Co Glimepiride Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

CO 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 or sulfonamides or any other component of the formulation. For a complete listing, see the 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 CO 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 (HbA_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. 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 CO 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 CO 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 CO GLIMEPIRIDE, add insulin in combination with CO GLIMEPIRIDE or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including CO 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. Should secondary failure occur or if target blood glucose levels are not attainable with CO GLIMEPIRIDE monotherapy, metformin may be added until the maximum dose of both agents is reached. Should secondary failure occur with CO GLIMEPIRIDE-metformin combination therapy, CO GLIMEPIRIDE -insulin combination therapy may be instituted.

Hypoglycemia: 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 CO 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 Drug-Drug Interactions 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 (UGDP), 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, glimepiride 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.

Nonteratogenie 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:

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, CO GLIMEPIRIDE should be discontinued in nursing mothers. If CO GLIMEPIRIDE is discontinued, and if diet and exercise alone are inadequate for controlling blood glucose, insulin therapy should be considered (See above Pregnant Woman, Nonteratogenic Effects).

Pediatrics:

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

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 glycemic control.

Occupational Hazards

Driving a vehicle or operating machinery:

Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when beginning or after altering treatment or when CO GLIMEPIRIDE is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The safety profile of glimepiride has been evaluated in clinical trials and further assessed during post-marketing experience. A total of 2,013 patients were exposed to glimepiride in US controlled trials, 1,489 patients in European trials and 783 patients in Japanese trials. More than 1,800 of these patients were treated for at least 1 year.

The overall incidence of hypoglycemia with glimepiride was approximately 14% in placebo controlled trials, the incidence of hypoglycemia ranged from 2.1 to 3.1% in two long-term, well-controlled studies, and hypoglycemic episodes occurred in 22 and 51% in clinical trials involving patients treated with glimepiride in combination with metformin or insulin, respectively.

The most frequent adverse events occurring in US placebo-controlled trials were: dizziness (1.7%); asthenia (1.6%); headache (1.5%); nausea (1.1%).

Clinical Trial Adverse Drug Reactions

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

The overall incidence of hypoglycemia with glimepiride in placebo controlled trials was approximately 14% versus 2% for placebo. In two long-term (2-2.5 years) and well-controlled studies, the incidence of hypoglycemic reaction ranged from 2.1 to 3.1%. In clinical trials involving patients treated with glimepiride in combination with metformin or insulin, hypoglycemic episodes occurred in 22 and 51% of the patients, respectively.

Adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with glimepiride are shown below.

Adverse Events Occurring in > 1% Glimepiride Patients

Endocrine and Metabolism:

Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however, no cases have yet been reported with glimepiride. Cases of hyponatremia have been reported with glimepiride and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increased release of antidiuretic hormones. Although there have been no reports for glimepiride, the syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increased release of ADH.

Gastrointestinal:

Gastrointestinal (GI) disturbances e.g. nausea, GI fullness, occur occasionally. Vomiting, gastrointestinal pain, and diarrhea have been reported, but the incidence in placebo-controlled trials was similar to that of placebo. In rare cases, there may be elevation of liver enzyme levels. Sulfonylureas, including glimepiride, may also - in isolated instances - cause impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis which may also lead to liver failure.

Skin:

Allergic skin reactions, e.g., pruritus, erythema, urticaria, vasculitis, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. Such mild reactions may develop into serious reactions sometimes progressing to shock. These may be transient and may disappear despite continued use of glimepiride; if skin reactions persist, the drug should be discontinued. Although there have been no reports for glimepiride, porphyria cutanea tarda has been reported with sulfonylureas.

Other Adverse Reactions:

Changes in accommodation and/or blurred vision may occur with the use of glimepiride. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment. In placebo-controlled trials of glimepiride the incidence of blurred vision was placebo, 3.4%, and glimepiride, 1.7%.

Skin and appendages: pruritus and urticaria

Special Senses: blurred vision

Urogenital System: increased urinary frequency and nocturia

Post-Market Adverse Drug Reactions

The following adverse events, not seen in clinical trials, have been reported during post-marketing surveillance:

Hematologic: Changes in the blood picture may occur. Rarely (≥ l/10,000 and < l/1000), thrombopenia and, in isolated cases (< l/10,000), leucopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop.

Skin: In isolated cases (< l/10,000), allergic vasculitis or hypersensitivity of the skin to light may occur.

Other: In isolated cases (< 1/10,000), a decrease in serum sodium concentration may occur.

DRUG INTERACTIONS

Overview

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is co-administered 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 CO GLIMEPIRIDE (glimepiride) in an unpredictable fashion.

Drug-Drug Interactions

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 anabolic steroids and male sex hormones, ACE inhibitors, nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, cyclophosphamide, 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 CO GLIMEPIRIDE, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving CO 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 CO GLIMEPIRIDE, the patient should be closely observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving CO 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.

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.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Short-term administration of CO 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 CO 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 HbA_1C levels, for example every 3 to 6 months.

CO GLIMEPIRIDE - Metformin Combination Therapy

Combination therapy with CO GLIMEPIRIDE and metformin may be used in patients who do not respond adequately to the maximal dose of CO GLIMEPIRIDE or in secondary failure patients. With concomitant CO GLIMEPIRIDE and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. Attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With combination CO GLIMEPIRIDE and metformin therapy, the risk of hypoglycemia may increase. Appropriate precautions should be taken.

CO GLIMEPIRIDE - Insulin Combination Therapy

Combination therapy with CO GLIMEPIRIDE and insulin may be used in secondary failure patients. The recommended CO 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 HbA_1C levels.

Specific Patient Populations

CO 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 ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions and WARNINGS AND PRECAUTIONS, General).

Changeover from Other Oral Hypoglycemic Agents

No exact dosage relationship exists between glimepiride and the other oral hypoglycemic agents. When substituting CO GLIMEPIRIDE for other oral hypoglycemic agents, it is recommended 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 CO 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

The missed dose should be taken as soon as possible, unless it is almost time for the next dose. The patient should be advised not to take two doses at the same time.

OVERDOSAGE

Overdosage of sulfonylureas, including CO 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 [T_min]) 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 (HbA_1C) 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 CO GLIMEPIRIDE up to 8 mg once daily. No difference in the decrease in blood glucose and HbA_1C 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 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 HbA_1C. 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 HbA_1C levels was seen after up to 2.5 years of glimepiride therapy (N=445).

Combination therapy with glimepiride and metformin was compared with glimepiride and metformin monotherapy in Type 2 diabetic patients. The results of the study indicated that the combination of metformin and glimepiride was more effective than either treatment alone, with regards to improving HbAic, fasting blood glucose and postprandial blood glucose levels.

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

(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 (Ml) and the carboxyl derivative (M2). Cytochrome P450 2 C9 has been shown to be involved in the biotransformation of glimepiride to Ml. Ml is further metabolized to M2 by one or several cytosolic enzymes. Ml, 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 Ml 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 Ml (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and Ml 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 Ml 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. (WARNINGS 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 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 Ml 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 (T_1/2) for glimepiride did not change, while the half-lives for Ml and M2 increased as renal function decreased. Mean urinary excretion of Ml 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 WARNINGS 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 C_max and AUC. However, since neither C_max nor AUC values were normalized for body surface area, the lower values of C_max 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

Store between 15 and 30°C. Protect from moisture.

Dispense in well-closed container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability Of Dosage Forms and Packaging:

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

1 mg: A pink, capsule-shaped tablet, with ‘G1’ scoreline ‘G1’ on one side and “> ” scoreline “> ”

on the other side.

Plastic HDPE bottles of 30 and 100 tablets and blister packs of 30 tablets.

2 mg: A green, capsule-shaped tablet, with ‘G2’ scoreline ‘G2’ on one side and “> ” scoreline “> ”

on the other side.

Plastic HDPE bottles 30, 100 and 500 tablets and blister packs of 30 tablets.

3 mg: A pale yellow, capsule-shaped tablet, with ‘G3’ scoreline ‘G3’ on one side and “> ” scoreline

“> ” on the other side.

Plastic HDPE bottles 30, 100 and 500 tablets and blister packs of 30 tablets.

4 mg: A blue, capsule-shaped tablet, with ‘G4’ scoreline ‘G4’ on one side and “> ” scoreline “> ” on the other side.

Plastic HDPE bottles of 30, 100 and 500 tablets and blister packs of 30 tablets.

Composition:

CO GLIMEPIRIDE (glimepiride) is formulated into tablets of 1 mg, 2 mg, 3 mg and 4 mg strengths for oral administration. CO GLIMEPIRIDE tablets contain the active ingredient glimepiride and the following non medicinal ingredients: lactose monohydrate, sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. In addition: CO GLIMEPIRIDE 1 mg tablets contain Iron Oxide Red, CO GLIMEPIRIDE 2 mg tablets contain Iron Oxide Yellow and Indigo Carmine (FD&C Blue No.2 Lake), CO GLIMEPIRIDE 3 mg tablets contain Iron Oxide Yellow and CO GLIMEPIRIDE 4 mg tablets contain Indigo Carmine (FD&C Blue No.2 Lake).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

N

CH3

CH3

O

O NH

S

O O

NH

O

NH

CH3

CLINICAL TRIALS

Comparative Bioavailability

s tabulated below.

Summary Table of Comparative Bioavailability Data

* Glimepiride 4mg Tablets (Batch #: E0102; Manufacturing Date: Jan-2004)

† Amaryl TM 4mg Tablets (Batch #: 8015788; Expiry Date: 2005-AU; Manufactured by: Aventis Pharma Inc., Canada). The reference product was purchased in Canada.

§ Expressed as the arithmetic mean (CV%) only

║ Expressed as the arithmetic mean (CV%) only

Efficacy: Indication I

The primary indication (Indication I) for glimepiride is for use as an adjunct to diet and exercise in patients with non-insulin-dependent Type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone. This indication is supported by the results of three pivotal placebo-controlled trials. In addition, four non-pivotal trials provide complementary information to support the primary indication.

Trials Supporting the Efficacy of Glimepiride for Indication I.

All dosages of glimepiride produced significant and clinically meaningful reductions in the primary efficacy variables, when compared to placebo.

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 (10-13.3 mmol/L; -2.5 mmol/L). Likewise, in the longer term placebo controlled trial, when stratified by baseline HbA_1C, glimepiride subjects in the high HbA_1C percentile group (≥ 75; HbA_1C > 10.5% (0.105)) had a greater reduction of the HbA_1C ( -3.7% (0.037)) than those in the low percentile (< 75 ; HbA_1C ≤ 10.5% (0.105)) (-1.6%). These two findings suggest patients with more severe type 2 diabetes can also benefit from glimepiride treatment.

Subjects in study 2 showed significant and clinically meaningful improvements in FPG and HbA_1C 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 HbA_1C levels between glimepiride and glyburide treatment after up to 30 months of therapy.

Efficacy: Indication II

The primary objective of this trial was to compare glycemic control in NIDDM patients with less than optimal response to metformin monotherapy by either switching to glimepiride alone or to combination therapy with glimepiride and metformin (End point: HbA_1C). The third group consisted of the control receiving metformin alone. The secondary objectives were: Fasting blood glucose (FBG), postpandrial blood glucose (PPBG), Body mass index (BMI), triglyceride, total cholesterol, HDL cholesterol and apolipoprotein B, serum insulin and serum C-peptide, and blood pressure.

As there was no placebo group, the effect of the combination is to be interpreted as an additive effect of the two groups, rather than as an interactive drug effect.

With regard to the primary efficacy variable (HbA_1C), the combination of metformin and glimepiride was more effective than either treatment alone. Mean HbA_1C was similar in each group at baseline, 6.52% (0.0652) in the glimepiride group, 6.42% (0.0642) in the glimepiride + metformin group and 6.79% (0.0679) in the metformin group, for all patients without missing values, and with estimation for missing patients.

With regard to the secondary variables FBG and PPBG, the combination of metformin and glimepiride was more effective than either treatment alone. Mean FBG was similar in each group at baseline: 1.89 g/1 in the glimepiride group, 1.87 g/1 in the glimepiride + metformin group and 1.90 g/1 in the metformin group. The mean change (± SD) from baseline to Week 20 was 0.13 ± 0.56 g/1 in the glimepiride group, -0.32 ± 0.39 g/1 in the glimepiride + metformin group, and 0.15 g/1 ± 0.64 g/1 in the metformin group. Mean PPBG was similar in each group at baseline: 2.67 g/1 in the glimepiride group, 2.62 g/1 in the glimepiride + metformin group and 2.74 g/1 in the metformin group. The mean change (± SD) from baseline to Week 20 was 0.01 ± 0.89 g/1 in the glimepiride group, -0.46 ± 0.67 g/1 in the glimepiride + metformin group and 0.19 ± 1.06 g/1 in the metformin group.

No treatment effect was detected for the other variables, although BMI was lower in the metformin group.

Efficacy: Indication III

The third 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 randomized, 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 HbA_1C 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.

¹Riddle 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.

²Riddle 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.

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 g/kg) and intravenous (5-500 g/kg) doses of glimepiride were more acutely and chronically potent than glyburide. Following oral administration to dogs (60 and 120 g/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, Ml 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 (µg/kg intravenous and 90 (µg/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 g/kg) and/or orally (90 g/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 C_max 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:

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 µg 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 (Ml) and the carboxylic acid derivative (M2). A study in biliary cannulated rats indicated that a substantial part of the radioactivity (predominantly metabolites Ml [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

Carcinogenicitv Studies and Associated Dose-Finding Studies

Mutagenicity Studies

Reproduction Toxicity Studies

Other Toxicity Studies

Toxicokinetics Studies

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    Version 4.0 Control No. 099592.