Euglucon Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

EUGLUCON^® (glyburide) is indicated:

• To control hyperglycemia in glyburide-responsive diabetes mellitus of stable, mild, non-ketosis prone, maturity-onset or adult type (Type 2) which cannot be controlled by proper dietary management and exercise, or when insulin therapy is not appropriate.

Geriatrics:

Elderly with type 2 diabetes when treated with EUGLUCON^® (glyburide) may be more prone to hypoglycaemia⁸ (see WARNINGS and PRECAUTIONS, Special Populations).

Pediatrics (< 18 years of age):

Safety and effectiveness of EUGLUCON^® (glyburide) have not been established in this population. Use in patients under 18 years of age is not recommended (see WARNINGS and PRECAUTIONS, Special Populations).

CONTRAINDICATIONS

EUGLUCON^® (glyburide) is contraindicated in patients with:

• Known hypersensitivity or allergy to glyburide, to any sulfonylurea or sulfonamides or any other component of the formulation. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Unstable and/or Type 1 diabetes (formerly known as insulin-dependent diabetes mellitus).
• Diabetic ketoacidosis with or without coma. This condition should be treated with insulin.
• Diabetic precoma or coma.
• Severe liver disease or frank jaundice.
• Severe renal impairment (creatinine clearance less than 30 mL/min).
• Patients treated with bosentan (see DRUG INTERACTIONS).

• Pregnancy and lactation.

  During pregnancy, no oral antidiabetic agent should be given.

  Due to the possible excretion in human milk, the patient should discontinue nursing or discontinue taking the drug depending on the importance of the drug to the mother. If glyburide is discontinued, the patient should be transferred to insulin therapy.

WARNINGS AND PRECAUTIONS

General

Use of EUGLUCON^® must be viewed by both the physician and patient as a treatment in addition to diet and exercise and not as a substitute for proper dietary management, exercise and weight reduction or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet and exercise alone may be transient, thus requiring only short-term administration of EUGLUCON^®. As is necessary during treatment with any blood-glucose-lowering drug, the patient and the physician must be aware of the risk of hypoglycaemia.

In initiating treatment for Type 2 diabetes, non-pharmacologic therapy (proper dietary management, exercise and weight reduction) should be emphasized as the initial form of treatment. Caloric restriction, weight loss and exercise are essential in the obese diabetic patient.

Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycaemia. If non-pharmacologic therapy fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea should be considered.

Patient Selection and Follow-Up

Careful selection of patients is important.

It is imperative that there be careful ongoing attention to diet, adherence to regular exercise, reduction of body weight in obese patients, careful adjustment of dosage, instruction of the patient on hypoglycaemic reactions and their control, as well as regular, thorough follow-up

examinations. Cardiovascular risk factors should be identified.

The effectiveness of any oral hypoglycaemic drug, including EUGLUCON^®, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon, known as secondary failure, is distinctive of primary failure, in which the drug is ineffective in an individual patient when given for the first time.

Patients should therefore be monitored with regular clinical and laboratory evaluations, including blood glucose and glycosylated hemoglobin (A_1C) determinations, to determine the minimum effective dosage and to detect primary failure (inadequate lowering of blood glucose concentrations at the maximum recommended dosage) or secondary failure (progressive deterioration in blood sugar control following an initial period of effectiveness). The rate of primary failure will vary greatly depending upon patient selection and adherence to diet and exercise. The etiology of secondary failure is multifactorial and may involve progressive β-cell failure as well as exogenous diabetogenic factors such as obesity, illness, drugs, or tachyphylaxis to the sulfonylurea.

Cardiovascular

Some literature studies have suggested an association between the use of sulfonylureas and the risk of cardiovascular events including cardiovascular mortality, since these agents may potentially impair cardioprotective processes. Although, there is inconsistency in the literature regarding a definite conclusion for this association, a cautious approach is nevertheless warranted. All patients on sulfonylureas, particularly high risk patients with cardiovascular disease, should be closely monitored for cardiovascular complications.

Some literature studies have suggested an association between glyburide and QTc interval prolongation. Particular caution should be observed in patients who have risk factors for torsade de pointes, such as QTc prolongation at baseline, cardiovascular disease, or electrolyte abnormalities, or who are receiving other QTc interval prolonging drugs (see DRUG INTERACTIONS).

Endocrine and Metabolism

Hypoglycaemia

Hypoglycaemia, sometimes prolonged and even life-threatening, may occur as a result of the blood-glucose-lowering action of EUGLUCON^®. Severe hypoglycaemia can be induced by all sulfonylurea drugs. Thus, proper patient selection, dosage, and instructions are important to avoid hypoglycaemic episodes. Hepatic and/or renal disease, inadequate caloric intake, malnutrition and/or irregular meals, exercise without adequate caloric supplementation, debility, advanced age, patient non-compliance, when alcohol is ingested (especially in combination with skipped meals), certain disorders of thyroid function, adrenal or pituitary insufficiency, excessive glyburide dosage, treatment with glyburide in the absence of indication or concurrent use with other agents with blood glucose lowering potential (see DRUG-DRUG INTERACTIONS) may be predisposing factors. Oral hypoglycaemic agents should be administered with caution to

patients with Addison's disease.

The patient should be questioned about such factors, as well as about pertinent lifestyle changes, concomitant illnesses and hypoglycemic episodes as these may indicate the need for particularly careful monitoring. If necessary, the dosage of EUGLUCON^® may need to be modified.

The manifestations of hypoglycaemia include: flushing or pallor, chilliness, excessive hunger, trembling, headache, dizziness, nausea, vomiting, restlessness, aggressiveness, depression, speech disorders, aphasia, sensory and/or visual disturbances, helplessness, lassitude, shallow respiration or bradycardia. In more severe cases, the clinical symptoms of a stroke or coma appear. However, symptoms of hypoglycaemia are not necessarily as typical as described above and sulphonylureas may cause insidious development of symptoms mimicking cerebrovascular insufficiency (e.g., disordered sleep, somnolence, impaired alertness and reactions, confusion, delirium, cerebral convulsions, paralytic symptoms or loss of consciousness).

Signs of adrenergic counter-regulation to hypoglycaemia include: sweating, damp skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmias. However, these symptoms may be milder or absent in patients who develop hypoglycaemia gradually, patients with autonomic neuropathy, elderly or patients who receive concurrent treatment with sympatholytic agents (e.g., beta blockers, clonidine, reserpine, guanethidine) (see DRUG-DRUG INTERACTIONS).

Mild to moderate episodes of hypoglycaemia can usually be treated by immediate intake of oral carbohydrates. Patients should be advised to carry an adequate amount of glucose with them at all times. Patients may require the assistance of other persons. Artificial sweeteners are ineffective in controlling hypoglycaemia. The symptoms of hypoglycaemia nearly always subside when hypoglycaemia is corrected. Despite initially successful countermeasures, hypoglycaemia may recur. Patients must, therefore, remain under close observation after an episode of hypoglycemia.

Severe hypoglycaemia, which may be prolonged and has occasionally been life-threatening, may occur and mimics acute CNS disorders. Signs of severe hypoglycaemia can include disorientation, loss of consciousness, and seizures. Severe hypoglycaemia, or a protracted episode, which can only be temporarily controlled by usual amounts of sugar requires in-patient hospital care.

Drug interactions: Severe hypoglycemia has been reported following coadministration of clarithromycin and glyburide. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has also been reported. See DRUG INTERACTIONS.

Loss of control of blood glucose

If loss of adequate blood glucose lowering response to sulfonylurea is detected, treatment must be reassessed.

When a patient stabilized on any diabetic regimen is exposed to stress such as illness during therapy, fever, trauma, infection, or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to adjust the dosage of EUGLUCON^® or consider discontinuation of EUGLUCON^® and administration of insulin.

Lactose

EUGLUCON^® tablets contain lactose monohydrate. Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this product.

Hematologic

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD)-deficiency with sulfonylurea agents can lead to haemolytic anemia. Since EUGLUCON^® belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a nonsulfonylurea alternative should be considered.^29,55

Hepatic/Biliary/Pancreatic

The metabolism and excretion of sulfonylureas including EUGLUCON^® may be slowed in patients with impaired hepatic function (see MONITORING AND LABORATORY TESTS below). EUGLUCON^® is contraindicated in patients with severe liver disease or frank jaundice. Patients with liver disease may be more susceptible to glyburide-induced hypoglycaemia. Elevation of liver enzyme levels has been reported very rarely in patients treated with glyburide (see Monitoring and Laboratory Tests; ADVERSE REACTIONS - Adverse Drug Reaction Overview).

Immune

Persons allergic to sulfonamide derivatives may also develop an allergic reaction to glyburide.

Peri-operative considerations

See Endocrine and Metabolism section - Loss of control of blood glucose.

Renal

EUGLUCON^® is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min).¹⁹ In patients with mild to moderate renal insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycaemic reactions. See Monitoring and Laboratory Tests; ACTION AND CLINICAL PHARMACOLOGY, Special Populations.

Special Populations

Pregnant Women: The use of EUGLUCON^® is contraindicated in pregnancy (see CONTRAINDICATIONS). EUGLUCON^® should be discontinued in patients who become pregnant or who are planning a pregnancy. These patients should be changed over to insulin. Recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Experts, including the Canadian Diabetes Association and the Canadian Medical Association recommend that insulin be used during

pregnancy to maintain glucose levels as close to normal as possible.⁸

Nursing Women: The use of EUGLUCON^® is contraindicated in lactating women (see CONTRAINDICATIONS).

Pediatrics (< 18 years of age): Safety and effectiveness of EUGLUCON^® (glyburide) have not been established in this population. Use in patients under 18 years of age is not recommended.

Geriatrics: Elderly patients with Type 2 diabetes are more susceptible to hypoglycaemia.⁸

Monitoring and Laboratory Tests

Fasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylated hemoglobin (HbA_1C) should also be monitored, usually every 3 to 6 months, to more precisely assess long-term glycaemic control. Blood glucose self-monitoring is also recommended.

Periodic assessment of cardiovascular, ophthalmic, hematologic, renal and hepatic status is recommended.

EUGLUCON^® is contraindicated in patients with severe liver disease and frank jaundice. Glyburide is extensively metabolized by the liver (see ACTION AND CLINICAL PHARMACOLOGY – Pharmacokinetics), thus patients with liver disease may be more susceptible to glyburide-induced hypoglycaemia. Patients with mild to moderately impaired hepatic function should be monitored carefully for hypoglycaemia and should have their hepatic function reassessed periodically.

Elderly patients, particularly those who are malnourished or who have mild to moderate hepatic or renal insufficiency or impaired adrenal function, will require special care.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Hypoglycemia and weight gain are common side effects of treatment with glyburide.⁸

Blood and lymphatic system disorders: Potentially life-threatening hematological changes may occur. Rare cases of mild to severe thrombocytopenia which can manifest as purpura have been reported. Leukopenia, agranulocytosis, pancytopenia (which may be due to myelosuppression), erythrocytopenia, granulocytopenia, hemolytic anemia (immune, G6PD-deficiency) and aplastic anemia have been observed very rarely with glyburide therapy. These reactions may be reversible following discontinuation of the sulphonylurea antidiabetic agent.^{1,29,30,36,55}

Endocrine disorders: Reduced radioactive iodine uptake by the thyroid gland has been reported.

Eye disorders: Transient visual disturbances may occur at the commencement of treatment due to fluctuations in blood glucose levels.

Gastrointestinal disorders: Nausea, epigastric fullness and heartburn are common reactions. Vomiting, diarrhea and abdominal pain have also been reported. These tend to be dose-related and may disappear when dosage is reduced.

General disorders and administration site conditions: Fatigue, malaise, and weakness have been reported.

Hepatobiliary disorders: Elevation of liver enzyme levels has been reported very rarely in patients treated with glyburide. In isolated cases, impairment of liver function (e.g. cholestasis and jaundice) and hepatitis have been observed, which can regress after withdrawal of the drug or may lead to life-threatening liver failure.

Immune system disorders: Allergic skin reactions such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions have been observed following sulfonylurea therapy. These may subside with continued use of the drug, but if they persist, the drug should be discontinued.

Reactions such as urticaria may very rarely develop into serious and life-threatening reactions including dyspnea, hypotension or shock. The patient should be advised to contact a physician immediately if urticaria develop.

Allergic vasculitis has been observed very rarely in patients receiving glyburide and in some circumstances may be life-threatening, including a severe skin reaction in one patient that occurred as a result of a generalized hypersensitivity to glyburide; hepatic, splanchnic and renal complications, followed by bronchopneumonia and renal failure resulted in a fatal outcome.¹⁰

A hypersensitivity reaction may occur in response to exposure to glyburide or to any of the excipients in EUGLUCON^®. Cross-sensitivity to sulfonamides or their derivatives may occur in patients treated with oral sulphonylurea hypoglycaemic agents.

Metabolism and nutrition disorders: Severe hypoglycemia which mimics acute central nervous system disorders may occur (see WARNINGS AND PRECAUTIONS).

Hepatic porphyria and disulfiram-like reactions have been observed.

Cases of hyponatremia have been reported with sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increased release of antidiuretic hormones. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increased release of ADH.

Nervous system disorders: Headache, tinnitus, and dizziness have been reported.

Skin and subcutaneous tissue disorders: Porphyria cutanea tardis and photosensitivity reactions have been reported.

Clinical Trial Adverse Drug Reactions

No clinical trial adverse drug reaction data available.

Post-Market Adverse Drug Reactions

The following serious and unexpected adverse events not previously listed in the Adverse Drug Reaction Overview section of the Product Monograph have been reported. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: anaemia, neutropenia

Cardiac disorders: cardiac arrest, cardiac failure acute, myocardial infarction, torsade de pointes

Eye disorders: blindness

Gastrointestinal disorders: ascites, constipation, large intestinal obstruction, lower gastrointestinal haemorrhage, melaena, pancreatitis acute, varices oesophageal

General disorders and administration site conditions: death, drug ineffective, drug interaction, general physical health deterioration, ill-defined disorder, multi-organ failure, oedema peripheral

Hepatobiliary disorders: cryptogenic cirrhosis, hepatic cirrhosis, hepatitis acute, hepatitis toxic, hepatocellular injury, liver disorder, liver injury

Infections and infestations: Acinetobacter infection, candiduria, cytomegalovirus enteritis, gastroenteritis, staphylococcal infection, zygomycosis

Injury, poisoning and procedural complications: accidental exposure, drug toxicity, fall, overdose, poisoning, therapeutic agent toxicity, traumatic brain injury

Investigations: antinuclear antibody positive, blood creatinine increased, blood glucose increased, electrocardiogram QT prolonged, Glasgow coma scale abnormal, haemoglobin decreased, transaminases increased

Metabolism and nutrition disorders: decreased appetite, dehydration, diabetes mellitus, failure to thrive, hypoglycaemic unconsciousness, lactic acidosis, metabolic acidosis

Musculoskeletal and connective tissue disorders: myalgia, polymyalgia rheumatica, rheumatoid arthritis

Neoplasms benign, malignant and unspecified (including cysts and polyps): neoplasm malignant, rectal adenoma

Nervous system disorders: altered state of consciousness, coma, depressed level of consciousness, dysarthria, haemorrhagic stroke, hemiparesis, hypoglycaemic coma, hypoglycaemic encephalopathy, motor dysfunction, neurological symptom

Psychiatric disorders: abnormal behaviour, confusional state, delirium, disorientation, hallucination, intentional drug misuse, mental disorder, mental status changes

Renal and urinary disorders: anuria, glomerulonephritis membranous, renal failure, renal failure acute, renal vein thrombosis

Respiratory, thoracic and mediastinal disorders: hypoxia, lung disorder, pneumonia aspiration, pulmonary arterial hypertension, respiratory failure, tachypnoea

Skin and subcutaneous tissue disorders: dermatitis exfoliative, hyperhidrosis, linear IgA disease, toxic skin eruption

Vascular disorders: circulatory collapse, hypertension, hypotension

DRUG INTERACTIONS

Serious Drug Interactions

The concomitant use of bosentan and EUGLUCON^® (glyburide) is contraindicated (see CONTRAINDICATIONS and DRUG-DRUG INTERACTIONS, Table 1).

Overview

Glyburide is extensively metabolized in the liver by cytochrome P450. The isoforms 2C9, 2C19 and 3A4 are involved, each to an unknown extent. Glyburide is also a substrate for p-glycoprotein. ^{25-27,30,35,38,39,54} Blood glucose should be monitored carefully if EUGLUCON^® is administered with other drugs whose metabolism is dependent upon CYP 2C9, 2C19, 3A4 and p-glycoprotein. In addition, the hypoglycaemic action of sulfonylureas is potentiated when used with insulin and other oral antidiabetics. Patients should be monitored accordingly. See Table 1, below. See also ACTION AND CLINICAL PHARMACOLOGY, Metabolism.

Drug-Drug Interactions

Patients who take or discontinue taking certain other medicines while undergoing treatment with EUGLUCON^® may experience changes in blood glucose control.

A study in 12 healthy volunteers showed that the concomitant administration of clarithroymycin increases plasma concentrations of glyburide. Severe hypoglycemia has been reported following coadministration of these two drugs. ^6,26,27,47 See Table 1, below.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known. See Table 1, below.

Table 1 - Established or Potential Drug-Drug Interactions

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

QTc Prolonging Drugs: Some literature studies have suggested an association between glyburide and QTc interval prolongation. Caution should be observed if glyburide is to be used concomitantly with QT/QTc-prolonging drugs. Drugs that have been associated with QT/QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QT/QTc prolongation and/or torsade de pointes:

Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide); Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide); Class 1C antiarrhythmics (e.g., flecainide, propafenone); antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone); antidepressants (e.g., fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline); opioids (e.g., methadone); macrolide antitibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus); quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxazin); antimalarials (e.g., quinine, chloroquine); azole antifungals (e.g., ketoconazole, fluconazole, voriconazole); domperidone; 5-hydroxytryptamine (5-HT) 3 receptor antagonists (e.g., dolasetron, ondansetron); tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, lapatinib); histone deacetylase inhibitors (e.g., vorinostat); beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

Caution should be exercised if using EUGLUCON^® with drugs that can disrupt electrolyte levels, including, but not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high dose corticosteroids.

The above lists of potentially interacting drugs are not comprehensive. Current information sources should be consulted for newly approved drugs that prolong the QT/QTc interval or cause electrolyte disturbances, as well as for older drugs for which these effects have recently been established.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Alertness and reactions may be impaired due to hypoglycaemic or hyperglycaemia episodes, especially when beginning or after altering treatment or when EUGLUCON^® is not taken regularly. This may, for example, affect the ability to drive a vehicle or to operate machinery.

Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of EUGLUCON^® in an unpredictable fashion. Intolerance to alcohol (disulfiram-like reaction: flushing, sensation of warmth, giddiness, nausea, and occasionally tachycardia) may occur in patients treated with a sulfonylurea. These reactions can be prevented by avoiding the use of alcohol.

DOSAGE AND ADMINISTRATION

Dosing Considerations

In diabetic subjects, there is no fixed dosage regimen for the management of blood glucose levels. Individual determination of the minimum dose that will lower the blood glucose adequately should be made.

Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycaemic agents because of deterioration of their diabetic state. Patients should therefore be monitored with regular clinical and laboratory evaluations, including blood glucose and glycosylated hemoglobin (A_1C) measurements, to determine the minimum effective dosage and to detect primary failure or secondary failure (see WARNINGS AND PRECAUTIONS).

Adjustment of glyburide dosage should be considered whenever factors predisposing the patient to the development of hypo- or hyperglycaemia are present (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS). As an improvement in control of diabetes is, in itself, associated with higher insulin sensitivity, glyburide requirements

may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of EUGLUCON^® therapy must therefore be considered.

Timing of doses should be decided by the prescriber, taking into consideration the patient’s current lifestyle.

The first dose should be given during or immediately after breakfast. Patients who eat only a light breakfast should defer the first dose of the day until lunchtime. If a second daily dose is required, the second dose should be taken with the evening meal.

It is very important not to skip meals after the tablets have been taken.

Renal: EUGLUCON^® is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min). In patients with mild to moderate renal insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycaemic reactions.

Pediatrics (< 18 years of age): Safety and effectiveness of EUGLUCON^® (glyburide) have not been established in this population. Use in patients under 18 years of age is not recommended.

Geriatrics (>60 years of age): Elderly patients with Type 2 diabetes are more susceptible to hypoglycaemia. Caution should be applied when initiating or escalating doses of EUGLUCON^® in patients over 60 years of age. It is recommended that treatment be started with the smallest dose (2.5mg) in this population. See Usual Starting Dose, below.

Recommended Dose and Dosage Adjustment

Usual Starting Dose

In newly-diagnosed diabetics, the initial dose is 5 mg daily; however, it is recommended that treatment be started with the smallest dose (2.5 mg) in patients over 60 years of age, and in patients who have a tendency to hypoglycemia (see WARNINGS AND PRECAUTIONS) or who weigh less than 50 kg. The initial dose should be administered with breakfast or a first meal of the day and should be continued for five to seven days. Depending on the response, the dosage should then be either increased or decreased in steps of 2.5 mg. The increases or decreases should be guided by regular blood glucose monitoring.

Usual Maintenance Dose

Occasionally, glycemic control is maintained with 2.5 mg daily. The majority of cases can be controlled by 5 mg to 10 mg daily given as a single dose during or immediately after breakfast. Patients who eat only a light breakfast should defer the first dose of the day until lunchtime. A single dose of 10 mg must not be exceeded. If more than 10 mg daily is required, the excess should be taken with the evening meal.

Maximum Daily Dose

The maximum daily dose of EUGLUCON^® is 20 mg. A single dose of 10 mg must not be

exceeded. Large daily doses must be divided into at least 2 separate single doses.

Changeover From Other Oral Hypoglycaemic Agents

There is no exact dosage relationship between EUGLUCON^® and other oral antidiabetic agents. Discontinue previous oral medication and start EUGLUCON^® 5 mg daily (2.5 mg in patients over 60 years of age, and in patients who have a tendency to hypoglycaemia (see WARNINGS AND PRECAUTIONS) or who weigh less than 50 kg). This also applies to patients changed over from the maximum dose of another oral antidiabetic medication. Consideration must be given to the potency and duration of action of the previous antidiabetic agent. A break from medication may be required to avoid any summation of effects entailing a risk of hypoglycemia.

Determine maintenance dosage as in newly-diagnosed diabetics.

Changeover From Insulin

If a change from insulin to glyburide is contemplated in a patient with stable, mild, maturity-onset (Type 2) diabetes, treatment with insulin should be discontinued for a period of two or three days to determine whether any therapy other than dietary regulation and exercise is needed. During this insulin-free interval, the patient's urine should be tested at least three times daily for glucose and ketone-bodies, and the results monitored carefully by a physician. 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.

Missed Dose

The missed dose should be taken as soon as possible, unless it is almost time for the next dose. Forgetting to take a dose must never be corrected by subsequently taking a larger dose.

Prior to starting treatment with EUGLUCON^®, the physician and patient should discuss how to address missed doses or skipped meals.

If it is discovered that too high a dose or an extra dose of EUGLUCON^® has been taken, a physician must be notified immediately (see OVERDOSAGE).

Method of Administration

EUGLUCON^® tablets must be swallowed whole with sufficient amounts of liquid; half a glass to one glass of water is recommended.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Acute overdosage as well as long-term treatment with too high a dose of glyburide may lead to severe, protracted, life-threatening hypoglycaemia. The dosage which causes hypoglycaemia varies widely, and may be within the accepted therapeutic range in sensitive individuals. Significant overdoses and severe reactions with serious neurological signs and/or loss of consciousness are medical emergencies that require immediate treatment and admission to hospital.

Symptoms

The manifestations of hypoglycemia include sweating, flushing or pallor, numbness, chilliness, hunger, trembling, headache, dizziness, increased pulse rate, palpitations, increase in blood pressure and apprehensiveness in mild cases. In more severe cases, coma occurs. Symptoms of hypoglycaemia are not necessarily as typical as described above and sulfonylureas may cause insidious development of symptoms which mimic cerebrovascular insufficiency.

Treatment

Discontinue medication and treat hypoglycaemia by giving dextrose promptly and in sufficient quantity. After acute glucose replacement has been completed, it may be necessary to give an intravenous glucose infusion to ensure that the hypoglycaemia does not recur. Continuous dextrose infusions for hours to days have been necessary. The patient's blood-glucose level should be carefully monitored for at least 24 hours. Admission to hospital may sometimes be necessary as a precautionary measure.

The symptoms of hypoglycaemia nearly always subside when blood glucose control is attained; however, some sulfonylurea-induced hypoglycaemias may be refractory to treatment and susceptible to relapse, especially in elderly or malnourished patients. In severe cases with a protracted course, hypoglycaemia or the danger of slipping back into hypoglycaemia may persist for several days. Patients must therefore remain under close observation.

Patients who have ingested life-threatening amounts of glyburide require detoxification (for instance by gastric lavage and medicinal charcoal).^24,50

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The principal action of EUGLUCON^® is to increase the amount of insulin released from the pancreas. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycaemic drugs. The insertion of an alkyl chain on the benzene nucleus results in a product of very high potency. The hypoglycaemic activity of 5 mg of EUGLCON^® is approximately equal to that of 1g of tolbutamide, 500mg of acetohexamide or 250mg chlorpropamide.

Pharmacodynamics

Cardiac Electrophysiology: A clinical trial was performed in which patients with type 2 diabetes were randomised to receive glibenclamide (N=15) or metformin (N=15). ECG recordings were performed at baseline and after two months of treatment. Glibenclamide was associated with a significant increase in QTc (433±24 to 467±24 ms, p <0.001) from baseline to month 2 of treatment, whilst metformin was associated with a decrease in QTc (444±15 to 432±15 ms, p <0.01).³⁴

Pharmacokinetics

Absorption: EUGLUCON^® is largely absorbed from the intestinal tract.^4,45 The pharmacokinetics of glyburide have been studied using orally administered ¹⁴C-labelled glyburide in two subjects, and were shown to follow a complex multicompartmental pattern.⁴ Plasma concentrations showed a steep rise and fall immediately before and after reaching the peak value.

Distribution: Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycaemic action.

Metabolism: Glyburide is extensively metabolized in the liver by cytochrome P450. The isoforms 2C9, 2C19 and 3A4 are involved, each to an unknown extent. Glyburide is also a substrate for p-glycoprotein.^{25-27,30,35,38,39,54} Blood glucose should be monitored carefully if EUGLUCON^® is administered with other drugs dependent on CYP 2C9, 2C19, and 3A4 and p-glycoprotein for metabolism.

The principal metabolites of glyburide result from hydroxylation of the cyclohexyl ring to the 4-trans-hydroxyl (major metabolite) and 3-cis-hydroxy (minor metabolite) derivatives. In rabbits, these metabolites contribute no significant hypoglycemic action as they are only weakly active (1/400^th and 1/40^th respectively, as glyburide).¹⁴ However, the results of one small (n=8) placebo-controlled cross-over study in humans in which these two metabolites were administered by the intravenous route suggest that these metabolites may contribute to the blood-glucose-lowering effect in humans.^22,46 The role of the kidneys in the biotransformation of the drug appears minimal.

Excretion: Glyburide is excreted as metabolites in the bile and urine.^{9,14,15,41,46} Reported biological half-lives ranged from 1.9 to 16.0 hours.

Special Populations and Conditions

Renal Insufficiency: In a study of diabetic patients with impaired renal function (n=13) administered a single oral dose of glyburide as a solution, there was no relationship between creatinine clearance (CL_CR) and glyburide clearance in patients with normal to moderately impaired renal function (CL_CR 29 – 131 mL/min). In one patient with severe renal impairment (CL_CR of 5mL/min), however, glyburide clearance was significantly reduced, resulting in an

elimination half-life of 11 hours compared to 2 – 5 hours in patients without severe renal impairment.⁴¹

In another study of diabetic patients administered a single oral dose of glyburide, there were decreased levels of metabolites excreted in the urine of renally impaired patients (n=11) compared with patients with normal renal function (n=11), suggesting that in renal impairment, the metabolites of glyburide may be eliminated via the complementary non-renal route of biliary excretion.²³

STORAGE AND STABILITY

EUGLUCON^® should be stored at room temperature between 15 and 30^oC, and not beyond the expiry date indicated on the package.

Keep in a safe place out of the reach of children and pets.

Unused medication should not be disposed of down the drain or in household garbage.

DOSAGE FORMS, COMPOSITION AND PACKAGING

EUGLUCON^® 5 mg contains 5 mg glyburide (non-micronised). Each tablet also contains as non-medicinal ingredients: colloidal anhydrous silica, lactose monohydrate, magnesium stearate, starch (corn starch, and pre-gelatinized corn starch) and talc.

EUGLUCON^® (glyburide) 5 mg tablets are white to off-white, oblong tablets, with bilateral break-marks. They are debossed “BM/EU” on both faces. EUGLUCON^® 5 mg tablets are available in bottles of 100 and 500 tablets and blister packs of 30 tablets. The blister format is 3 x 5 tablets per blister sheet; 2 blister sheets per carton.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Glyburide (as per USP), Glibenclamide (as per Ph.Eur.)

Chemical name: 1-[[4-[2-[(5-Chloro-2-

methoxybenzoyl)amino]ethyl]phenyl]sulphonyl]-3-cyclohexylurea

Molecular formula: C₂₃H₂₈ClN₃O₅S

Molecular mass: 494

Structural formula:

Physiochemical properties:

Description: White or almost white, odourless to almost odourless, crystalline powder.

Melting Point: 169 – 174^oC

Solubility: Practically insoluble in: water, ether Slightly soluble in: ethanol, methanol Sparingly soluble in: chloroform, methylene chloride Sparingly soluble (with salt formation) in: alkaline solution Freely soluble in: dimethylformamide

CLINICAL TRIALS

No clinical data available.

DETAILED PHARMACOLOGY

Animals

In rabbits, the oral administration of 0.2 mg/kg of EUGLUCON^® lowered the blood sugar level 25%, an effect which occurred 3 hours after administration of the drug and lasted longer than 24 hours. The duration of action of 200 mg/kg of tolbutamide was much shorter.⁵ In the isolated rat pancreas, EUGLUCON^® produced a long-lasting rise in insulin output while tolbutamide had an effect of a faster onset and a shorter duration.²⁸ A short period of exposure of isolated rat pancreas to tolbutamide caused a brief release of insulin, but the effect of EUGLUCON^® lasted longer and exceeded the time of exposure.¹⁸ In the presence of 0.5 ug/mL of EUGLUCON^®, isolated rat pancreatic islets released insulin continuously; in contrast, the effect of 0.3 mg/ml of tolbutamide could not be maintained.¹⁶

Safety Pharmacology

Glibenclamide has been reported to block the ATP-sensitive potassium channels in cardiac myocytes and pancreatic beta cells ⁵⁶ and the neural and cardiac delayed rectifier potassium current (IKr) channels.⁴⁴ In post-infarcted anaesthetised dogs (N=10/treatment), glibenclamide (0.3 to 10 mg/kg iv) had proarrhythmic effects, as reflected by increased inducibility, lowered ventricular fibrillation threshold, and reduced survival.¹¹

Humans

Improved glucose tolerance levels and random blood sugar levels over diet alone were described; the improvement in glucose tolerance was ascribed to a combination of a reduced fasting plasma sugar level and an improved tolerance to the glucose load.¹²

In a study comparing the effects of phenformin, metformin and glyburide on six patients with maturity-onset diabetes³⁷, it was found that the greatest reduction of the blood glucose concentration was obtained following treatment with glyburide, and corresponded with the observed higher serum insulin levels. Although gross and moderate elevation of blood lactate concentrations were observed in the patients treated with phenformin and metformin respectively, normal blood lactate levels were observed in the patients treated with glyburide. Similar effects were observed on the lactate/pyruvate ratios, and on the levels of alanine, glycerol and ketone bodies; only phenformin administration resulted in significantly increased levels of serum triglycerides.

TOXICOLOGY

The LD₅₀ for white mice, rats and guinea pigs was found to be more than 15 g/kg body weight and for rabbits and beagles more than 10 g/kg body weight when glyburide was given orally. The LD₅₀ in rats following intraperitoneal injection was found to be from 6.3 to 8.4 g/kg body weight.

Long-term feeding experiments were carried out in rats and dogs over the course of one year. Rats were given glyburide in their food in doses of approximately 0.2, 1.0 and 5.0 mg/kg body weight daily. The highest dose is equivalent to 350 times the minimal effective hypoglycaemic dose in man. Organ function tests were carried out continuously. Hematological examinations, blood sugar tests and urine analyses were performed every three months. None of the rats showed any abnormal findings in the function tests, or in the blood and urine studies. Subsequent post-mortem examination revealed no macroscopic or histological changes attributable to a toxic effect of glyburide.

Dogs were given glyburide by mouth at dose levels of 0.4, 2.0 and 10.0 mg/kg body weight daily. The highest dose is equivalent to 650 times the minimal effective hypoglycaemic dose in man. Regular checks of blood cell counts, blood glucose, urine, electrolytes, electrophoresis, BUN and serum enzyme levels (GPT, GOT, LDH, AP) showed no abnormalities. All the animals behaved normally during the period of experiment. There was no vomiting or diarrhea, and their weights remained unchanged. Subsequent post-mortem examination and histological investigation showed no abnormality.

Teratological tests were carried out in rats and rabbits. Rats were given 0.2, 20 and 2000 mg/kg body weight of glyburide from days 7 to 16 of gestation. For rabbits, the doses were 0.035, 3.5 and 350 mg/kg given from day 7 to 17 of gestation, in a starch suspension by gastric tube. Examination of the intact fetuses, followed by examination of transverse sections and of the stained skeletons, showed no evidence of teratogenic action.

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