PRODUCT MONOGRAPH

PrRhoxal-glimepiride Glimepiride tablets 1mg, 2mg, 3mg and 4 mg

PHARMACOLOGIC CLASSIFICATION

Oral Hypoglycemic (Sulfonylurea)

ACTION AND CLINICAL PHARMACOLOGY

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 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 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 (glimepiride tablets) 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 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 effectrive than either treatment alone, with regards to improving HbA1C, 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

Absorption and bioavailability

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 and excretion

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 II C9 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. 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.

Pharmacokinetics in special populations

Age and Gender

Comparison of glimepiride pharmacokinetics in type 2 diabetic patients PS 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 Precautions, hypoglycemia section below). No studies were performed in pediatric patients. 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).

Renal impairment

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 Precautions - Use in renal failure section below).

Hepatic Impairment

No studies were performed in patients with hepatic insufficiency.

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. A randomized, 2-way crossover, bioequivalence study was performed using Rhoxal-glimepiride 1 mg tablets and Amaryl tablets as a single dose 1 mg in healthy adult males under fasting conditions. The table below shows that Rhoxal-glimepiride and Amaryl (Canadian Reference) are bioequivalent.

TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA GLIMEPIRIDE

(1 x 1 mg) From measured data

Geometric Mean Arithmetic Mean (CV%)

T

max

* expressed as median (range) only.

* * expressed as arithmetic mean (CV%) only.

Reference drug product: AmarylTM manufactured by Aventis Pharma Inc.

Origin of the reference drug product (i.e. Country of purchase) used in the conduct of the study: Canada

CONTRAINDICATIONS

Rhoxal-glimepiride (glimepiride) is contraindicated in patients with

1. Type 1 diabetes (formerly known as insulin-dependent diabetes mellitus or IDDM)

2. Known hypersensitivity or allergy to any sulfonylurea or any other component of the formulation.

3. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

4. 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

Use of Rhoxal-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 $-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.

PRECAUTIONS

General

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 Rhoxal-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 Rhoxal-glimepiride.

Loss of control of blood glucose:

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of glycemic control may occur. At such times, it may be necessary to add insulin in combination with Rhoxal-glimepiride or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including Rhoxal-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 Rhoxal-glimepiride monotherapy, metformin may be added until the maximum dose of both agents is reached. Should secondary failure occur with Rhoxal-glimepiride -metformin combination therapy, Rhoxal-glimepiride -insulin combination therapy may be instituted.

Hypoglycemia:

All sulfonylurea drugs are capable of producing severe hypoglycemia. 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 Rhoxal-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 Interactions section below). In clinical trials, patients receiving glimepiride in combination with insulin reported more incidence of hypoglycemia than patients on monotherapy.

Pediatric Use

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

Pregnancy

There are no adequate and well-controlled studies in pregnant women. On the basis of results from animal studies, 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 Mothers

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, glimepiride should be discontinued in nursing mothers. If Rhoxal-glimepiride is discontinued, and if diet and exercise alone are inadequate for controlling blood glucose, insulin therapy should be considered (See above Pregnancy, Nonteratogenic Effects).

Patients with Heart Disease

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.

Patients with Renal Failure

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

Drug Interactions

Coadministration of acetylsalicylic acid (1 g tid) and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean Cl/F. The mean Cmax had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of acetylsalicylic acid and other salicylates. Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg bid) with a single 4-mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of H2-receptor antagonists. Concomitant administration of propranolol (40 mg tid) and glimepiride significantly increased Cmax, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%, respectively, and it decreased Cl/F by 18%. The recovery of M1 and M2 from urine, however, did not change. The pharmacodynamic responses to glimepiride were nearly identical in normal subjects receiving propranolol and placebo. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of beta-blockers. However, if beta- blockers are used, caution should be exercised and patients should be warned about the potential for hypoglycaemia. Concomitant administration of glimepiride (glimepiride tablets) (4 mg once daily) did not alter the pharmacokinetic characteristics of R- and S-warfarin enantiomers following administration of a single dose (25 mg) of racemic warfarin to healthy subjects. No changes were observed in warfarin plasma protein binding. Glimepiride treatment did result in a slight, but statistically significant, decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important. The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg glimepiride were unaffected by coadministration of ramipril (an ACE inhibitor) 5 mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of ACE inhibitors. Potential interactions of glimepiride with other drugs metabolized by cytochrome P450 II C9 also include phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid. 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, nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, cyclophosphosphamine, disopyramide, fibrates, 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 glimepiride, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving 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 glimepiride, the patient should be closely observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for hypoglycaemia. H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.

Information for Patients

Patients should be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. The potential for primary and secondary failure should also be explained. Patients should report any edema or weight gain to their physician.

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.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Overdosage of sulfonylureas, including Rhoxal-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 over dosage, 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.

DOSAGE AND ADMINISTRATION

The patient's fasting blood glucose and HbA1C must be measured periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels should be performed to monitor the patient's response to therapy. Short-term administration of Rhoxal-glimepiride (glimepiride) may be sufficient during periods of transient loss of glycemic control in patients usually controlled well on diet and exercise.

Usual Starting Dose

The usual starting dose of Rhoxal-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 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 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.

Rhoxal-glimepiride - Metformin Combination Therapy Combination therapy with Rhoxal-glimepiride and metformin may be used in patients who do not respond adequately to the maximal dose of Rhoxal-glimepiride or in secondary failure patients. With concomitant Rhoxal-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 Rhoxal-glimepiride and metformin therapy, the risk of hypoglycemia may increase. Appropriate precautions should be taken.

Rhoxal-glimepiride -Insulin Combination Therapy

Combination therapy with Rhoxal-glimepiride and insulin may be used in secondary failure patients. The recommended Rhoxal-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

CLINICAL PHARMACOLOGY, Special Populations PRECAUTIONS, General).

Rhoxal-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

and

Changeover from Other Oral Hypoglycemic Agents

As with other sulfonylurea hypoglycemic agents, no transition period is necessary when transferring patients to rhoxal-glimepiride. No exact dosage relationship exists between rhoxal-glimepiride and the other oral hypoglycemic agents. The maximum starting dose of rhoxal-glimepiride should be no more than 1 mg. Patients should be observed carefully (1-2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to rhoxal-glimepiride due to potential overlapping of drug effect.

Drug Substance

PHARMACEUTICAL INFORMATION

Proper 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:

O O

O

O N N

CH3

H H

N N

H H3C Empirical formula: C24H34N4O5S Molecular weight: 490.62 Physical form: Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder Solubility: Glimepiride is practically insoluble in water, soluble in dimethylformamide, slightly soluble in methylene chloride, very slightly soluble in methanol. It dissolves in dilute alkali hydroxides and dilute acids. pKa values: 6.2 +- 0.1 at 37 oC Melting point: 207 oC

Composition

Rhoxal-glimepiride is formulated into tablets of 1 mg, 2 mg, 3 mg and 4 mg strengths for oral administration. Rhoxal-glimepiride tablets contain the active ingredient glimepiride and the following non medicinal ingredients: Lactose monohydrate, Microcrystalline cellulose, Sodium starch glycolate, Povidone, Magnesium stearate, Ferric oxide red (1 mg tablets only), Ferric oxide yellow (2 mg and 3 mg tablets only), Indigotine (FD&C Blue no. 2 Aluminium Lake) (2 mg and 4 mg tablets only).

Stability and Storage Recommendations

Store between 15 and 30/C. Dispense in well-closed container.

AVAILABILITY OF DOSAGE FORMS

Rhoxal-glimepiride tablets are available in the following strengths and package sizes:

1. mg: A light red, flat, modified oblong tablet, scored on both sides, embossed "G" on the left side of the score and "1" on the right side. The embossment is only on one side of the tablet. Plastic bottles of 30 or 100 tablets and blister packs of 30 tablets.

2. mg: A light green, flat, modified oblong tablet, scored on both sides, embossed "G" on the left side of the score and "2" on the right side. The embossment is only on one side of the tablet. Plastic bottles of 30 or 100 tablets and blister packs of 30 tablets.

3. mg: A light yellow, flat, modified oblong tablet, scored on both sides, embossed "G" on the left side of the score and "3" on the right side. The embossment is only on one side of the tablet. Plastic bottles of 30 or 100 tablets and blister packs of 30 tablets.

4. mg: A light blue, flat, modified oblong tablet, scored on both sides, embossed "G" on the left side of the score and "4" on the right side. The embossment is only on one side of the tablet. Plastic bottles of 30 or 100 tablets and blister packs of 30 tablets.

INFORMATION FOR THE PATIENT

What is Rhoxal-glimepiride?

Rhoxal-glimepiride is a medication that is used to treat type 2 diabetes. The chemical name for Rhoxal-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 recommendations.

Taking the medicine:

Rhoxal-glimepiride is usually taken once daily, with breakfast or the first main meal of the day. Rhoxal-glimepiride tablets must be swallowed without chewing. Your doctor will prescribe for you how much to take and how often. It is important that you follow your doctor's instructions carefully. If you miss a 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.

Precautions:

Talk with your doctor before taking this medicine if you have kidney, liver, or heart disease. Do not take this medicine if you have had an allergic reaction to Rhoxal-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 and I.D. card in your wallet or purse that says that you have diabetes and a list of your medicines.

Low blood sugar (hypoglycemia):

Signs of low blood sugar: 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. You may have low blood sugar while you are taking Rhoxal-glimepiride, especially if you miss a meal, exercise for a long time, drink alcohol or use another antidiabetic medication with rhoxal- 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:

Rhoxal-glimepiride should not be used during pregnancy or if you are breastfeeding. Make sure your doctor knows if you are breastfeeding, pregnant, or think you might be pregnant. Your doctor may want you to use insulin during this time.

Side effects:

As with any type of medication, Rhoxal-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-colored bowel movements Skin rash or hives Oedema, swelling of the legs or unexpected weight gain. If you have other side effects that you think might be caused by this medicine, tell your doctor or pharmacist.

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 rhoxal-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 diuretics (water pills), corticosteroids (such as prednisone), birth control pills, and some kinds of cold and allergy drugs. Make sure your doctor and pharmacist know if you are taking these or any other medicines.

How to store this medicine tablets:

Store the tablets at room temperature (15-30degC), 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.

Who supplies Rhoxal-glimepiride?

RhoxalPharma Inc. 4600 Thimens Boulevard Saint-Laurent, Quebec H4R 2B2

Animal Pharmacology

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 mg/kg) and intravenous (5-500 mg/kg) doses of glimepiride were more acutely and chronically potent than glyburide. Following oral administration to dogs (60 and 120 mg/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 :g/kg intravenous and 90 :g/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 mg/kg) and/or orally (90 mg/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 :M inhibiting selectively the cyclooxygenase pathway at concentrations up to 40 :M, 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 :g 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 (Day14 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.

Acute Toxicity Studies

TOXICOLOGY

PO = orally IP = intraperitoneally IV = intravenously * * glimepiride production intermediates

Multidose Toxicity Studies

ecies/

Group

. losf

(M, F)

Route

Dose Levels

ound

Test

Duration

Key Observations

PO = orally IP = intraperitoneally IV = intravenously

Carcinogenicity Studies and Associated Dose-Finding Studies

Mutagenicity Studies

Reproduction Toxicity Studies

Other Toxicity Studies

Toxicokinetics Studies

CLINICAL TRIALS

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 Rhoxal-glimepiride for 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 (3 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.

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

2. PPG is the 2-hour level after breakfast for study 3 and the 4-hour average after breakfast for study 4. Significance indicated at *pPS0.05.

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 with metformin when diet and exercise, and glimepiride or metformin alone do not result in adequate glycaemic control. The study which supports this indication is a multicenter, randomized, double-blind, double dummy study of 20 weeks duration with the following 3 parallel groups:

1. Glimepiride 1-6 mg qd + Metformin placebo tid; n = 150

2. Glimepiride 1-6 mg qd + Metformin 850 mg tid; n = 147

3. Metformin 850 mg tid + Glimepiride placebo qd; n = 75

The primary objective of this trial was to compare glycaemic 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: HbA1c). 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 (HbA1c), the combination of metformin and glimepiride was more effective than either treatment alone. Mean HbA1c 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/l in the glimepiride group, 1.87 g/l in the glimepiride + metformin group and 1.90 g/l in the metformin group. The mean change (+- SD) from baseline to Week 20 was 0.13 +- 0.56 g/l in the glimepiride group, -0.32 +- 0.39 g/l in the glimepiride + metformin group, and 0.15 g/l +- 0.64 g/l in the metformin group. Mean PPBG was similar in each group at baseline: 2.67 g/l in the glimepiride group, 2.62 g/l in the glimepiride + metformin group and 2.74 g/l in the metformin group. The mean change (+- SD) from baseline to Week 20 was 0.01 +- 0.89 g/l in the glimepiride group, -0.46 +- 0.67 g/l in the glimepiride + metformin group and 0.19 +- 1.06 g/l 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 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 PS 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 hypoglycaemia, 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.

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