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.

 

Geriatrics (≥ 65 years of age):

No significant differences in efficacy and tolerance were observed between patients over 65 years of age and younger patients, however greater sensitivity of some older individuals cannot be ruled out.

 

Pediatrics (< 18 years of age):

Safety and effectiveness of Gliclazide modified release tablets in children have not been established. Gliclazide modified release tablets is therefore not recommended for use in children and adolescents.

Dosing Considerations

Determination of the proper dosage for CLAZ 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 CLAZ MR may vary from 30 to 120 mg once daily (i.e., one half tablet to 2 tablets of CLAZ MR 60 mg, or 1 to 4 tablets of CLAZ MR 30 mg).

 

Recommended Dose and Dosage Adjustment

The recommended starting dose of CLAZ MR is 30 mg daily, i.e. one half tablet of CLAZ MR 60 mg or one tablet of CLAZ MR 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 30 mg and 90 mg, or even 120 mg. 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.

 

Missed Dose

If a dose is forgotten, the patient should be advised to skip the missed dose and take his or her usual dose at the regular time the next day. The dose taken on the next day should not be increased to account for the missed dose.

 

Administration

It is recommended that the medication be taken at breakfast time. The 30 mg tablets cannot be split in half and should be swallowed whole. The 60 mg tablets can be halved. Both the 30 mg and 60 mg tablets must not be chewed or crushed.

• Previously untreated patients should commence with a dose of 30 mg and will benefit from dose adjustment until the appropriate dose is reached.
• One CLAZ MR 60 mg tablet is equivalent to two CLAZ MR 30 mg tablets. The breakability of the CLAZ MR 60 mg tablet allows the use of a dose of 30 mg as a half tablet and of 90 mg as one and a half tablets.
• CLAZ MR can replace an antidiabetic treatment without any transitional period.

If a patient is switched from a hypoglycemic sulfonylurea with a prolonged half-life (i.e. chlorpropamide) he/she should be carefully monitored (for 1 to 2 weeks) in order to avoid hypoglycemia due to possible residual effects of the previous therapy

 

Geriatrics

No significant differences in efficacy and tolerance were observed between patients over 65 years of age and younger patients, however greater sensitivity of some older individuals cannot be ruled out. Patients over 65 years of age should be started with 30 mg of Gliclazide modified release tablet with dosage adjustments being made cautiously.

 

Hepatic or Renal Impairment

Patients with renal or hepatic impairment should be started with 30 mg of gliclazide with dosage adjustments being made cautiously (see WARNINGS AND PRECAUTIONS - Hypoglycemic reactions).

 

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 CLAZ MR therapy after cessation of insulin.

If a change from insulin to CLAZ MR 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.

CLAZ MR is contraindicated in patients with: • Known hypersensitivity or allergy to gliclazide, other sulfonylureas, sulfonamides, or to any of the excipients of this product (For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section). • Unstable and/or insulin-dependent (Type 1) 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 severe hepatic impairment (see WARNINGS AND PRECAUTIONS). • In the presence of severe renal impairment (see WARNINGS AND PRECAUTIONS). • Treatment with miconazole via systemic route or oromucosal gel (see DRUG INTERACTIONS). • Pregnancy and lactation (see WARNINGS AND PRECAUTIONS - Special Populations, Pregnant Women and Nursing Women).

Use of CLAZ MR must be considered as treatment in addition to proper dietary regimen and not as substitute for diet.

Careful selection of patients is important. It is imperative that there be rigid attention to diet, careful adjustment of dosage and instruction of the patient on hypoglycemic reactions, their recognition, remedies and control as well as regular, thorough medical follow-up.

Since the effects of oral hypoglycemic agents on the vascular changes and other long-term sequelae of diabetes mellitus are not fully known, patients receiving such drugs must be closely observed for both short-and long-term complications. Periodic assessment of cardiovascular, ophthalmic, renal and hepatic status is advisable.

CLAZ MR use is not recommended with medications containing alcohol, phenylbutazone (systemic route) and danazol and precautions are required when used with chlorpromazine, glucocorticoids, ritodrine, salbutamol, terbutaline and anticoagulant therapy (see DRUG INTERACTIONS).

 

Carcinogenesis and Mutagenesis

Acute toxicity

The LD 50 is greater than 3000 mg/kg in the mouse, rat and dog (i.e., 300 times the therapeutic dose) and than 2000 mg/kg in the guinea-pig (i.e. 200 times the therapeutic dose).

Symptomatology is essentially linked to the hypoglycemic effect of the drug.

Sub-chronic toxicity:

-  Maximum tolerated dose:

In the dog, this dose is between 150 and 200 mg/kg by daily administration.

-  Four-week oral toxicity study in the Beagle dog:

Groups of 4 Beagle dogs (2 males, 2 females) were treated for 30 days with 0, 15, 30, 45 or 90 mg/kg/day. At the dose of 90 mg/kg, 2 animals died as a result of prolonged hypoglycemic coma following 2 weeks of treatment. All others showed normal behavior, with the exception of an increase in the weight of the liver. No evidence was found of any change in biochemical (apart from the fall in blood glucose), hematological and histopathological parameters.

-  Two-month oral toxicity study in the guinea-pig:

Groups of 10 guinea-pigs (5 males, 5 females), were treated 6 days out of 7 for 2 months with 0, 25, 50 or 100 mg/kg/day. Only male animals in the 50 mg/kg group showed delayed weight gain. All others had normal biochemical, hematological and histopathological results.

Chronic toxicity:

-  Six-month study in the Sprague-Dawley rat:

Groups of 20 rats (10 males, 10 females) weighing 300 g, were treated for 6 days out of 7 for 6 months with 0, 25, 100 or 200 mg/kg/day. Seven deaths occured as a result of technical problems. All other animals showed normal behavior and haematological results. From a biochemical standpoint, blood urea decreased significantly in the male rats as did blood glucose in the males of the 100 mg/kg/day group.

Histological examination showed an increase in the weight of the liver and kidneys in male animals, not accompanied by any histological lesion.

In a six-month rat study carried out in Japan with higher doses (0, 50, 100, 200, 400 and 800 mg/kg/day) females exhibited greater systemic toxicity when compared with males, suggesting that females may be more sensitive to the product: slight increases in liver enzymes together with slight decreases in erythrocytes counts, hematocrit values and hemoglobin concentrations at doses of 200 mg/kg and higher.

-  Six-month study in the Beagle dog:

Groups of 6 dogs (3 males, 3 females) were treated daily for 6 months with 0, 15 or 30 mg/kg of gliclazide or 50 mg/kg of tolbutamide.

From a clinical standpoint:

-  3 deaths (one at 15 mg/kg, two at 30 mg/kg) in the gliclazide group as a result of hypoglycemic coma;

-  1 convulsion, 4 cases of severe gastro-intestinal disturbances in the tolbutamide group;

-  weight changes and food consumption were similar with both drugs. From a laboratory standpoint:

-  40% fall in blood glucose in animals treated with gliclazide;

-  signs of hepatotoxicity in the tolbutamide group. From a histological standpoint:

-  increase in weight of the liver in the 3 deaths of the gliclazide group;

-  increase in the weight of the liver and lesions of toxic hepatitis in 5 animals out of 6 of the tolbutamide group.

-  Twelve-month oral toxicity study in the Beagle dog:

Groups of 8 dogs (4 males, 4 females) were treated for 12 months with 0, 12 or 24 mg/kg/day of gliclazide.

Four animals in each group were sacrificed after 90 days.

-  there were no deaths;

-  no evidence of any modification in behavior and body weight;

-  significant fall in blood glucose;

-  fluctuation in certain parameters (liver enzymes, lipid profile, creatinine);

-  at autopsy: swelling of the renal and hepatic parenchyma and at the highest dose a slight increase in the weight of the thyroid and slight decrease in the weight of the pituitary gland.

-  Twelve-month oral toxicity study in the rhesus monkey:

Groups of 8 rhesus monkeys (4 males, 4 females) were treated daily for 12 months with 0, 20, 60 or 180 mg/kg of gliclazide.

-  no evidence was found of any modification in weight gain nor food consumption;

-  significant fall in blood glucose;

-  irregular rise in some liver enzymes in some animals;

-  no abnormality by histopathological examination. Teratogenicity

Teratogenicity studies have been carried out in three species: mouse, rat and rabbit.

-  In the CD/SPF mouse (group of 30 females), administration of gliclazide at doses of 0, 50, 250 and 500 mg/kg/day starting from mating and throughout gestation did not modify fertilization and abortion rates and had no apparent teratogenic effect.

-  In the CFY-SPF rat (groups of 20 females), administration of gliclazide at doses of 0, 50, 100 and 200 mg/kg/day from the 6th to the 15th day of gestation did not show any embryotoxic effect.

-  In the SD/SPF rat (groups of 60 females), administration of gliclazide at the doses of 0, 15, 30, 60, 120, 240 and 480 mg/kg/day starting from mating and throughout gestation had no effect on fertilization, gestation, mean number of foetuses or incidence of foetal abnormalities. The number of offspring surviving at 48 hours was decreased in the 15, 60, 120 and 480 mg/kg groups. No other abnormality was seen.

-  In the common rabbit (group of 15 females), administration of gliclazide at doses of 0, 10, 25 and 50 mg/kg/day from the 6th to the 18th day of gestation had no effect on the number of foetal resorptions, percentage of abortion nor the mean number of foetuses per litter.

-  In the New Zealand rabbit (group of 6 females), administration of gliclazide at doses of 0, 50, 75, 100 and 200 mg/kg/day for 13 days followed by an observation period of 8 days, was associated with maternotoxicity and embryotoxicity in the form of gastro-intestinal and renal lesions accompanied by anorexia and weight loss. However, there was no evidence of any teratogenic effect.

Fertility and reproduction

In the SD rat, groups of 40 females and of 20 males were treated for 8 and 70 days respectively before mating and until weaning in the females, and until 15 days after littering in the males, with gliclazide at doses of 0, 10, 50 and 200 mg/kg/day.

There was no evidence of any change in fertilization nor abortion rates. Foetal resorption, placental haemorrhage and foetal atrophy rates were unaffected. The genital tract of treated parents showed no abnormality imputable to treatment. No embryotoxic effect was seen on foetuses of females sacrificed before littering. In females in which gestation was allowed to run to term, a significant decrease in the viability of offspring was seen at 48 hours. No abnormality was seen during the study of fertility and reproduction in first generation offspring born of treated animals.

Carcinogenicity studies

Specific carcinogenicity studies have not been performed; the following safety data are now available:

-  gliclazide belongs to the chemical class of the phenylsulfonylurea which did not demonstrate any mutagenic or carcinogenic potential. Its metabolic pathway is consistent with the general metabolic pathway of the class;

-  gliclazide was not associated with any mutagenic action in the numerous studies performed;

-  long term toxicity studies did not reveal any evidence of carcinogenicity;

-  gliclazide has been studied in several thousands of patients during clinical trials and has been marketed for numerous years all over the world and in particular in Europe and Japan without any suspicion of carcinogenicity.

 

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 hypoglycaemia 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.

If a hypoglycemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalisation are required.

Other factors which increase the risk of hypoglycemia are: overdose of CLAZ MR, certain endocrine disorders (thyroid disorders, hypopituitarism and adrenal insufficiency) as well as withdrawal of prolonged and/or high dose corticosteroid therapy, severe  vascular disease (severe coronary heart disease, severe carotid impairment, diffuse vascular disease) and concomitant administration of certain medicines (see DRUG INTERACTIONS).

 

Poor Blood Glucose Control

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. This phenomenon is known as secondary failure and should be distinguished from primary failure, when the drug is ineffective when prescribed as first-line treatment. Adequate dose adjustment and compliance with dietary measures should be

considered before classifying the patient as secondary failure. If a loss of adequate blood glucose-lowering response to CLAZ MR is detected, the drug should be discontinued.

In patients stabilized on gliclazide therapy, loss of blood sugar control may occur in cases of acute intercurrent disease such as a fever and serious infection, in stressful situations such as trauma or surgery, or if used concomitantly with herbs such as St. John's Wort (Hypericum perforatum) preparations or of any treatment that may interact with gliclazide metabolism (see DRUG INTERACTIONS & Drug-Herb Interactions). Under these conditions, discontinuation of gliclazide extended release tablets and administration of insulin should be considered.

 

Dysglycaemia

Fluoroquinolones should be used with caution in patients receiving Gliclazide modified release tablets. Hypoglycaemia and hyperglycaemia have been reported in diabetic patients receiving concomitant treatment with fluoroquinolones, especially in elderly patients. Careful monitoring of blood glucose is recommended in all patients taking Gliclazide modified release tablets and a fluoroquinoloneconcomitantly.

 

Hematologic

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD)-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since CLAZ MR belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non- sulfonylurea alternative should be considered.

 

Hepatic/Biliary/Pancreatic

The metabolism and excretion of sulfonylureas including CLAZ MR may be slowed in patients with impaired hepatic function. Isolated cases of impairment of liver function with cholestasis and jaundice, and hepatitis which can regress after withdrawal of the drug or may lead to life- threatening liver failure have been observed. Discontinue treatment if cholestatic jaundice appears. Therefore, CLAZ MR is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Tests).

 

Peri-Operative Considerations

In patients stabilized on gliclazide therapy, loss of blood sugar control may occur in cases of acute intercurrent disease or in stressful situations such as trauma or surgery. Under these conditions, discontinuation of CLAZ MR (gliclazide) and administration of insulin should be considered (see WARNINGS AND PRECAUTIONS - Endocrine and Metabolism, Poor blood glucose control).

 

Renal

The metabolism and excretion of sulfonylureas including CLAZ MR may be slowed in patients with impaired renal function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted. Therefore, CLAZ MR is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS — Monitoring and Laboratory Tests).

 

Sensitivity/Resistance

Due to the presence of lactose in CLAZ MR 60 mg, patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactose deficiency should not take CLAZ MR 60 mg.

CLAZ MR 30 mg does not contain lactose.

 

Skin

Serious skin and hypersensitivity reactions including rash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported.

 

Special Populations

Pediatrics (< 18 years of age):

Safety and effectiveness of Gliclazide modified release tablets in children have not been established. Gliclazide modified release tablets is therefore not recommended for use in children and adolescents.

 

Geriatrics (≥ 65 years of age):

Efficacy and tolerance of Gliclazide modified release tablets prescribed using the same therapeutic regimen in subjects over 65 years, has been confirmed in clinical trials, however greater sensitivity of some older individuals cannot be ruled out.

Severe hypoglycemia can be induced by all sulfonylurea drugs. Elderly subjects are particularly susceptible.

 

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 Gliclazide modified release tablets treatment may be affected by fever, infection, surgical intervention or when used concomitantly with St. John's Wort (Hypericum perforatum) preparations. Close 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 mild to moderately impaired hepatic function.

In patients with mild to moderately impaired renal function, renal function should be assessed periodically. Blood glucose and glycated hemoglobin levels should be regularly monitored in all patients.

Elderly patients (malnourished, with impaired hepatic, renal, or adrenal function) will require periodic monitoring and special care.

 

Serious Drug Interactions

The concomitant use of miconazole and gliclazide is contraindicated (see CONTRAINDICATIONS).

 

Overview

As a result of drug interaction, hypoglycemia may be potentiated when a sulfonylurea is used concurrently with agents such as: long-acting sulfonamides, tuberculostatics, NSAIDs, fibrates, monoamine oxidase inhibitors, salicylates, probenecid, beta-blockers, azole antifungal agents (oral and parenteral preparations), H2 receptor antagonists, angiotensin converting enzyme inhibitors and clarithromycin. In addition, while not approved for use with other antidiabetic agents, hypoglycaemia is potentiated when gliclazide is used in combination with other antidiabetic agents.

Certain drugs tend to induce hyperglycemia and may lead to loss of blood sugar control. These include diuretics (thiazides, furosemide), corticosteroids, oral contraceptives (estrogen plus progestogen), chlorpromazine, ritodrine, salbutamol, terbutaline 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.

Sulfonylureas may potentiate the action of anticoagulants. Adjustment of the anticoagulant dose may be necessary.

 

Drug-Drug Interactions

 

Table 2 – Established or Potential Drug-Drug Interactions

 

Gliclazide	Reference	Effect	Clinical Comment
Miconazole (systemic route, oromucosal gel)	C	Increases the risk of hypoglycaemia	Contra-indicated combination. Increases the hypoglycaemic effect with possible onset of hypoglycaemic symptoms, or even coma.
Phenylbutazone (systemic route)	C	Increases the risk of hypoglycaemia	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 hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
Beta-blockers	C	Increases the risk of hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
Fluconazole	C	Increases the risk of hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
Angiotensin converting enzyme inhibitors	C	Increases the risk of hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
H2-receptor antagonists	C	Increases the risk of hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
MAOIs	C	Increases the risk of hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
Sulfonamides	C	Increases the risk of hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
Nonsteroidal anti- inflammatory agents	C	Increases the risk of hypoglycaemia	Combinations requiring precautions for use. Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur.
Clarithromycin	T	Increases the risk of hypoglycaemi	Combinations requiring precautions for use. May potentiate the hypoglycemic action of sulfonylurea agents.
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.
Glucocorticoids (systemic and local route: intra-articular, cutaneous and rectal preparations) and tetracosactide	C	Causes an increase in blood glucose levels	Combination requiring precautions during use  Increase in blood glucose levels with possible ketosis (reduced tolerance to carbohydrates due to glucocorticoids). Warn the patient and emphasise 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.)	C	Causes an increase in blood glucose levels	Combination requiring precautions during use. Increased blood glucose levels due to beta-2 agonist effects. Emphasise the importance of monitoring blood glucose levels. If necessary, switch to insulin.
Anticoagulant therap (Warfarin and other)	C	Potentiation of anticoagulation	Combination which must be taken into account. Sulfonylureas may lead to potentiation of anticoagulation during concurrent treatment. Adjustment of the anticoagulant may be necessary.
Drugs containing alcohol	C	Increases the risk of hypoglycaemia	Intolerance to alcohol (disulfiram-like reaction: flushing, sensation of warmth, giddiness, nausea and occasionally tachycardia) may occur in patients treated with sulfonylurea.
Fluoroquinolones	T	Increases the risk of dysglycaemia	Combinations requiring precautions for use. Warn the patient and emphasise the importance of monitoring blood glucose.

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

There are no established drug-food interactions.

 

Drug-Herb Interactions

St. John’s Wort

Pharmacodynamic interactions between gliclazide and the herbal remedy St. John’s Wort may occur and may lead to hyperglycemia or loss of blood glucose control.

 

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

 

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 CLAZ MR can have effects on ability to drive and use machines. 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.

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:

CLAZ MR (gliclazide) is contraindicated in breast-feeding mothers. Some sulfonylurea drugs are excreted in human milk although it is not known whether gliclazide is one of them. Because the potential for hypoglycemia in nursing infants may exist, the product is contraindicated in breast-feeding mothers (see CONTRAINDICATIONS).

Patients should be made aware of the signs and symptoms of hypoglycaemia and should be careful if driving or operating machinery, especially at the beginning of treatment.

Adverse Drug Reaction Overview

Gliclazide modified release tablets 30 mg has 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 most frequent adverse drug reactions are hypoglycaemia and gastrointestinal disturbances (including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation).

Serious adverse drug reactions that resulted in hospitalization during clinical trials were malaise, acute renal failure, and thrombophlebitis.

 

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

 

Hypoglycemia

Severe hypoglycemia which mimics acute CNS disorders may occur. Hepatic and/or renal impairment, malnutrition, debility, advanced age, alcoholism, adrenal or pituitary insufficiency may be predisposing factors.

In long-term studies, the percentage of patients experiencing hypoglycemic episodes was similar between patients treated with gliclazide modified release tablets 30 mg (11.6%) and those treated with gliclazide 80 mg tablets (11.1%). However, the number of hypoglycemic episodes for 100 patient-months was lower in the gliclazide modified release tablets 30 mg group (3.5) than in the gliclazide 80 mg tablets group (4.8).

Analysis in elderly patients (over 65 years old) showed that this population experienced, overall, less hypoglycemia than the whole population with a prevalence of hypoglycemic episodes lower in the gliclazide modified release tablets 30 mg group (2.6 hypoglycemic episodes for 100 patient-months) than in the gliclazide 80 mg tablets group (4.1).

 

Other adverse events

Adverse events reported during controlled clinical trials with gliclazide modified release tablets 30 mg were those expected in the population of interest, a population whose underlying disease is recognized atheromatous risk factor.

Adverse events that have been reported in at least 1.0% of diabetic patients in long-term controlled studies, whatever their relationship to treatment, are listed by body system in Table 1. The most frequent adverse events were unspecific of the disease as respiratory infections or back pain.

 

Table 1 – Adverse events reported in ≥1% of type 2 diabetic patients in long-term controlled studies with Gliclazide Modified Release Tablets 30 mg vs. Gliclazide 80 mg

	Gliclazide 30 mg Modified Release Tablets (n= 728) %	Gliclazide 80 mg tablets (n=734) %
Resistance mechanism
Infection viral	7.7	5.6
Otitis media	1.1	0.8
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
Pneumonia	1.5	1.4
Sinusitis	1.5	1.1
Musculo-skeletal Back pain	5.2	4.1
Arthralgia	3.0	3.5
Arthrosis	2.2	2.2
Arthritis	1.4	2.3
Tendinitis	1.1	1.0
Myalgia	2.3	1.5
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
Oedema legs	1.2	1.4
Urinary Urinary tract infections	2.6	3.0
Gastrointestinal Diarrhea	2.5	2.0
Constipation	1.6	1.2
Gastritis	1.2	0.5
Gastroenteritis	1.1	1.5
Nausea	1.1	0.7
Abdominal pain	1.1	1.4
Central, periph. nervous system
Dizziness	2.2	2.3
Neuralgia	1.2	0.7
Metabolism and nutrition
Hypoglycemia	11.6	11.1
Hyperglycemia	1.9	2.2
Lipid metabolism disorder	1.4	0.5
Hyperlipaemia	1.0	0.8
Skin and appendages disorders
Dermatitis	1.6	1.2
Rash	1.0	1.2
Skin disorder	1.9	2.0
Pruritis	1.0	0.4
Vision disorders
Conjunctivitis	1.0	0.8
Psychiatric disorders
Depression	1.9	1.2
Insomnia	1.1	2.0

Analysis of adverse events in sub-populations led to similar pattern as in the whole population and showed that sex, age and renal insufficiency had no significant influence on the safety profile of 30 mg.

 

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Adverse events other than those already specifically mentioned in this product monograph and that have been reported with gliclazide modified release tablets 30 mg during long-term studies in more than one patient and/or that have been previously reported with gliclazide 80 mg tablets or with other sulfonylurea drugs include the following (drug relationship has not been proved for all cases):

 

Body as a whole: allergy, carpal tunnel syndrome, chest pain, fever, infection, fungal infection, leg pain, malaise, pain, weight increase.

Cardiovascular: arteritis, cardiac failure, cerebrovascular disorder, coronary artery disorder, epistaxis, hypotension, myocardial infarction, palpitation, tachycardia, thrombophlebitis, vein disorder.

Central, peripheral nervous system: anxiety, confusion, depression, insomnia, nervousness, neuropathy.

Endocrine: hypothyroidism. 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 gliclazide 80 mg tablets during a study involving 15 patients.

Gastrointestinal: 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 test 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, gastrointestinal disturbance, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea and constipation have been 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 drug rash with eosinophilia and systemic symptoms (DRESS) have been 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).

The following adverse events have also been observed with gliclazide: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, allergic vasculitis, hyponatremia, and elevated liver enzyme levels (AST, ALT, alkaline phosphatase); isolated cases of impairment of liver function with cholestasis and jaundice which can regress after withdrawal of the drug or may lead to life- threatening liver failure. Discontinue treatment if cholestatic jaundice appears.

 

-  To report any side effects:

 

Saudi Arabia: The National Pharmacovigilance and Drug Safety Centre (NPC) Fax: +966‐11‐205‐7662 Call NPC at +966‐11‐2038222, Exts: 2317‐2356‐2353‐2354‐2334‐2340. Toll free phone: 8002490000 E‐mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

 

Other GCC States: Please contact the relevant competent authority.

Symptoms

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.

 

Treatment of Overdosage

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 hospitalization.

Dialysis is of no benefit to patients due to the strong binding of gliclazide to proteins.

ATC Code: A10BB09

 

Hypoglycemic activity

The main mechanism of action of gliclazide consists of an increase in the insulin secretory potential of pancreatic beta-cells in a situation of hyperglycemia. This effect of gliclazide on insulin secretion is maintained during long-term treatment in type 2 diabetic patients. It was observed that the administration of gliclazide was followed by:

• a consistent and significant decrease in fasting blood glucose;
• a more than 1% decrease in mean glycated hemoglobin;
• an inhibition by 12 to 27% of the rise in blood glucose after a standard meal or an oral glucose load.

 

A slight and transitory increase in mean fasting plasma insulin levels was occasionally observed with gliclazide treatment.

Regarding the biphasic nature of insulin secretion, the first peak that is severely blunted in type 2 diabetes is improved during gliclazide treatment.

In addition to the effect of gliclazide on the secretion of insulin, extrapancreatic effects have also been evidenced. Gliclazide improves peripheral sensitivity to insulin and increases glucose utilization rate:

• with euglycemic hyperinsulinemic clamps in obese and non-obese type 2 diabetic patients, it has been shown that gliclazide, after 3 months of treatment, increases the disappearance rate and metabolic clearance of glucose at the highest insulin infusion rates (100 and 300 mU/kg/h);
• in comparison to diet treatment, gliclazide also enhances insulin-stimulated glucose
• metabolism after 8 weeks of treatment by potentiating insulin action on skeletal muscle glycogen synthetase.

Studies on glucose turnover have also shown that basal hepatic glucose production, measured by tracer methodology, was markedly reduced (28-50%) after 3 months of treatment.

 

Hemovascular activity

Gliclazide possesses anti-platelet properties which are independent of its antidiabetic action, and improves the fibrinolytic potential in diabetic patients:

• numerous studies have shown inhibitory effects of gliclazide on platelet aggregation and hyperadhesiveness.
• A statistically significant 22% decrease in collagen-induced platelet aggregation has been observed after 3 and 6 months of treatment with gliclazide in 15 patients previously well controlled under glibenclamide. A concentration-dependent inhibition of PAF-induced platelet aggregation has also been reported with gliclazide in vitro in platelet-rich plasma from healthy subjects and type 2 diabetic patients. Finally, a consistent decrease in markers of platelet activation (e.g. beta thromboglobuline and thromboxane B2 levels) has been observed with gliclazide whether glycemic control improved or not; change to gliclazide of patients treated since several years by chlorpropamide is followed by normalisation of the t-PA activity, sustained over 24-48 months. This has been confirmed by 2 studies in type 1 and glibenclamide-treated type 2 diabetics: in both, the addition of gliclazide to insulin or the switch to this sulfonylurea were followed by significant increase in t-PA and in the activity of the intrinsic fibrinolytic system.

 

Antioxidant activity

Gliclazide is a strong free radical scavenging agent, an effect demonstrated both in vitro and in patient. In 17 type 2 diabetic patients switched to gliclazide and seen at regular intervals during a 36-week period, peroxidized lipids and oxidized damaged IgG decreased significantly. These effects of gliclazide on the oxidative stress have been confirmed in a double-blind study in diabetic patients. Highly significant and sustained decrease in peroxidized lipid levels and increase in erythrocyte superoxide dismutase activity were obtained with gliclazide, but not with glibenclamide.

Absorption:

Gliclazide is slowly and completely absorbed from the gastro-intestinal tract (mean absolute bioavailability of 97%).

After administration, plasma concentrations rise gradually and the maximum concentration is usually reached after about 6 hours, with a plateau maintained for another 4 to 6 hours. Intra- individual variability is low. Food intake does not affect the rate and extent of absorption. The relationship between the dose administered and the area under the concentration curve as a function of time is linear. Linear kinetics were observed with gliclazide modified release tablets 30 mg in the dose range up to 120 mg.

 

Distribution:

The volume of distribution is relatively small, which can partially be explained by high protein binding (about 95%).

A single daily dose of Gliclazide modified release tablets 30 mg maintains effective gliclazide plasma concentrations over 24 hours.

 

Metabolism:

Although more than 90% of unchanged gliclazide is found in plasma following oral administration, this is extensively metabolized with little of the unchanged compound (<1%) found in urine. Six principal metabolites have been identified in urine, essentially oxidized and hydroxylated derivatives, and two glucuronoconjugates. No active metabolites have been detected in plasma.

 

Excretion:

Gliclazide metabolites and conjugates are primarily (60 to 70%) eliminated via the urine, with about 10 to 20% elimination via feces.

The mean elimination half life is 16 h (range 12 to 20 h).

 

Special Populations and Conditions

Pediatrics: Safety and effectiveness of gliclazide in children have not been established. Gliclazide is therefore not recommended for use in children and adolescents.

Geriatrics: No clinically significant modifications in the pharmacokinetic parameters have been observed in elderly patients.

Gender: No significant relationship was found between any of the pharmacokinetic parameters and the covariates gender, body weight and creatinine clearance.

Not Available

Each tablet of CLAZ MR 30 mg contains: Drug substance: 30 mg gliclazide

Excipients: colloidal silicon dioxide, hydroxypropyl methylcellulose and stearic acid

Each tablet of CLAZ MR 60 mg contains: Drug substance: 60 mg gliclazide

Excipients: colloidal silicon dioxide, hypromellose, lactose, stearic acid

None Applicable

24 months

Store below 30°C. Protect from moisture.

Strength	Unit Count or Fill Size	Container Size(s)	Description
30 mg	30’s	Blisters	Film PVC/PVdC Clear 10 MIL 205/60 205MM: Clear transparent plastic film, smooth on both sides. Approximately 205 mm wide. Foil Silver Plain 205MM 25µM: Dull silver on one side, shiny silver on other. Rolled material approximately 205 mm wide.

 

60 mg

30’s

Blisters

Film PVC/PVdC Clear 10 MIL 205/60 205MM: Clear transparent plastic film, smooth on both sides. Approximately 205 mm wide. Film PVC/PVdC Clear 10 MIL 205/60 205MM Clear transparent plastic film, smooth on both sides. Approximately 205 mm wide. Cold Formable Foil 205MM: Dull silver on one side, shiny silver on other. Rolled material approximately 205 mm wide.. Foil Silver Plain 205MM 25µM: Dull silver on one side, shiny silver on other. Rolled material approximately 205 mm wide Foil White Coated 205MM 25µM: Light grey on one side, dull silver on other. Rolled material approximately 205 mm wide.

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.