Glycinorm M Gliclazide and Metformin Hydrochloride Tablets

Glycinorm-M
Gliclazide and Metformin Hydrochloride Tablets

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory.

 

DESCRIPTION

Glycinorm-M combines two antidiabetic agents, gliclazide belonging to the class of sulphonylurea and metformin hydrochloride belonging to the group of biguanides.

Glidazide is a hypoglycaemic sulphonylurea oral antidiabetic differing from other related compounds by the addition of an azabicyclo-octane ring. It is a second generation sulphonylurea drug that has hypoglycaemic and potentially useful hemobiological properties. It has chemical formula N-[[Hexahydrocyclopental[c]pyrrol-2(IH)-yl)-amino]carbonyl]-4-methylbenzene sulfonamide. Its empirical formular is C15H21N3O3S.

Metformin is an oral antihyperglycemic drug used in the management of type 2 diabetes.

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any otherclasses of oral antihyperglycemic agents. The molecular formula of metformin is C4H11N5NCl and molecular weight is 165.63.

 

COMPOSITION

Glycinorm-M 40

Each tablet contains:

Gliclazide BP 40mg

Metformin Hydrochloride BP 400mg

Glycinorm-M 80

Each tablet contains:

Gliclazide BP 80mg

Metformin Hydrochloride BP 500mg.

 

PHARMACOLOGY

Pharmacodynamics

Gliclazde

Gliclazide reduces blood glucose levels by stimulating insulin secretion from the beta cells of the islets of Langerhans.

It corrects both defective insulin secretion and peripheral insulin resistance. Unstimulated and stimulated insulin secretion from pancreatic β-cells is increased following administration of gliclazide, with both the first and second phases of secretion being affected. This occurs via the binding of gliclazide to specific receptors on pancreatic β-cells which results in a decrease in potassium efflux and causes subsequent depolarisation of the cell. Subsequently, calcium channels open, leading to an increase in intracellular calcium and induction of insulin release. In addition gliclazide increases the sensitivity of β-cells to glucose.

In type 2 diabetics, gliclazide restores the first peak of insulin secretion in response to glucose and increases the second phase of insulin secretion. Significant increase in insulin response is seen in response to stimulation induced by a meal or glucose.

Gliclazide may have extra pancreatic effects which restore peripheral insulin sensitivity, such as decreasing hepatic glucose production and increasing glucose clearance and skeletal muscle glycogen synthase activity. These effects do not appearto be mediated by an effect on insulin receptor number, affinity or function.
In addition to these metabolic properties, gliclazide has haemovascular properties.

 

Haemovascular properties

Gliclazide decreases microthrombosis by two mechanisms which may be involved in complications of diabetes:

• A partial inhibition of platelet aggregation and adhesion, with a decrease in the markers of platelet activation (beta thromboglobulin, thromboxane B2).

• An action on the vascular endothelium fibrinolytic activity an increase in tPA activity.
Limited data suggest that gliclazide may reduce levels of free radicals hence preventing vascular damage mediated by these chemical species.

 

Metformin

Metformin is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial pIasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

 

Pharmacokinetics

Gliclazide

Gliclazide is readily absorbed from the gastrointestinal tract. Food intake does not affect the rate or degree of absorption. Plasma protein binding is approximately 95%.
Gliclazide is mainly metabolised in the liver and excreted in the urine: less than 5% of the dose is excreted unchanged in the urine. No active metabolites have been detected in plasma. The half life is about 10 to 12 hours.

No clinically significant changes in pharmacokinetic parameters have been observed in elderly patients.

 

Metformin

The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Food decreases the extent of and slightly delays the absorption of metformin.

Metformin is negligibly bound to plasma proteins. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor billary excretion. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half life of approximately 6.2 hours.

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

 

INDICATIONS

Glycinorm-M is indicated in patients with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control not controlled by either drug alone.

 

CONTRAINDICATIONS

– Known hypersensitivity to gliclazide, metformin hydrochloride or to any of the excipients, other sulphonylureas, sulphonamides.

– Type 1 diabetes.

– Acute or chronic metabolic acidosis including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

– Severe hepatic insufficiency, acute alcohol intoxication, alcoholism.

– Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels >1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.

– Treatment with miconazole.

– Pregnancy and lactation.

– Juvenile onset diabetes.

– Congestive heart failure requiring pharmacologic treatment.

– It should not be used when the following medical problems exists; severe burns, significant acidosis, major surgery, severe trauma, infections or any conditions that causes severe glucose fluctuations or in which insulin needs change rapidly.

– It should be temporarily discontinued patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

 

WARNINGS

Lactic Acidosis

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with gliclazide and metformin combination; when it occurs, it is fatal in approximately 51% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported case have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple a concomitant medical/surgical problems and multiple concomitant medications.

The risk of lactic acidosis can be significantly decreased by regular monitoring of renal function in patients taking the combination. In addition, the combination should be promptly withheld in the presence of a condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, gliclazide and metformin combination should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking the combination, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, the combination should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.

In a patient with lactic acidosis who is taking gliclazide and metformin, the drug should be discontinued immediately and general supportive measures promptly instituted.

 

Diet/exercise

In initiating treatment for type 2 diabetes, emphasize diet as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. Loss of blood glucose control in diet-managed patients may be transient, thus requiring only short-term pharmacologic therapy. Also, stress the importance of regular physical activity and aid the patient in identifying cardiovascular risk factors and taking corrective measures where possible. If this treatment program fails to reduce symptoms or blood glucose, consider the use of drug.

 

PRECAUTIONS

Hypoglycaemia

It is important to have regular carbohydrate intake due to the increased risk of hypoglycaemia if a meal is taken late, if an inadequate amount of food is consumed or if the food is Iow in carbohydrate. Hypoglycaemia is more likely to occur during low-calorie diets, following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycaemic agents is being used.

Hypoglycaemia may occur following administration of sulphonylureas. Some cases may be severe and prolonged. Hospitalisation may be necessary and glucose administration may need to be continued for several days.

Careful selection of patients, of the dose used, and clear patient directions are needed to reduce the risk of hypoglycaemic episodes.

Factors which increases the risk of hypoglcycaemia:

– patient refuses or (particularly in elderly subjects) is unable to co-operate.

– malnutrition, irregular mealtimes, skipping meals, periods of fasting or dietary changes.

– imbalance between physical exercise and carbohydrate intake

– renal Insufficiency.

– severe hepatic insufficiency.

– overdose.

– certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency.

– concomitant administration of certain other medicines (See Drug interactions).

 

Poor blood glucose control

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such limes, it may be necessary to withhold the drug and temporarily administer insulin. The combination may be reinstituted after acute episode is resolved.

The hypoglycaemic efficacy of any oral antidiabetic agent, including gliclazide, is attenuated over time in many patients; this may be due to progression in the severity of the diabetes, or to a reduced response to treatment. This phenomenon is known as secondary failure which is distinct from primary failure, when an active substance is ineffective as first line treatment. Adequate dose adjustment and dietary compliance should be considered before classifying the patient as secondary failure.

 

Monitoring of renal function

Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive the combination. In patients with advanced age, the combination should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥ 80 years of age, renal function should be monitored regularly and, generally, the combination should not be titrated to the maximum dose.
Before initiation of the combination therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and the combination discontinued if evidence of renal impairment is present.

 

Use of concomitant medications that may affect renal function or metformin disposition

Concomitant medications that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.

 

Radiologic studies involving the use of intravascular iodinated contrast materials

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, gliclazide and metformin combination should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

 

Hypoxic states

Cardiovascular lapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on combination therapy, the drug should be promptly discontinued.

 

Surgical procedures

The combination therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patients oral intake has resumed and renal function has been evaluated as normal.

 

Alcohol intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving the combination therapy.

 

Impaired hepatic function

Because impaired hepatic function has been associated with cases of lactic acidosis, the combination therapy should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

 

Vitamin B12 levels

In extended clinical trials of metformin, a decrease to subnormal level of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation.

Measurement of hematologic parameters on an annual basis is advised in patients on Metformin and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In the patients, routine serum Vitamin B12 measurements at two to three-year intervals may be useful.

 

Laboratory Tests

Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosyIated hemoglobin levels, with a goal of decreasing these levels toward the nominal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control.

Regular hepatic and haematological monitoring (especially leucocytes and thrombocytes) are required during treatment with glimepiride.

Initial and periodic monitoring of hematologic parameters (e.g. hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamm B12 deficiency should be excluded.

 

Effect on ability to drive and use machines

Patients should be informed that their concentration may be affected if their diabetes is not satisfactorily controlled, especially at the beginning of treatment.

 

Usage in pregnancy and lactation

Glycinorm-M is contraindicated in pregnancy and lactation.

 

Usage in paediatrics

There are no data and clinical studies available in children.

 

Usage in geriatrics

Clinical experience in the elderly to date shows that gliclazide is effective and well tolerated. Care should be exercised however, when prescribing sulphonylureas in the elderly due to a possible age-related increased risk of hypoglycaemia.

Some elderly patients may be more sensitive to the drug, but the plasma clearance is not altered so that increased plasma levels are unlikely. All sulphonylureas should be used with caution in the elderly because of the greater likelihood of their missing meals and the more severe outcome of significant hypoglycemia.

Because aging is associated with reduced renal function, Glycinorm-M should be used with caution as age increases. Care should be taken in dose selection and should be based on useful and regular monitoring of renal function.

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half life is prolonged and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Metformin should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

 

Drug Interactions

Miconazole (systemic route, oromucosal gel)

Increases the hypoglycemic effect with possible onset of hypoglycaemic symptoms or even coma.

 

Phenylbutazone (systemic route)

Increases the hypoglycaemic effect of sulphonylureas (displaces their binding to plasma proteins and/or reduces their elimination) and hence their use in combination with sulphonylurea is not recommended.

 

Alcohol

Increases the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Hence their use in combination with sulphonylurea is not recommended.

 

Danazol

Diabetogenic effect of danazol. Hence their use in combination with sulphonylurea is not recommended.

 

Furosemide

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the elimination half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

 

Nifedipine

Co-administration of nifedipine increased pIasma metformin Cmax and AUC by 20% and 9%. respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

 

Cationic drugs

Cationic drugs (e.g. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of Glycinorm-M tablets and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

 

Glibenciamide

In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glibenclamide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glibenclamide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glibenclamide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain.

 

Other drug interactions

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. The drugs include the thiazides and other diuretics, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Glycinorm-M, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glycinorm-M, the patient should be observed closely for hypoglycemia.

Care should be taken when giving gliclazide and metformin combination with drugs which are known to alter the diabetic state or potentiate the drug’s action.

The hypoglycaemic effect of gliclazide may be potentiated by phenylbutazone, salicylates, sulphonamides, nonsteroidal anti-inflammatory agents, coumarin derivatives, other antidiabetic agents (insulins, acarbose, biguanides), MAOIs, beta adrenergic blocking agents, tetracycline compounds, chloramphenicol, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H2 receptor antagonists, clofibrate, disopyramide, miconazole (oral forms) and cimetidine.

Chlorpromazine (neuroleptic agent) in high doses (>100mg per day of chlorpromazine) increase blood glucose levels (reduced insulin release). Glucocorticoids by systemic and local route (intra-articular, cutaneous and rectal preparations) and tetracosactrin increase blood glucose levels with possible ketosis (reduced tolerance to carbohydrate due to glucocorticoids). Ritodrine, salbutamol, terbutaline by l.V. route increased blood glucose levels due to beta-2 agonist effects.

Sulfonlyureas may lead to potentiation of anticoagulation during concurrent treatment with anticoagulant (warfarin). Adjustment of the anticoagulant may be necessary.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformim and ibuprofen were not affected when co-administered in single-dose interaction studies.

 

ADVERSE DRUG REACTIONS

Gliclazide-related

Hypoglycaemia

As for other sulphonylureas, treatment with gliclazide can cause hypoglycaemia, if mealtimes are irregular, and in particular, if meals are skipped. Possible symptoms of hypoglycaemia are: headaches, intense hunger, nausea, vomiting, lassitude, drowsiness, 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, drowsiness and loss of consciousness, possibly resulting in coma and lethal outcome.

In addition, signs of adrenergic counter-regulation may be observed: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.

Usually symptoms disappear after intake of carbohydrate (sugar). However, artificial sweeteners have no effect. Experience with other sulphonylureas shows that hypoglycaemia can recur even when measures prove effective initially.

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 are required.

 

Gastrointestinal disturbances

Including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea, and constipation have been reported; if these should occur they can be avoided or minimised if gliclazide is taken with breakfast.

 

Skin reactions

Including rash, pruritus, erythema, bullous eruption have been observed during treatment with gilclazide but are not known to be directly attributable to the drug.

 

Blood dyscrasia

Including anaemia, leucopenia, thrombocytopenia and granulocytopenia have also been observed during treatment with gliclazide. Again they are not known to be directly attributable to the drug.

 

Hepatic disorders

Abnormalities of hepatic function are not uncommon during gliclazide therapy. There are rare reports of hepatic failure, hepatitis and jaundice following treatment with gliclazide.

In addition to above adverse effects the following undesirable effects have been more rarely reported with modified release gliclazide: Allergic vasculitis, rare cases of erythrocytopenia, agranulocytosis, haemolytic anaemia and pancytopenia have been described for other sulphonylureas. Raised hepatic enzyme levels (AST, ALT, alkaline phosphatase) have been reported. Discontinue treatment if cholestatic jaundice appears. Transient visual disturbances may occur especially on initiation of treatment, due to changes in blood glucose levels.

 

Metformin-related

The most common adverse reactions (>5%) with metformin included diarrhoea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort and headache.
Additionally the following adverse reactions were reported in ≥ 1.0 – ≤ 5.0% of metformin patients and were more commonly reported with metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, increased sweating, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

Lactic acidosis and mild erythema in some hypersensitive individuals are very rare side effects of metformin.

During initiation of metformin therapy, approximately 3% of patients may complain of an unpleasant or metallic taste, which usually resolves spontaneously.

A decrease in vitamin B12 absorption with decrease of serum levels has been observed in patients treated long term with metformin and appears generally to be without clinical significance.

 

OVERDOSAGE

Gliclazide

The symptom to be expected of overdose would be hypoglycaemia.

The treatment is gastric lavage and correction of the hypoglycaemia. Dialysis is of no benefit to patients due to the strong binding of gliclazide to proteins.

Moderate symptoms of hypoglycaemia, without any loss of consciousness or neurological signs, must be corrected by carbohydrate intake, dose adjustment and/or change of diet. Strict monitoring should be continued until the doctor is sure that the patient is out of danger.

Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as 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 that will maintain blood glucose levels above 1g/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.

 

Metformin

Overdose of metformin has occurred, including ingestion of amounts greater than 50g. Hypoglycemia was retorted in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

 

DOSAGE AND ADMINISTRATION

Dosage must be individualized on the basis of effectiveness and tolerance while not exceeding the maximum recommended daily dose. The patient’s fasting blood glucose and HbA1C must be measured periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e. inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e. loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels should be performed to monitor the patient’s response to therapy.

Glycinorm M tablets are to be administered to patients of type II diabetes mellitus with inadequate glycemic control on gliclazide or metformin monotherapy.
The initial dosage is one tablet of Glycinorm M 40 once daily, to be given with breakfast or with the first main meal.

In patients who do not achieve glycemic control with the above dose, the dosage can be increased one tablet per day every 2 weeks, depending on the clinician’s judgment and on the basis of both effectiveness and tolerance, not exceeding total daily dose of 320mg of gliclazide and total duty dose of 2000mg of metformin.

A single dose of gliclazide should not exceed 160mg. When higher doses are required, Glycinorm M should be taken twice daily and according to the main meals of the day. Dosage of Glycinorm-M must not exceed the maximum recommended daily dose of 5 tablets of Glycinorm-M 40 or 4 tablets of Glycinorm-M 80.

With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to the combination and to identify the minimum effective dose for the patient.

For patients previously treated with combination therapy of another sulphonylurea plus metformin, if switched to this combination, the starting dose should not exceed the daily dose of the other sulphonylurea and metformin already being taken.

 

Dosage in renal and hepatic impairment

Because of the risk of lactic acidosis, which often is fatal, the drug should not be used in patients with renal disease or dysfunction and should be avoided in those with clinical or laboratory evidence of hepatic disease.

 

Dosage in elderly debilitated or malnourished patients

The initial and maintenance dosing of the combination should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of the combination to avoid the risk of hypoglycemia. Monitoring of renal function is to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly.

 

PRESENTATION

Glycinorm-M 40: Blister strip of 10 tablets.

Glycinorm-M 80: Blister strip of 10 tablets.

 

STORAGE

Store below 30oC, in a dry place.

KEEP OUT OF REACH OF CHILDREN

 

Made in India by

Ipca Laboratories Ltd.

Regd. Off.: 48, Kandivli Ind. Estate,

Mumbai 400 067

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