Tablets 1 mg, 2 mg and 4 mg

Oral Hypoglycemic (Sulfonylurea) Novopharm Limited 30 Novopharm Court Toronto, Ontario M1B 2K9 Submission Control No: 091409 Date of Preparation: November 22, 2005

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 12 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 18 DOSAGE FORMS, COMPOSITION AND PACKAGING 18

PART II: SCIENTIFIC INFORMATION 19

PHARMACEUTICAL INFORMATION 19 CLINICAL TRIALS 19 DETAILED PHARMACOLOGY 24 TOXICOLOGY 28 REFERENCES 37

PART III: CONSUMER INFORMATION. 42

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NOVO-GLIMEPIRIDE

(glimepiride tablets)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

NOVO-GLIMEPIRIDE (glimepiride) is contraindicated in patients with: Type 1 Diabetes (formerly known as insulin-dependent diabetes mellitus or IDDM) Known hypersensitivity or allergy to any sulfonylurea, sulfonamides or any other component of the formulation. For a complete listing, see Dosage Forms, Composition and Packaging section of the product monograph. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. Pregnant or breast-feeding women. No experience has been gained concerning the use of glimepiride in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of renal or hepatic function, change-over to insulin is indicated, to achieve optimal metabolic control.

WARNINGS AND PRECAUTIONS

General

Use of NOVO-GLIMEPIRIDE (glimepiride) must be considered as treatment in addition to a proper dietary regimen and not as a substitute for diet. Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycemic 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 (HbAlC) 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 b-cell failure as well as exogenous diabetogenic factors such as obesity, illness, drugs, or tachyphylaxis to the sulfonylurea. If a loss of adequate blood glucose lowering response to a sulfonylurea is detected, the addition of a different type of oral antidiabetic may be considered, although insulin is often required. Certain patients who demonstrate an inadequate response or true primary or secondary failure to one sulfonylurea may benefit from a switch to another sulfonylurea. 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 hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken when possible.

Patient Selection and Follow-up

: Careful selection of patients is important. Patients most likely to respond to sulfonylurea therapy are: obese or normal body weight; duration of diabetes less than 5 to 10 years before initiation of therapy; and, absence of ketoacidosis. It is imperative that there be careful attention to diet, careful adjustment of dosage, instruction of the patient on hypoglycemic reactions and their treatment, as well as regular, thorough follow-up examinations. If non-pharmacologic therapy fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea should be considered. Use of NOVO-GLIMEPIRIDE (glimepiride) 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 NOVO- GLIMEPIRIDE.

Loss of control of blood glucose:

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 glycemic control may occur. At such times, it may be necessary to adjust the dosage of NOVO- GLIMEPIRIDE, add insulin in combination with NOVO-GLIMEPIRIDE or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including glimepiride, 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.

Hypoglycemia: Drug-Drug Interactions

All sulfonylurea drugs are capable of producing severe hypoglycemia. Signs of severe hypoglycemia can include disorientation, loss of consciousness, and seizures. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly, debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of NOVO-GLIMEPIRIDE. A starting dose of 1 mg once daily followed by appropriate dose titration is also recommended in those patients. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when other drugs with blood-glucose lowering potential are used. (see

section below). In clinical trials, patients receiving glimepiride in combination with insulin reported more incidence of hypoglycemia than patients on monotherapy.

Cardiovascular

It has been suggested, based on a study conducted by the University Group Diabetes Program (UDGP), that certain sulfonylurea antidiabetic agents increase cardiovascular mortality in diabetic patients, a population at greater risk of cardiovascular disease. This finding was not confirmed by a more recent trial, the United Kingdom Prospective Diabetes Study (UKPDS) which showed that intensive glycemic control with either sulfonylureas or insulin did not have an adverse effect on cardiovascular outcomes. Despite questions regarding the design of these studies and interpretation of the results, the results of these studies provide a basis for caution, especially high risk patients with cardiovascular disease. In clinical trials more patients receiving glimepiride and insulin reported an increase in peripheral edema compared to patients receiving insulin alone. Patients receiving this combination therapy should be asked to report any edema or weight gain.

Renal

In patients with renal insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions.

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. On the basis of results from animal studies, NOVO-GLIMEPIRIDE (glimepiride tablets) should not be used during pregnancy. 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.

Teratogenic Effects

: Glimepiride did not produce teratogenic effects in rats exposed orally up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximum recommended human dose based on surface area). Glimepiride has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride.

Nonteratogenic Effects

: In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformations consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride.

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. Patients who are planning a pregnancy should consult their physician, and it is recommended that they change over to insulin for the entire course of pregnancy and lactation.

Nursing Women: Pregnant Woman, Nonteratogenic Effects

In rat reproduction studies, significant concentrations of glimepiride were observed in the serum and breast milk of the dams, as well as in the serum of the pups. Although it is not known whether glimepiride is excreted in human milk, other sulfonylureas are excreted in human milk. Since the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, NOVO-GLIMEPIRIDE should be discontinued in nursing mothers. If NOVO-GLIMEPIRIDE is discontinued, and if diet and exercise alone are inadequate for controlling blood glucose, insulin therapy should be considered (See above

).

Pediatrics:

Safety and efficacy in pediatric Type 2 patients have not been established.

Monitoring and Laboratory Tests

Fasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylated hemoglobin (HbA1C) should also be monitored, usually every 3 to 6 months, to more precisely assess long-term glycemic control.

Occupational Hazards

Driving a vehicle or operating machinery:

Hypo- or hyperglycemia may impair alertness and reactions, especially when beginning or after altering treatment or when NOVO-GLIMEPIRIDE is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.

DRUG INTERACTIONS

Overview

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is coadministered with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) of CYP 2C9. Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of glimepiride in an unpredictable fashion.

Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated).

Table 1 - Established or Potential Drug-Drug Interactions

1. 34% mean glimepiride C1/F

2. 4% mean glimepiride Cmax

1. glimepiride T1/2 by 15%

2. glimepiride C1/F by 18%

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

Although no specific interaction studies were performed, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of calcium-channel blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors, sulfonamides, or thyroid hormone. The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including ACE inhibitors, anabolic steroids and male sex hormones, nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, cyclophosphosphamine, disopyramide, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, monoamine oxidase inhibitors, para-aminosalicylic acid, pentoxifylline (high dose parenteral), phenylbutazone, probenecid, quinolones, salicylates, sulfonamide antibiotics and tetracyclines. When these drugs are administered to a patient receiving NOVO- GLIMEPIRIDE, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving NOVO-GLIMEPIRIDE, the patient should be observed closely for loss of glycemic control. Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, acetazolamide, barbiturates, corticosteroids, diazoxide, epinephrine and other sympathomimetic agents, glucagon, isoniazid, laxatives (after protracted use), nicotinic acid (in high dose), estrogens and progestogens, phenothiazines, phenytoin, rifampicin and thyroid products. When these drugs are administered to a patient receiving NOVO-GLIMEPIRIDE, the patient should be closely observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving NOVO-GLIMEPIRIDE, the patient should be observed closely for hypoglycemia. H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.

DOSAGE AND ADMINISTRATION

Dosing Considerations

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 (HbA1C) should be performed to monitor the patient's response to therapy. Short-term administration of NOVO-GLIMEPIRIDE (glimepiride) may be sufficient during periods of transient loss of glycemic control in patients usually controlled well on diet and exercise.

Recommended Dose and Dosage Adjustment

Usual Starting Dose

The usual starting dose of NOVO-GLIMEPIRIDE as initial therapy is 1 mg once daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be titrated carefully. (See WARNINGS AND PRECAUTIONS Section). Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary, exercise, weight loss and drug regimen are more prone to exhibit unsatisfactory response to therapy. Adjustment of dosage must also be considered, whenever: The patient's weight changes, The patient's life-style changes, other factors arise which cause an increased susceptibility to hypoglycemia or hyperglycemia (see WARNINGS AND PRECAUTIONS Section)

Usual Maintenance Dose

The usual maintenance dose is 1 to 4 mg once daily. The maximum recommended dose is 8 mg once daily. After reaching a dose of 2 mg, dosage increases should be made in increments of no more than 1 mg at 1 - 2 week intervals based upon the patient's blood glucose response. Long- term efficacy should be monitored by measurement of HbA1C levels, for example every 3 to 6 months.

NOVO-GLIMEPIRIDE -Insulin Combination Therapy

Combination therapy with NOVO-GLIMEPIRIDE and insulin may be used in secondary failure patients. The recommended NOVO-GLIMEPIRIDE dose is 8 mg once daily administered with the first main meal. After starting with low-dose insulin, upward adjustments of insulin can be done approximately weekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily. Periodic adjustments of insulin may also be necessary during maintenance as guided by glucose and HbA1C levels.

Specific Patient Populations

NOVO-GLIMEPIRIDE is not recommended for use in pregnancy, nursing mothers, or children. In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions (See CLINICAL PHARMACOLOGY, Special Populations and Conditions and WARNINGS AND PRECAUTIONS, General).

Changeover from Other Oral Hypoglycemic Agents

No exact dosage relationship exists between NOVO-GLIMEPIRIDE and the other oral hypoglycemic agents. When substituting NOVO-GLIMEPIRIDE for other oral hypoglycemic agents, it is recommeded that the procedure be the same as for initial dosage starting with daily doses of 1 mg. Consideration must be given to the potency and duration of the previous antidiabetic agent. Patients should be observed carefully (1 -2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to NOVO- GLIMEPIRIDE due to potential overlapping of drug effect. A break from medication may be required to avoid any summation of effects entailing a risk of hypoglycemia.

Missed Dose

Take the miss dose as soon as possible, unless it is almost time for the next dose. Do not take two doses at the same time.

OVERDOSAGE

Overdosage of sulfonylureas, including NOVO-GLIMEPIRIDE (glimepiride), can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. In case of overdosage, current medical intervention for the treatment of hypoglycemia should be followed according to the condition of the patient. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extra-pancreatic effects may also play a role in the activity of glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

Pharmacodynamics

A mild glucose-lowering effect first appeared following single oral doses as low as 0.5 - 0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [Tmin]) was about 2 to 3 hours. In Type 2 Diabetes (formerly known as non-insulin- dependent diabetes mellitus or NIDDM) patients, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours. In larger dose-ranging studies, blood glucose and glycosylated hemoglobin (HbA1C) were found to respond in a dose-dependent manner over the range of 1 to 4 mg of glimepiride once daily. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of NOVO-GLIMEPIRIDE up to 8 mg once daily. No difference in the decrease in blood glucose and HbA1C concentrations were found when glimepiride was administered once or twice daily. In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in HbA1C for glimepiride patients treated with 8 mg once daily was 2.0% (0.02) in absolute units compared with placebo-treated patients. Efficacy results were not affected by age, gender, weight, or race. In a 22-week, randomized, placebo-controlled study of Type 2 Diabetic patients unresponsive to dietary management, glimepiride therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and HbA1C. The results of three long-term studies demonstrated that glimepiride, when administered over a prolonged treatment period of one-year (N = 986), was effective in maintaining metabolic control in Type 2 Diabetic patients who were responders to sulfonylurea therapy. In an extension of long-term trials with patients previously treated with glimepiride, no meaningful deterioration in mean fasting blood glucose (FBG) or HbA1C levels was seen after up to 2.5 years of glimepiride therapy (N=445). Combination therapy with glimepiride and insulin (70% NPH/30% regular) was compared to placebo/insulin in secondary failure patients whose body weight was > 130% of their ideal body weight. Initially, 5-10 units of insulin were administered with the main evening meal and titrated upward weekly to achieve predefined FPG values. Both groups in this double-blind study achieved similar reductions in FPG levels but the glimepiride/insulin therapy group showed an insulin sparing effect with a use of 38% less insulin. Glimepiride therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for Type 2 Diabetes.

Pharmacokinetics

Absorption

: After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 Diabetes have shown significant absorption of glimepiride within 1 hour after

administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively). In normal healthy volunteers, the intra-individual variabilities of Cmax, AUC, and total body clearance after oral dosing (Cl/F) for glimepiride were 23%, 17%, and 15%, respectively, and the inter- individual variabilities were 25%, 29%, and 24%, respectively. The pharmacokinetics of glimepiride obtained from a single-dose, crossover, dose- proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose-proportionality (4 and 8 mg) study in patients with Type 2 Diabetes are summarized below:

(n) = number of subjects Vd/f = Volume of distribution calculated after oral dosing These data indicate that glimepiride did not accumulate in serum, and the pharmacokinetics of glimepiride were not different in healthy volunteers and in Type 2 Diabetic patients. Oral clearance of glimepiride did not change over the 1 - 8 mg dose range, indicating linear pharmacokinetics.

Distribution:

After intravenous dosing in normal subjects, the volume of distribution (Vd) was

8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.

Metabolism:

Glimepiride is completely metabolized by oxidative biotransformation after either IV or oral administration. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful in humans is not clear.

Excretion: When 14C-glimepiride was given as a single dose orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.

Special Populations and Conditions

Pediatrics:

No studies were performed in pediatric patients.

Geriatrics: Comparison of glimepiride pharmacokinetics in Type 2 Diabetic patients # 65 years and those > 65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients. (See WARNING AND PRECAUTIONS, General).

Gender:

There were no differences between males and females in the pharmacokinetics of glimepiride when adjusting for differences in body weight.

Race:

No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of glimepiride (glimepiride tablets) in patients with Type 2 Diabetes, the hypoglycemic effect was comparable in whites (n = 536), blacks (n = 63), and Hispanics (n = 63).

Hepatic Insufficiency:

No studies were performed in patients with hepatic insufficiency.

Renal Insufficiency:

A single-dose, open-label study was conducted in 15 patients with renal impairment. Glimepiride (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CLcr): Group I, CLcr = 77.7 mL/min (1.30 mL/sec), n = 5; Group II, CLcr = 27.7 mL/min (0.462 mL/sec), n = 3; and Group III, CLcr = 9.4 mL/min (0.16 mL/sec), n

= 7. Glimepiride was found to be well tolerated in all 3 groups. The results showed that M1 and M2 serum levels (mean AUC values) increased 2.2 and 6.1 times from Group I to Group III as renal function decreased. The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III). A multiple-dose titration study was also conducted in 16 Type 2 Diabetic patients with renal impairment using doses ranging from 1 - 8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CLcr less than 22 mL/min (0.37 mL/sec) had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of 1 mg glimepiride may be given to Type 2 Diabetic patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels. (See WARNING AND PRECAUTIONS, Renal section).

Other Populations

: There were no important differences in glimepiride metabolism in subjects identified as phenotypically different drug-metabolizers by their metabolism of sparteine.

The pharmacokinetics of glimepiride in morbidly obese patients were similar to those in the normal weight group, except for a lower Cmax and AUC. However, since neither Cmax nor AUC values were normalized for body surface area, the lower values of Cmax and AUC for the obese patients were likely the result of their excess weight and not due to a difference in the kinetics of glimepiride.

STORAGE AND STABILITY

Protect from heat, moisture and direct light. Store between 15 and 30 @C. Dispense in well-closed container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms and Packaging

:

NOVO-GLIMEPIRIDE (glimepiride) tablets are available in the following strengths and package sizes:

1. mg: Mottled pink, round tablet, bisected on both sides. One side of the tablet debossed with "9" on one side of score and "3" on the other. The other side of the table debossed with "72" on one side of score and "54" on the other. Supplied in bottles of 30 and 100 tablets, and unit dose of 10.

2. mg: Mottled green, round tablet, bisected on both sides. One side of the tablet debossed with "9" on one side of score and "3" on the other. The other side of the table debossed with "72" on one side of score and "55" on the other. Supplied in bottles of 30 and 100 tablets, and unit dose of 10.

4 mg: Mottled light blue, round tablet, bisected on both sides. One side of the tablet debossed with "9" on one side of score and "3" on the other. The other side of the table debossed with "72" on one side of score and "56" on the other. Supplied in bottles of 30 and 100 tablets, and unit dose of 10.

Composition

:

NOVO-GLIMEPIRIDE (glimepiride) is formulated into tablets of 1 mg, 2 mg, and 4 mg strengths for oral administration. NOVO-GLIMEPIRIDE tablets contain the active ingredient glimepiride and the following non medicinal ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. In addition: NOVO- GLIMEPIRIDE 1 mg tablets contain Ferric Oxide, NOVO-GLIMEPIRIDE 2 mg tablets contain FD&C Blue #2 Aluminum Lake and Ferric Oxide, and NOVO-GLIMEPIRIDE 4 mg tablets contain FD&C Blue #2 Aluminum Lake.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Glimepiride Chemical name: 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1- carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea Structural formula: Empirical formula: C24H34N4O5S Molecular weight: 490.62 Physical form: Glimepiride is a white crystalline powder Solubility: Glimepiride is practically insoluble in water. Soluble in N,N dimethylformamide, very slightly soluble in methanol, acetonitrile and acetone. pKa values: 6.2 +- 0.1 at 37 oC Melting point: 205 oC to 208 oC

CLINICAL TRIALS

Efficacy: Indication I

MC = Multicentre; DB = Double Blinded; R = Randomised; PC = Placebo controlled,

AC = Active Controlled, CO = Glim = Glimepiride; Gly = Glyburide; Pbo = Placebo

The key efficacy variables measured in each of the three pivotal studies were:

• Primary: Fasting Plasma Glucose, HbA1C, 2-hour Postprandial Plasma Glucose;

• Secondary: C-peptide, Insulin

Clinically meaningful differences, based on general clinical experience were defined as 1.4 mmol/L for FPG levels and 0.6% (0.006) for HbA1C levels.

Primary Efficacy Results

All glimepiride treatment regimens (1-16 mg qd; 4 and 8 mg bid) produced significant and clinically meaningful reductions from Baseline in Fasting Plasma Glucose (FPG) and Postprandial Glucose (PPG) levels and HbA1C with one exception (HbA1C at 1 mg/day). All dosages of glimepiride produced significant and clinically meaningful reductions in the primary efficacy variables, when compared to placebo.

a

All differences from placebo were significant (p<0.001) and clinically meaningful.

When stratified by baseline FPG levels, glimepiride subjects in the high glucose stratum (13.4 - 16.7 mmol/L) achieved greater reduction in median FPG levels (-4.72 mmol/L) than subjects in the lower stratum (10 - 13.3mmol/L; -2.5 mmol/L). Likewise, in the longer term placebo controlled trial, when stratified by baselineHbA1C, glimepiride subjects in the high HbA1C percentile group ($75; HbA1C> 10.5% (0.105)) had a greater reduction of the HbA1C (-3.7% (0.037)) then those in the low percentile (< 75; HbA1C< 10.5% (0.105)) (-1.6%). These two findings suggest patients with more severe Type 2 Diabetes can also benefit from glimepiride treatment.

Dose regimen

No significant differences were detected between the qd and bid dose regimens for FPG or PPG levels at any of the 6, 8 or 16 mg total daily dosages as shown in the table below. These results were obtained from one pivotal and one non-pivotal trial.

a

Change from baseline is the median for study 3 and the mean for study 4.

b

Data for the 8/16-mg daily dosage is the combined data for both dosage levels.

c PPG is the 2-hour level after breakfast for study 3 and the 4-hour average after breakfast for study 4. Significance indicated at *p # 0.05.

Long-Term Efficacy

The benefits of glimepiride were maintained over long treatment periods and the treatment was as efficacious as higher and often divided dosages of glyburide or gliclazide. Subjects in study 2 showed significant and clinically meaningful improvements in FPG and HbA1C levels after 22 weeks of treatment with glimepiride in comparison with placebo. Subjects in the studies 5, 6 and 7 showed no clinically meaningful differences in FPG/FBG and HbA1C levels between glimepiride and glyburide treatment after up to 30 months of therapy.

C-Peptide and Insulin Results

The C-peptide and insulin response to glimepiride administration was evaluated in the three pivotal studies. Results showed that glimepiride increased fasting C-peptide and insulin levels by statistically significant but not clinically meaningful amounts when compared with placebo. Glimepiride increased postprandial C-peptide and insulin levels by statistically significant and clinically meaningful amounts over placebo levels. These results suggest that in Type 2 patients, the effects of glimepiride mimic the physiologic response to food intake with insulin levels comparable to placebo during fasting conditions.

Efficacy: Indication II

The second indication for glimepiride is for use in combination therapy with insulin to lower blood glucose levels in patients who are secondary failures to sulfonylurea therapy, that is, in patients whose hyperglycemia can no longer be effectively controlled by diet and oral hypoglycemic agents alone. Support for this indication was obtained through the results of a double-blind study that compared the efficacy of combination therapy with glimepiride plus insulin vs. that obtained with placebo plus insulin. A total of 145 Type 2 patients participated in the 24-week randomised, double-blind phase of this study; 72 received glimepiride plus insulin and 73 received placebo plus insulin. Each subject took fixed, oral dosages of glimepiride (8 mg bid) or placebo before breakfast and dinner, plus injections of insulin (qd, titrated to an optimised dose) before dinner. The two primary efficacy variables were the 4-week average insulin dose at Endpoint and the change from baseline in HbA1C levels at Endpoint. The mean daily insulin dose in the glimepiride group was approximately 30 U lower than in the placebo group, and this difference was clinically meaningful as well as statistically significant. Fewer subjects in the glimepiride group (6%) than in the placebo group (14%) required more than 100 U per day of insulin. Similarly, a greater percent of patients in the glimepiride group (64%) than in the placebo group (28%) required # 50 unit of insulin. This suggests that fewer patients would require multiple daily insulin injections if treated with combination therapy rather than insulin monotherapy. The results of this study also demonstrated that variability in the insulin-titration procedure did not affect the overall outcome of combination therapy. In smaller studies, success has previously been obtained with titration procedures that were either more aggressive1 or generally less aggressive2 than those used in the present study. Taken together, these results suggest that glimepiride plus insulin therapy would be efficacious using a variety of insulin titration procedures. Glycemic variability (as measured by the mean within-subject variance) was lower in the glimepiride group (433 mg2/dl2) than in the placebo group (627 mg2/dl2), indicating a trend to more stable glycemic control in the glimepiride-treated group. This may become more important with very aggressive insulin titration procedures, during which the risk of serious hypoglycemia is greater.

Riddle M, Hart J, Bingham P, Garrison C, and McDaniel P (1992) Combined therapy for obese Type 2 diabetes: suppertime mixed insulin with daytime sulfonylurea. American Journal of Medical Sciences 303, 151-156.

Riddle M, Hart J, Bouma D, Phillipson B, and Youker G (1989) Efficacy of bedtime NPH insulin with daytime sulfonylurea for subpopulation of type II diabetic subjects. Diabetes Care 12, 623-629.

Safety

Overall, glimepiride demonstrated a very safe adverse event profile, differing little from that of placebo. In both US and European trials, there was no drug-related pattern of deaths. No laboratory abnormalities could be attributed to the use of the drug. The most commonly reported adverse events possibly or probably related to the use of glimepiride occurring in at least 1% of subjects in placebo-controlled studies were hypoglycemia, dizziness, asthenia, headache, rash and nausea. No medically important interactions were seen between glimepiride and any of the demographic, disease or drug groups reviewed.

Human Ophthalmology Data

Ophthalmic examinations were carried out in over 500 subjects during long-term studies using the methodology of Taylor and West and Laties et al. No significant differences were seen between glimepiride and glyburide in the number of subjects with clinically important changes in visual acuity, intra-ocular tension, or in any of the five lens-related variables examined. Ophthalmic examinations were carried out during long-term studies using the method of Chylack et al. No significant or clinically meaningful differences were seen between glimepiride and glipizide with respect to cataract progression by subjective LOCS II grading and objective image analysis systems, visual acuity, intraocular pressure, and general ophthalmic examination.

COMPARATIVE BIOAVAILABILITY

A single-dose, randomized crossover comparative bioavailability study of two Glimepiride tablet products, NOVO-GLIMEPIRIDE 4 mg Tablets and AMARYLTM 4 mg tablets in healthy subjects, under fasting conditions. The pharmacokinetic data calculated for the NOVO-GLIMEPIRIDE and AMARYLTM tablet formulation, under fasting conditions, is tabulated below: Module 4, Volume 1, pages 1-006

Table of the Comparative Bioavailability Data Glimepiride

(1 x 4 mg tablet) From measured data Geometric Mean

Arithmetic Mean (CV%)

Expressed as the arithmetic mean (C.V.%) only.

* *Amaryl(r) manufactured by Aventis Pharm Inc., and purchased in Canada.

DETAILED PHARMACOLOGY

Animal Pharmacology

Blood glucose decreasing activity

Compared to other conventional sulfonylureas, glimepiride had more pronounced blood glucose decreasing activity in animals. In normal fasted rats and rabbits, single oral (5 - 400 ug/kg) and intravenous (5 - 500 ug/kg) doses of glimepiride were more acutely and chronically potent than glyburide. Following oral administration to dogs (60 and 120 ug/kg), glimepiride produced faster glucose decrease and longer lasting blood glucose reduction than did glyburide. When orally administered to rabbits and rats, the metabolites of glimepiride, M1 and M2, were found to be 3 to 2000 times less active then the parent drug.

Insulin releasing activity

In perfused islets of Langerhans and pancreas of rats, glimepiride had a more pronounced insulin secretion activity when compared to glyburide at normal and high glucose concentrations. This effect on insulin secretion is thought to be due to a different molecular interaction with ATP- sensitive potassium channel in the beta cell membrane. Unlike other sulfonylureas, glimepiride binds specifically to a 65 kDa protein located in the membrane of the beta cell. This interaction of glimepiride with its binding protein determines the probability of the ATP-sensitive potassium channel being open or closed. In the whole-cell patch clamp, glimepiride had a higher (EC50 of 3.1 nM) depolarization activity of the beta cell membrane of the mouse than glyburide (EC50 of 4.0 nM). Glimepiride had a higher exchange rate with the binding protein resulting from a more rapid association and dissociation kinetics and a higher in vitro insulin releasing activity of glimepiride compared to that of glyburide. The in vitro higher insulin releasing activity of glimepiride compared to that of glyburide with and in islets and pancreas of rats is only partially reflected in vivo, probably due to species specificity in dogs. In dogs, after 60 ug/kg intravenous and 90 ug/kg oral doses, at neither phase did glimepiride induce a higher plasma insulin release than glyburide, indicating species specificity. The relation between plasma insulin releasing and blood glucose decreasing activity of glimepiride and other sulfonylureas in vivo suggested that the insulin-independent glucose lowering effects are more pronounced with glimepiride. In rabbits and dogs, treated intravenously (10 - 60 ug/kg) and/or orally (90 ug/kg) with glimepiride the lower early phase plasma insulin levels to that after glyburide was reflected in a lower blood glucose decreasing activity. In dogs, blood glucose levels remained relatively constant or decreased for up to 48 to 52 hours after dose administration although the plasma insulin values did not differ markedly from those of the control animals. The longer-lasting blood glucose decreasing activity of glimepiride, compared to glyburide, after oral and intravenous administration, despite low insulin release in dogs, can be explained in terms of a higher extrapancreatic activity.

Extrapancreatic effects

Extrapancreatic effects may be defined as a direct stimulation or enhancement of insulin stimulation of the peripheral and/or hepatic glucose disposal. In vitro studies with diaphragm, fat cells and hepatocytes showed a direct insulin-mimetic activity of glimepiride:

• concentration-dependently inhibited gluconeogenesis and ketogenesis from alanine;

• concentration-dependently stimulated the TCA cycle;

• stimulated glucose transport, the rate limiting step of lipogenesis and glycogenesis, time- and concentration-dependently more effectively than glyburide.

In addition to the activation of glucose transport via Glut4 dephosphorylation, glimepiride also stimulated subsequent steps of glucose metabolism, the key enzymes of lipid and glycogen synthesis, which may be mediated by activation of the glycosyl-phosphatidylinositol-specific phospholipase C (GPI-PLC). In vitro studies showed that glimepiride regulated the following activities slightly more efficiently than glyburide: cellular cAMP-specific phosphodiesterase activity; reduction of protein kinase A activity; stimulation of glycogen synthase activity; stimulation of glycerol-3-P-acyltransferase activity. In isolated rat hepatocytes, glimepiride inhibited hepatic glucose output by increasing the concentration of fructose-2,6-biphosphate. However, direct insulin-mimetic effects (in the absence of insulin), observed in vitro, were not observed in animal's models of insulin deficiency. In streptozotocin-diabetic rats (20 mg/kg twice daily for 5 days) and pancreatectomized and alloxan-diabetic dogs (100 mg/kg once daily for 8 days) treated orally with glimepiride and glyburide, neither compound had any effect on blood glucose. This suggested that the direct insulin-mimetic activity of sulfonylureas may depend on the presence of insulin which may control positively the expression of genes coding for certain components of the signal transduction cascade which mediates the direct insulin- mimetic effects of glimepiride in fat and muscle cells. In vitro study in 3T3 adipocytes, suggested that glimepiride increases the sensitivity of peripheral tissues for glucose transport stimulation by insulin slightly more efficiently than glyburide, which may explain the extrapancreatic effects of sulfonylureas and especially of glimepiride.

Effect on glucagon secretion

In perfused islets of Langerhans and pancreas of rats, glimepiride when compared to glyburide had no effect on glucagon release. In vivo, in normal fasted dog, a plasma glucagon increase was observed during intravenous infusion of glyburide but was not observed with glimepiride.

Safety Pharmacology

CNS-related effects

After oral administration to mice, glimepiride had no CNS-stimulating or depressant effects. Oral doses of up to 1.0 mg/kg did not affect pentobarbital anesthesia, amphetamine group toxicity, motor coordination or pentetrazole-induced ptosis and had neither an anti-convulsive nor an analgesic effect.

Cardiovascular effects

In vivo and in vitro studies showed that glimepiride has an approximately 3 - 4 fold lower cardiovascular activity than glyburide, gliclazide or glipizide. Under physiological conditions, cardiovascular effects with glyburide and glimepiride (ECG rat studies and intracoronary infusion dog study) were observed at concentrations calculated to be 200 - 300 times higher than Cmax observed in clinical trials after oral administration of therapeutic doses. Under ischemic conditions, vascular and cardiomyocytic effects were observed with glyburide at a dose of 0.15 mg/kg, i.v., but no or only slight effects with glimepiride at a dose of 0.45 - 0.5 mg/kg, i.v. The maximal plasma concentrations in the ischemic studies were probably one order of magnitude higher than the therapeutic Cmax concentrations. As shown in various in vitro and in vivo studies, glimepiride had less influence than glyburide on the cardiomyocyte. Glimepiride had no effect on systemic blood pressure, arterial blood flow and left ventricular contractility in anesthetized normal cats at intraduodenal doses up to 1 mg/kg.

Anti-atherogenic effect

Glimepiride had been shown to have an anti-atherogenic effect. Rabbits treated for 10 weeks with pellet diet containing 1% cholesterol and 3 ppm glimepiride, showed significantly fewer fatty streaks were seen on the intimal surface of the thoracic aorta than the control animals (20% vs 60%). In animals treated with cholesterol diet with 7 ppm glyburide or 120 ppm gliclazide no significant inhibition of fatty streak deposition was seen. Glimepiride affected key steps of the thrombin-induced platelet activation and aggregation such as: Inhibiting dose-dependently, the decrease in the number of blood platelets after ADP infusion in rabbits treated with single i.v. doses up to 0.1 mg/kg or oral doses of 0.1 mg/kg once daily for 1 week. In contrast, single oral doses of up to 0.3 mg/kg were without effect. inhibiting the thrombin-stimulated increase of intracellular Ca2+ in platelets of human volunteers to a similar degree as glyburide at concentrations of 20 - 40 uM inhibiting selectively the cyclooxygenase pathway at concentrations up to 40 uM, whereas glyburide inhibited both the cyclooxygenase and 12-lipoxygenase pathways having no effect on thrombin-induced aggregation of human platelets. This missing inhibitory effect of glimepiride on thrombin aggregation of human platelets in vitro is not contradictory (even 1 mM acetylsalicylic acid had no effect) since at the thrombin concentration used (0.2 IU/mL) platelet aggregation is independent of thromboxane A2 formation.

Gastrointestinal effects

There was no effect on gastric emptying after oral doses of up to 1 mg/kg in rats. At doses of up to 1 mg/kg i.p. in rats, glimepiride had no effect on exocrine pancreatic secretion, bile secretion or histamine-induced gastric secretion.

Anti-inflammatory effects

After oral doses of up to 1 mg/kg once daily for 4 days, glimepiride had no antiexudative effect in the ganuloma pouch in rats. In yeast-induced fevered rats body temperature was not affected by an oral dose of glimepiride of 0.1 mg/kg; however, 1.0 mg/kg induced a slight but significant drop in temperature. The antifebrile effect seems to be related to the hypoglycemic effect since it was also observed after an oral dose of 1 mg/kg glyburide and after 5 IU/kg regular insulin s.c. A single oral dose of 0.1 mg/kg glimepiride did not affect, but 1 mg/kg inhibited carrageen paw edema in rats. The anti-inflammatory effect seems to be related to the hypoglycemic activity since it was also observed after an oral dose of 1 mg/kg glyburide and after 5 IU/kg insulin s.c.

Diuretic effects

Oral doses of up to 1.0 mg/kg glimepiride to rats had no diuretic effect.

Animal Pharmacokinetics

Glimepiride was slowly but completely absorbed after single oral administration of 0.5 mg/kg to male and female rats, male dogs and male rabbits compared with an intravenous dose. The serum protein binding was generally greater than 99% in all species studied. Following administration of 14C-glimepiride, peak blood levels were reached earlier in rats and dogs than in rabbits. Mean half-life was 1.7 h in rats, 12.5 h in the dog and 7 h in rabbits. In lactating rats, absorption was moderate and led to similar maximum blood levels of radioactivity (0.079 ug equiv./mL) as in male animals and non-lactating females. On the basis of the radioactivity measured in milk and daily milk production, the amount excreted via this route was estimated to be less than 0.1% of the total administered dose. After single or multiple oral dosing, the major organ of localisation in the rat was the liver. At 2, 4 and 8 hours after oral dosing of 14C-glimepiride, the concentration of radioactivity in the liver was approximately 16 fold higher than the blood. Other than the kidneys, all other organs including the pancreas contained concentrations similar to or less than those found in the blood. Similar distribution profiles were observed after intravenous administration. In rabbits, the major site of localisation was the kidneys. Pregnancy (Day 14 or Day 18) did not affect the distribution of radioactivity following oral administration of [14C]-glimepiride to rats. The concentration of radioactivity in fetal tissues was always lower than in the placenta, which in turn was lower than in maternal blood. There was no evidence of recirculation of radioactivity from the amniotic fluid to the fetus nor of accumulation of the drug or its metabolites in the fetus. The primary route of excretion in the rat, mouse and dog was through the feces while in the rabbit the majority of radioactivity was eliminated via the kidneys. Two major metabolites could be identified, the hydroxy derivative (M1) and the carboxylic acid derivative (M2). A study in biliary cannulated rats indicated that a substantial part of the radioactivity (predominantly metabolites M1 [41%] and M2 [21%] is subject to enterohepatic recirculation. Overall, the comparison between species revealed no major qualitative pharmacologic differences with respect to metabolism among animals and man, except for the observation that the metabolite M2 could not be found in dog.

TOXICOLOGY

Acute Toxicity Studies

• PO = orally IP = intraperitoneally IV = intravenously

* * glimepiride production intermediates

Multidose Toxicity Studies

* PO = orally IP = intraperitoneally IV = intravenously

Carcinogenicity Studies and Associated Dose-Finding Studies

Mutagenicity Studies

Reproduction Toxicity Studies

Reproduction Toxicity Studies

Other Toxicity Studies

Toxicokinetics Studies

REFERENCES

Pre-clinical publications:

1. Bahr M, Von Holtey M, Muller G, Eckel J. Direct stimulation of myocardial glucose transport and glucose transporter-1 (GLUT1) and GLUT4 protein expression by the sulfonylurea glimepiride. Endocrinology 1995; 136: 2547-53.

2. Bijlstra PJ, Lutterman JA, Russel FGM, Thien T, Smits P. Sulphonylurea derivatives interact selectively with vascular and pancreatic KATP channels in man. Neth J Med 1995; 47: A63-4.

3. Donaubauer HH, Mayer D. Acute, subchronic and chronic toxicity of the new sulfonylurea glimepiride in rats. Drug Res 1993; 43(I)5: 547-9.

4. Eckel J. Direct effects of glimepiride on protein expression of cardiac glucose transporters.

Horm Metab Res 1996; 28: 508-11. Gregorio F, Ambrosi F, Cristallini S, Filipponi P, Santeusanio F. Effects of glimepiride on insulin and glucagon release from isolated rat pancreas at different glucose concentrations. Acta Diabetol 1996; 33: 25-9. Kramer W, Muller G, Geisen K. Characterization of the molecular mode of action of the sulfonylurea, glimepiride at -cells. Horm Metab Res 1996; 28: 464-8. Ladriere L, Malaisse-Lagae F, Fuhlendorff J, Malaisse WJ. Repaglinide, glibenclamide and glimepiride administration to normal and hereditarily diabetic rats. Eur J Pharmacol 1997; 335: 227-34. Muller G, Dearey EA, Korndorfer A, Bandlow W. Stimulation of a glycosyl- phosphatidylinositol-specific phospholipase by insulin and the sulfonylurea, glimepiride, in rat adipocytes depends on increased glucose transport. J Cell Biol 1994; 126(5): 1267-76. Muller G, Geisen K. Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes. Horm Metab Res 1996; 28: 469-87. Muller G, Hartz D, Punter J, Okonomopulos R, Kramer W. Differential interaction of glimepiride and glibenclamide with the -cell sulfonylurea receptor. I. Binding characteristics. 1994; 1191: 267-77. Muller G, Wied S. The sulphonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro. Diabetes 1993; 42: 1852-67. Pan J, Chan EK, Yu E, Chen J, Schranz V, Charles MA. Prevention and cure of type I diabetes in the BB rat by islet allotransplantation and glimepiride treatment. Transplant Proc 1995; 27(6): 3194. Qi R, Ozaki Y, K, Kurota K, Asazuma N, Yatomi Y, Kume S. Sulphonylurea agents inhibit platelet aggregation and [Ca2+]i elevation induced by arachidonic acid. Biochem Pharmacol 1995; 49(12): 1735-9. Sato J, Ohsawa I, Oshida Y, Sato Y, Sakamoto N. Effects of glimepiride on in vivo insulin action in normal and diabetic rats. Diabetes Res Clin Pract 1993; 22: 3-9. Schollmeier U, Brunk R, Mayer D. Subchronic and chronic toxicity of the new sulfonylurea glimepiride in dogs. Drug Res 1993; 43(II)(10): 1068-71. Schwanstecher M, Manner K, Panten U. Inhibition of K+ channels and stimulation of insulin secretion by the sulfonylurea, glimepiride, in relation to its membrane binding in pancreatic islets. Pharmacol 1994; 49: 105-11.

Glimepiride clinical studies/reviews:

1. Anonymous (Diabetes Control and Complications Trial Research Group (DCCT)). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-86.

2. Anonymous (UK Prospective Diabetes Study (UKPDS) Group). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998; 352: 837-53.

3. Badian M, Korn A, Lehr K-H, Malerczyk V, Waldhaus W. Absolute bioavailability of glimepiride (Amaryl(r)) after oral administration. Drug Metab Drug Interact 1994; 11(4): 331-9.

4. Bijlstra PJ, Lutterman JA, Russel FGM, Thien T, Smits P. Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans. Diabetologia 1996; 39:1083-90.

5. Bijlstra PJ, Russel FGM, Thien T, Lutterman A, Smits P. Effects of tolbutamide on vascular ATP-sensitive potassium channels in humans. Comparison with literature data on glibenclamide and glimepiride. Horm Metab Res 1996; 28:512-6.

6. Bloomgarden ZT. New and traditional treatment of glycemia in NIDDM. Diabetes Care 1996; 19(3): 295-9.

7. Clark CM, Helmy AW, Clinical trials with Glimepiride. Drugs of Today 1998; 34(5):401-8

8. Clark HE, Matthews DR. The effect of glimepiride on pancreatic-cell function under hyperglycaemic clamp and hyperinsulinaemic, euglycaemic clamp conditions in non- insulin-dependent diabetes mellitus. Horm Metab Res 1996; 28: 445-50.

9. Dills DG, Schneider J. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Horm Metab Res 1996; 28: 426-9.

10. Draeger E. Clinical profile of glimepiride. Diabetes Res Clin Pract 1995; 28(Suppl): S139- 46.

11. Draeger KE, Wernicke-Panten K, Lomp H-J, Schuler E, Rosskamp R. Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl(r)) a double-blind comparison with glibenclamide. Horm Metab Res 1996; 28: 419-25.

12. Geisen K, Vegh A, Krause E, Papp JG. Cardiovascular effects of conventional sulfonylureas and glimepiride. Horm Metab Res 1996; 28: 496-507.

13. Goldberg RB, Holvey SM, Schneider J. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. Diabetes Care 1996; 19(8): 849-56.

14. Jack DB. Type II diabetes: how to use the new oral medications. Geriatrics 1996; 51(4): 33- 7.

15. Koltai MZ. Influence of hypoglucaemic sulphonylureas on the electrophysiological parameters of the heart. Diabetes Res Clin Pract 1996; Suppl 1: S15-20.

16. Langtry HD, Balfour JA. Glimepiride: a review of its use in the management of type 2 diabetes mellitus. Drugs 1998; 55(4): 563-84.

17. Levien T, Baker DE. Reviews of glimepiride and anastrozole. Hosp Pharm 1996; 31(10): 1297-1302.

18. Massi-Benedetti M, Herz M. Pfeiffer C. The effects of acute exercise on metabolic control in type II diabetic patients treated with glimepiride or glibenclamide. Horm Metab Res 1996; 28: 451-5.

19. Meltzer S, Leiter L, Daneman D, Gerstein H, Lau D, Ludwig S, Yale J-F, Zinman B, Lillie D, Steering and Expert Committees. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998; 159(8 Suppl): S1-S29.

20. Pogatsa G. What kind of cardiovascular alterations could be influenced positively by oral antidiabetic agents? Diabetes Res Clin Pract 1996; 31(Suppl): S27-31.

21. Ratheiser K, Korn A, Waldhausl W, Komjati M, Vierhapper H, Badian M, Malerczyk V. Dose relationship of stimulated insulin production following intravenous application of glimepiride in healthy man. Drug Res 1993; 43(II)(8): 856-8.

22. Riddle MC. Combined therapy with a sulfonylurea plus evening insulin: safe, reliable, and becoming routine. Horm Metab Res 1996; 28: 430-3.

23. Riddle MC, Tactics for type II diabetes. Current Therapies for Diabetes. 1997; 26(3):659- 77.

24. Rosenkranz B. Pharmacokinetic basis for the safety of glimepiride in risk groups of NIDDM patients. Horm Metab Res 1996; 28: 434-9.

25. Rosenkranz B, Profozic V, Metelko Z, Mrzljak V, Lange C, Malerczyk V. Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment. Diabetologia 1996; 39: 1617-24.

26. Rosenstock J, Samols E, Muchmore DB, Schneider J. Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Diabetes Care 1996; 19(11): 1194-9.

27. Rosskamp R. Safety aspects of oral hypoglycemic agents. Diabetologia 1996; 39: 1668-72.

28. Rosskamp R, Wernicke-Panten K, Draeger E. Clinical profile of the novel sulfonylurea glimepiride. Diabetes Res Clin Pract 1996; 31(Suppl): S33-42.

29. Schneider J. An overview of the safety and tolerance of glimepiride. Horm Metab Res 1996; 28: 413-8.

30. Smits P. Cardiovascular effects of sulphonylurea derivatives. Diabetologia 1997; 40: S160- 1.

31. Smits P, Bijlstra PJ, Russel FGM, Lutterman JA, Thien T. Cardiovascular effects of sulphonylurea derivatives. Diabetes Res Clin Pract 1996; 31(Suppl): S55-9.

32. Smits P, Bijlstra P, Thien T, Lutterman JA. Vascular effects of sulphonylurea derivatives in humans. J Mol Cell Cardiol 1995; 27:A430, Abstract PC-36.

33. Sonnenberg GE, Garg DC, Weidler DJ, Dixon RM, Jaber LA, Bowen AJ, DeCherney GS, Mullican WS, Stonesifer LD. Short-term comparison of once- versus twice-daily administration of glimepiride in patients with non-insulin-dependent diabetes mellitus. Ann Pharmacother 1997; 31: 671-6.

34. Toyota T, Fukao A, Kaneko T, Suda T, Maruhama Y, Satoh J. Clinical evaluation of glimepiride (HOE 490) in non-insulin-dependent diabetes mellitus - a double-blind placebo- controlled study / Phase III additional Study. July 14, 1997.

35. van der Wal PS, Draeger KE, van Iperen AM, Martini C, Aarsen M, Heine RJ. Beta cell response to oral glimepiride administration during and following a hyperglycaemic clamp in NIDDM patients. Diabet Med 1997; 14: 556-63.

36. Vegh A, Papp JG. Haemodynamic and other effects of sulphonylurea drugs on the heart.

Diabetes Res Clin Pract 1996; 31(Suppl): S43-53. Wolfe JK, Schneider J, Guzman J, Chylack LT. Glimepiride does not cause cataracts in humans. Invest Ophthalmol Vis Sci 1995; 36(4): S806. Zimmerman BR. Sulfonylureas. Current Therapies for Diabetes. 1997; 26(3): 511-22. Once-daily glimepiride in type 2 diabetes mellitus: possible tolerability advantages. Drug & Therapy Perspective 1998; 12(2): 1-5. Product Monograph for Amaryl(r), Aventis Pharma Inc., Laval, Quebec, Canada. Date of Revision: October 20, 2005. A Single-Dose, Randomized Crossover Comparative Bioavailability Study of Two Formulations of Glimepiride 4 mg Tablets in Healthy Subjects, under Fasting Conditions. Data on file at Novopharm Limited. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

NOVO-GLIMEPIRIDE

(glimepiride tablets)

This leaflet is part III of a three-part "Product Monograph" published when NOVO- GLIMEPIRIDE was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about NOVO-GLIMEPIRIDE. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

NOVO-GLIMEPIRIDE (glimepiride) is a medication that is used to treat Type 2 Diabetes. The chemical name for NOVO-GLIMEPIRIDE is "glimepiride"; it

belongs to a class of drugs called sulfonylureas.

To properly control your diabetes, it is essential that you follow the diet, exercise and weight loss program recommended by your doctor. It is also important that you test your blood for sugar according to your doctor's recommendations.

What it does:

NOVO-GLIMEPIRIDE (glimepiride) is indicated as an addition to proper dietary management, exercise

and weight reduction to lower the blood glucose in

patients with Type 2 Diabetes whose high blood sugar levels cannot be controlled by diet and exercise alone.

NOVO-GLIMEPIRIDE is also indicated for use in combination with insulin to lower blood glucose in patients with Type 2 Diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent (a drug used to lower blood sugar levels) alone.

When it should not be used:

NOVO-GLIMEPIRIDE should not be used:

• If you have Type 1 Diabetes.

• If you have known hypersensitivity or allergy to any sulfonylurea or any other component of the formulation. See "What the important nonmedicinal ingredients are".

• If you have diabetic ketoacidosis (an emergency condition with high blood glucose levels, a lack of insulin and an accumulation of ketones (chemicals) in the blood and urine), with or

without coma. This condition should be treated with insulin.

If you are pregnant or breast-feeding.

What the medicinal ingredient is:

The medicinal ingredient for NOVO-GLIMEPIRIDE is "glimepiride".

What the nonmedicinal ingredients are:

NOVO-GLIMEPIRIDE tablets contain the following non medicinal ingredients: lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone, and sodium starch glycolate. In addition: NOVO-GLIMEPIRIDE 1 mg tablets contain Ferric Oxide, NOVO-GLIMEPIRIDE 2 mg tablets contain FD&C Blue #2 Aluminum Lake and Ferric Oxide, and NOVO-GLIMEPIRIDE 4 mg tablets contain FD&C Blue #2 Aluminum Lake.

What dosage forms it comes in:

NOVO-GLIMEPIRIDE (glimepiride) is formulated into tablets of 1 mg, 2 mg, and 4 mg strengths for oral administration.

WARNINGS AND PRECAUTIONS

BEFORE you use NOVO-GLIMEPIRIDE talk to your doctor or pharmacist if you have kidney, liver, or heart disease.

• Do not take this medicine if you have had an allergic reaction to NOVO-GLIMEPIRIDE or other sulfonylurea drugs.

• This medicine has been prescribed for you alone because of your medical condition. This or any other prescription medicine should be used only by the person for whom it was prescribed. It should not be shared.

• Wear a medical identification (I.D.) bracelet or neck chain at all times. Also, carry an I.D. card in your wallet or purse that says that you have

diabetes and a list of your medicines.

Low blood sugar (hypoglycemia):

If your blood sugar gets too low, you may feel shaky, weak, drowsy, confused, or very hungry. You may sweat or have blurred vision, a fast

heartbeat, trouble concentrating, or a headache that

doesn't go away. Signs of severe hypoglycemia include disorientation, loss of consciousness and seizures.

You may have low blood sugar while you are taking NOVO-GLIMEPIRIDE, especially if you miss a meal, exercise for a long time, drink alcohol or use

IMPORTANT: PLEASE READ

another antidiabetic medication with NOVO- GLIMEPIRIDE. Make sure you know what to do if your blood sugar gets too low (ask your doctor, pharmacist or diabetes educator). Teach your friends, co-workers, or family members what they can do to help you if you have low blood sugar.

Pregnancy and breastfeeding:

NOVO-GLIMEPIRIDE should not be used during pregnancy or if you are breast feeding. Make sure your doctor knows if you are breast feeding,

pregnant, or think you might be pregnant. Your

doctor may want you to use insulin during this time.

Driving a vehicle or operating machinery:

Low or high blood sugar levels may impair alertness and reactions, especially when beginning or after altering treatment or when NOVO-GLIMEPIRIDE is not taken regularly. This may affect the ability to drive or to operate machinery.

INTERACTIONS WITH THIS MEDICATION

Drugs and foods to avoid:

Ask your doctor or pharmacist before taking any other medicine, including over-the-counter products.

Avoid drinking alcohol while you are taking this medicine.

There are various drugs that can interact with NOVO-GLIMEPIRIDE and change the way the

medicine works. Some of these drugs are

acetylsalicylic acid such as Aspirin, "sulfa" drugs, warfarin and beta-blockers.

Some medicines can make it harder for you to control your diabetes. These include ACE inhibitors (i.e. drugs used to treat high blood

pressure - hypertension), diuretics (water pills),

corticosteroids (such as prednisone), birth control pills, and some kinds of cold and allergy drugs.

Make sure your doctor and pharmacist knows if you are taking these or any other medicines.

how much to take and how often. It is important that you follow your doctor's instructions carefully.

Missed Dose:

Take the missed dose as soon as possible, unless it is almost time for your next dose.

Do not take two doses at the same time.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

As with any type of medication, NOVO- GLIMEPIRIDE is associated with some side effects. It may, however, affect different people in different ways. Just because side effects have occurred in other people does not mean you will get them.

If you have problems with these side effects, talk with your doctor or pharmacist:

• Mild nausea or vomiting

• Dizziness

• Low blood sugar (hypoglycemia), see above.

• This medicine may make your skin sensitive to sunlight and could cause a rash or sunburn. Use a sunscreen when outdoors. Avoid using sunlamps or tanning beds.

Call your doctor right away if you have any of these side effects:

Unexplained fever, chills or sore throat

Unusual bleeding or bruising

Yellowing of skin or eyes, dark-colored urine or light- coloured bowel movements

Skin rash or hives

Oedema, swelling of the legs or unexpected weight gain.

This is not a complete list of side effects. For any unexpected effects while taking NOVO- GLIMEPIRIDE, tell your doctor or pharmacist.

HOW TO STORE IT

PROPER USE OF THIS MEDICATION

Usual dose:

NOVO-GLIMEPIRIDE is usually taken once daily, with breakfast or the first main meal of the day. NOVO-GLIMEPIRIDE tablets must be swallowed

without chewing. Your doctor will prescribe for you

Store the tablets at room temperature (15 - 300C), away from heat, moisture, and direct light.

As with all medicines, keep this product out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, Novopharm Limited. at: at: 1-800-268-4127 ext. 5005

or druginfo @novopharm.com

This leaflet was prepared by: Novopharm Limited

30 Novopharm Court Toronto, Ontario

Canada, M1B 2K9

Last revised: November 22, 2005.