYADE MR
group (2.9%) than in the gliclazide 80mg group (4.5%).
Hypoglycaemia (refer to PRECAUTIONS and OVERDOSAGE)
As is the case with all sulphonylurea drugs, hypoglycaemic reactions have been reported following gliclazide administration. However, a number of studies have shown that hypoglycaemia is less common with gliclazide than with glibenclamide. 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/or death. 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 carbohydrate such as sugar (artificial sweeteners have no effect). Experience with other sulphonylureas shows that hypoglycaemia can recur even when these measures are initially effective. 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. In long-term comparative studies, the percentage of patients experiencing hypoglycaemic episodes was similar between patients treated with GLYADE MR (11.6%) and those treated with gliclazide 80mg (11.1%). However, the number of hypoglycaemic episodes per 100 patients.month was lower in the GLYADE MR group (3.5) than in the gliclazide 80mg group (4.8). Analysis of elderly patients (over 65 years old) showed less hypoglycaemia than in the general population, with a prevalence of hypoglycaemic episodes lower in the GLYADE MR group (2.6 hypoglycaemic episodes for 100 patients.months) than in the gliclazide 80mg group (4.1). The percentage of patients experiencing hypoglycaemic episodes in the sub-population with renal failure, was similar to that observed in the general population.
Other adverse events
Adverse events reported during controlled clinical trials with GLYADE MR were those expected in an ageing population with diabetes. Adverse events that were reported in at least 2.0% of patients, in long-term controlled clinical studies, are presented in the following table. The most frequent adverse events were not specifically related to the disease (such as respiratory infections or back pain).
Treatment emergent adverse events * (listed by body s ystem) occurring in >=2.0% of patients in long-term controlled clinical trials
| GLYADE MR (n=728) % | Gliclazide 80mg tablets (n=734) % | |
| Resistance mechanism | ||
| Infection viral | 7.7 | 5.6 |
| Respiratory | ||
| Rhinitis | 4.4 | 4.6 |
| Bronchitis | 4.4 | 4.6 |
| Pharyngitis | 4.3 | 3.5 |
| Upper respiratory infection | 3.3 | 3.7 |
| Coughing | 2.1 | 2.0 |
| Musculo-skeletal | ||
| Back pain | 5.2 | 4.1 |
| Arthralgia | 3.0 | 3.5 |
| Arthrosis | 2.2 | 2.2 |
| Secondary term | ||
| Inflicted injury | 4.3 | 4.5 |
| Body as a whole | ||
| Headache | 3.8 | 4.6 |
| Asthenia | 2.2 | 2.6 |
| Cardiovascular | ||
| Hypertension | 3.2 | 3.7 |
| Angina pectoris | 2.1 | 2.2 |
| Urinary | ||
| Urinary tract infections | 2.6 | 3.0 |
| Gastrointestinal | ||
| Diarrhoea | 2.5 | 2.0 |
| Central, periph., nervous system | ||
| Dizziness | 2.2 | 2.3 |
| Metabolism and nutrition | ||
| Hyperglycaemia | 1.9 | 2.2 |
*whatever the relationship to treatment Analysis of adverse events in sub-populations showed a similar pattern to that seen in the general population. Gender, age and renal insufficiency had no significant influence on the safety profile of DIAMICRON MR.
Other adverse effects reported with gliclazide
Gastrointestinal disturbances (reported with gliclazide), including nausea, dyspepsia, diarrhoea, abdominal pain, vomiting, and constipation may be avoided or minimised if gliclazide is taken with breakfast. The following adverse effects have been rarely reported Skin subcutaneous tissue disorders: pruritus, urticaria, maculopapular rashes, rash, angioedema, erythema and bullous reactions (such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) (as with other sulfur-containing medications). Blood and lymphatic system disorders (as with other sulphonylurea medications): anaemia, leucopenia, thrombocytopenia and agranulocytosis. These are in general reversible upon discontinuation of medication. Hepatobiliary disorders: elevations of serum bilirubin and hepatic enzymes (AST, ALT, alkaline phosphatase) levels, and exceptionally, hepatitis (isolated reports). Treatment should be discontinued if cholestatic jaundice appears. These symptoms usually disappear after discontinuation of treatment. Investigations: occasional elevations of serum creatinine, blood urea nitrogen. Eye disorders: transient visual disturbances may occur due to changes in blood glucose levels, particularly on initiation of treatment. As with any glucose-lowering medication, transient visual disturbances may occur on initiation of treatment due to changes in blood glucose levels.
Class effects
The following adverse events have been observed with sulphonylureas: cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia and 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.
For adult use only. The daily dose may vary from 30 to 120mg taken orally, once daily. GLYADE MR should be taken with food because there is 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. It is recommended that the medication be taken at breakfast time. If a dose is forgotten, the dose taken on the next day should not be increased.
GLYADE MR
tablets are modified release tablets and therefore should be neither broken nor chewed.
As with all hypoglycaemic agents, the dose should be titrated according to the individual patient's response. The initial recommended dose is 30mg daily, even in elderly patients (>= 65 years). Dose titration should be carried out in steps of 30mg, according to the fasting blood glucose response. Each step should last for at least two weeks. A single daily dose provides an effective blood glucose control. The single daily dose may be between one and three, or even four, tablets. The daily dose should not exceed 120mg. Previously untreated patients should commence with a dose of 30mg and will benefit from dose titration until the appropriate dose is reached.
GLYADE MR, can replace gliclazide 80mg tablets, tablet for tablet, for doses of 1 to 4 tablets per day.
GLYADE MR, may be used to replace other antidiabetic treatments without any transitional period. If a patient is switched from a hypoglycaemic sulphonylurea with a prolonged half-life he/she should be carefully monitored (for 1 to 2 weeks) in order to avoid hypoglycaemia due to possible residual effects of the previous therapy.
GLYADE MR, may be given in combination with biguanides, alpha glucosidase inhibitors or insulin.
Elderly subjects: The efficacy and tolerance of GLYADE MR has been confirmed in clinical trials in subjects over 65 years who were given the same dosage regimen as the general population. The dosage is therefore identical to that recommended for adults under the age of 65 years.
Renal insufficiency: The efficacy and tolerance of GLYADE MR has been confirmed in clinical trials of subjects with mild to moderate renal failure (creatinine clearance of between 15 and 80mL/min) who were given the same dosage regimen as the general population. No dosage adjustment is therefore required in subjects with impaired renal function.
Overdose of sulphonylureas may cause hypoglycaemia. Moderate symptoms of hypoglycaemia (without loss of consciousness or neurological signs), should be corrected by carbohydrate intake, dose adjustment and/or modification of diet. Strict monitoring should be continued until the doctor is sure that the patient is out of danger. Severe hypoglycaemic reactions are possible (with coma, convulsions or other neurological disorders) and should 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 50mL of concentrated glucose solution (20 to 30%). This should be followed by continuous infusion of a more dilute glucose solution (10%) at a rate necessary to maintain blood glucose levels above 5mmol/L. It is recommended that patients should be monitored closely for a 48 hour period at least. Plasma clearance of gliclazide may be prolonged in patients with hepatic disease. However, due to the strong binding of gliclazide to proteins, dialysis is not effective in these patients. Advice on overdose management can be obtained from the national Poisons Information Centre by telephoning 131126.
Modified release tablets, 30mg available in 100's. The tablets are white oblong tablets with an engraving of "DIA 30" on one face and on the other face. Store below 30degC
Servier Laboratories (Australia) Pty Ltd 8 Cato Street Hawthorn VIC 3122 Australia ABN 54 004 838 500
Alphapharm Pty Limited Level 1, 30 The Bond 30-34 Hickson Road Millers Point NSW 2000 ABN 93 002 359 739 www.alphapharm.com.au
S4
7 September, 2007
29 October, 2013