SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 15 ACTION AND CLINICAL PHARMACOLOGY. 15 STORAGE AND STABILITY 19 DOSAGE FORMS, COMPOSITION AND PACKAGING 19

PART II: SCIENTIFIC INFORMATION 21

PHARMACEUTICAL INFORMATION 21 CLINICAL TRIALS 22 DETAILED PHARMACOLOGY 27 TOXICOLOGY 32 REFERENCES 40

PART III: CONSUMER INFORMATION. 45

AMARYL(r)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

AMARYL(r) (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 AMARYL(r) 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

Use of AMARYL(r) (glimepiride) must be considered as treatment in addition to a proper dietary regimen and not as a substitute for diet. Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycemic agents because of deterioration of their diabetic state. Patients should therefore be monitored with regular clinical and laboratory evaluations, including blood glucose and glycosylated hemoglobin (HbAlC) determinations, to determine the minimum effective dosage and to detect primary failure (inadequate lowering of blood glucose concentrations at the maximum recommended dosage) or secondary failure (progressive deterioration in blood sugar control following an initial period of effectiveness). The rate of primary failure will vary greatly depending upon patient selection and adherence to diet and exercise. The etiology of secondary failure is multifactorial and may involve progressive b-cell failure as well as exogenous diabetogenic factors such as obesity, illness, drugs, or tachyphylaxis to the sulfonylurea. If a loss of adequate blood glucose lowering response to a sulfonylurea is detected, the addition of a different type of oral antidiabetic may be considered, although insulin is often required. Certain patients who demonstrate an inadequate response or true primary or secondary failure to one sulfonylurea may benefit from a switch to another sulfonylurea. In initiating treatment for type 2 diabetes, non-pharmacologic therapy (proper dietary management, exercise and weight reduction) should be emphasized as the initial form of treatment. Caloric restriction, weight loss and exercise are essential in the obese diabetic patient. Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken when possible.

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 AMARYL(r) (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 AMARYL(r). 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 AMARYL(r), add insulin in combination with AMARYL(r) or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including AMARYL(r), 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 AMARYL(r) monotherapy, metformin may be added until the maximum dose of both agents is reached. Should secondary failure occur with AMARYL(r) - metformin combination therapy, AMARYL(r) -insulin combination therapy may be instituted.

Hypoglycemia:

All sulfonylurea drugs are capable of producing severe hypoglycemia. In the initial weeks of treatment, the risk of hypoglycemia seen with glimepiride may be even further increased and necessitates closer and more frequent monitoring.

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 AMARYL(r). 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 causing lowering of blood glucose are used concomitantly with AMARYL(r) (See DRUG INTERACTIONS, Drug-Drug Interactions section). In clinical trials, patients receiving AMARYL(r) in combination with insulin reported more incidence of hypoglycemia than patients on monotherapy.

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 AMARYL(r) 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.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anemia. Since AMARYL(r) belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a nonsulfonylurea alternative should be considered.

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

Pregnant Women:

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

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 AMARYL(r) 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, AMARYL(r) should be discontinued in nursing mothers. If AMARYL(r) 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.

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.

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 AMARYL(r) (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 AMARYL(r) (glimepiride) has been evaluated in clinical trials and further assessed during post-marketing experience. A total of 2,013 patients were exposed to AMARYL(r) 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 AMARYL (r) (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 AMARYL (r) 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 AMARYL (r) (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 AMARYL (r) 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 AMARYL(r) are shown below.

Adverse Events Occurring in > 1% AMARYL(r) Patients

	AMARYL (r)		Placebo
	No. patients (n = 746)	%	No. patients (n = 294)	%
Dizziness	13	1.7	1	0.3
Asthenia	12	1.6	3	1.0
Headache	11	1.5	4	1.4
Nausea	8	1.1	0	0.0

Endocrine and Metabolism:

Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however, no cases have yet been reported with AMARYL(r) (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 AMARYL(r), 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 AMARYL(r) (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 or pseudoallergic 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 with dyspnoea and hypotension, sometimes progressing to shock. These may be transient and may disappear despite continued use of AMARYL(r); if skin reactions persist, the drug should be discontinued. Although there have been no reports for AMARYL(r), porphyria cutanea tarda has been reported with sulfonylureas.

Other Adverse Reactions:

Changes in accommodation and/or blurred vision may occur with the use of AMARYL(r). 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 AMARYL(r), the incidence of blurred vision was placebo, 3.4%, and AMARYL(r), 1.7%.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Clinical adverse events occurring in less than 1% of patients treated with AMARYL(r) in all US clinical trials are listed below by body system:

Body as a whole:

abdominal pain, laboratory test abnormal, and pain in extremity

Cardiovascular:

palpitation and vasodilation

Digestive:

diarrhea, increased appetite, dyspepsia, anorexia, and gastrointestinal pain

Metabolic and Nutritional Disorders:

hypoglycemic reaction and hyperglycemia

Nervous system:

tremor, insomnia, sweating increased, nervousness, dry mouth, hot flashes, and paresthesia

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 (>=1/10,000 and <1/1000), thrombopenia and, in isolated cases (<1/10,000), leucopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop.

Skin: .

In isolated cases (<1/10,000), 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

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

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

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, insulin and other oral antidiabetics, nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as azapropazone, sulfonamides (e.g. sulphaphenazole), chloramphenicol, clarithromycin, coumarins, cyclophosphamide, disopyramide, fenyramidol, fenfluramine, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, miconazole,monoamine oxidase inhibitors, oxyphenbutazone, para-aminosalicylic acid, pentoxifylline (high dose parenteral), phenylbutazone, probenecid, propranolol, quinolones, salicylates, sulfonamide antibiotics, sulfinpyrazone, and tetracycline. When these drugs are administered to a patient receiving AMARYL(r), the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving AMARYL(r), 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 AMARYL(r), the patient should be closely observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving AMARYL(r), the patient should be observed closely for hypoglycemia. Concurrent use of H2 receptor antagonists, beta-blockers, clonidine or reserpine with AMARYL(r) may lead to either potentiation or weakening of the blood-glucose-lowering effect. Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent. The effect of coumarin derivatives may be potentiated or weakened.

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 (HbA1c) should be performed to monitor the patient's response to therapy. Short-term administration of AMARYL(r) (glimepiride) may be sufficient during periods of transient loss of glycemic control in patients usually controlled well on diet and exercise.

The usual starting dose of AMARYL(r) 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)

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. AMARYL(r) - Metformin Combination Therapy Combination therapy with AMARYL(r) and metformin may be used in patients who do not respond adequately to the maximal dose of AMARYL(r) or in secondary failure patients. With concomitant AMARYL(r) 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 AMARYL(r) and metformin therapy, the risk of hypoglycemia may increase. Appropriate precautions should be taken. AMARYL(r) - Insulin Combination Therapy Combination therapy with AMARYL(r) and insulin may be used in secondary failure patients. The recommended AMARYL(r) 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.

AMARYL(r) 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).

No exact dosage relationship exists between AMARYL(r) and the other oral hypoglycemic agents. When substituting AMARYL(r) 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 AMARYL(r) 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.

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 AMARYL(r) (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

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 AMARYL(r) (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.

A mild glucose-lowering effect first appeared following single oral doses as low as 0.5 - 0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [Tmin]) was about 2 to 3 hours. In type 2 diabetes (formerly known as non-insulin- dependent diabetes mellitus or NIDDM) patients, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours. In larger dose-ranging studies, blood glucose and glycosylated hemoglobin (HbA1C) were found to respond in a dose-dependent manner over the range of 1 to 4 mg of AMARYL(r) once daily. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of AMARYL(r) up to 8 mg once daily. No difference in the decrease in blood glucose and HbA1C concentrations were found when AMARYL(r) was administered once or twice daily. In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in HbA1C for AMARYL(r) (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, AMARYL(r) 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 AMARYL(r), 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 AMARYL(r), no meaningful deterioration in mean fasting blood glucose (FBG) or HbA1C levels was seen after up to 2.5 years of AMARYL(r) therapy (n = 445). Combination therapy with AMARYL(r) 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 HbA1C, fasting blood glucose and postprandial blood glucose levels. Combination therapy with AMARYL(r) 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 AMARYL(r)/insulin therapy group showed an insulin sparing effect with a use of 38% less insulin. AMARYL(r) therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for Type 2 diabetes.

Absorption: After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively). In normal healthy volunteers, the intra-individual variabilities of Cmax, AUC, and total body clearance after oral dosing (Cl/F) for glimepiride were 23%, 17%, and 15%, respectively, and the inter- individual variabilities were 25%, 29%, and 24%, respectively. The pharmacokinetics of glimepiride obtained from a single-dose, crossover, dose- proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose-proportionality (4 and 8 mg) study in patients with type 2 diabetes are summarized below:

These data indicate that glimepiride did not accumulate in serum, and the pharmacokinetics of glimepiride were not different in healthy volunteers and in type 2 diabetic patients. Oral clearance of glimepiride did not change over the 1-8-mg dose range, indicating linear pharmacokinetics.

Distribution:

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

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

Metabolism:

Glimepiride is completely metabolized by oxidative biotransformation after either IV or oral administration. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2 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.

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 metabolites 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 metabolites 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.

Pediatrics:

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 AMARYL(r) (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:

Renal Insufficiency: A single-dose, open-label study was conducted in 15 patients with renal impairment. AMARYL(r) (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. AMARYL(r) was found to be well tolerated in all 3 groups. The results showed that M1 and M2 metabolites 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 metabolites M1 and M2 increased as renal function decreased. Mean urinary excretion of metabolites 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 AMARYL(r) 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 Cmax and AUC. However, since neither Cmax nor AUC values were normalized for body surface area, the lower values of Cmax and AUC for the obese patients were likely the result of their excess weight and not due to a difference in the kinetics of glimepiride.

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability Of Dosage Forms and Packaging:

AMARYL(r) (glimepiride) tablets are available in the following strengths and package sizes: 1 mg: Pink, flat-faced, oblong tablet with notched sides at the bisect imprinted with "AMARYL" on one side and plain with bisect on the other. Plastic bottles of 30

tablets.

2 mg: Green, flat-faced, oblong tablet with notched sides at the bisect imprinted with "AMARYL" on one side and plain with bisect on the other. Plastic bottles of 30 tablets. 4 mg: Blue, flat-faced, oblong tablet with notched sides at the bisect imprinted with "AMARYL" on one side and plain with bisect on the other. Plastic bottles of 30 tablets.

Composition:

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

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Tablet 1, 2, and 4 mg	Lactose For a complete listing see Dosage Forms, Composition and Packaging section

Proper Name	Ref	Effect	Clinical Comments
Acetylsalicylic acid (ASA)	CT	\| 34% mean glimepiride AUC \| 34% mean glimepiride Cl/F \| 4% mean glimepiride C m ax	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.
Cimetidine or ranitidine	CT	No clinically significant effect	Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg bid) with a single 4-mg oral dose of AMARYL (r) 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.
Propranolol	CT	\| glimiperide C ma x by 23% \| glimiperide AUC by 22% \| glimiperide T 1 /2 by 15% \| glimepiride Cl/F by 18%	The recovery of M1 and M2 metabolites from urine 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 hypoglycemia.
Warfarin	CT	No clinically significant effect	Concomitant administration of AMARYL (r) (glimepiride) (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. AMARYL (r) 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 AMARYL (r) treatment were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important.
Ramipril	CT	No clinically significant effect	The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg AMARYL (r) were unaffected by coadministration of ramipril 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.
Drugs metabolized by	T	Potential interactions	Potential interactions of glimepiride with other drugs metabolized by cytochrome P450 2C9 also include
Proper Name	Ref	Effect	Clinical Comments
cytochrome P450 2C9			phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid.

	Volunteers	Patients with Type 2 Diabetes
	Single Dose Mean +- SD (n)	Single Dose (Day 1) Mean +- SD (n)	Multiple Dose (Day 10) Mean +- SD (n)
C max (ng/mL), 1 mg	103 +- 34 (12)
2 mg	177 +- 44 (12)	-	-
4 mg	308 +- 69 (12)	352 +- 222 (12)	309 +- 134 (12)
8 mg	551 +- 152 (12)	591 +- 232 (14)	578 +- 265 (11)
T m ax (h), 1 mg	2.3 +- 0.5 (12)	-	-
2 mg	2.4 +- 0.5 (12)	-	-
4 mg	2.1 +- 0.6 (12)	2.08 +- 0.51 (12)	2.22 +- 1.21 (12)
8 mg	2.8 +- 1.2 (12)	2.80 +- 1.46 (14)	3.46 +- 2.82 (11)
Cl/F (mL/min), 1 mg	55.3 +- 16.3 (12)	-	-
2 mg	53.5 +- 15.5 (12)	-	-
4 mg	53.6 +- 10.6 (12)	54.2 +- 41.1 (12)	63.4 +- 53.5 (12)
8 mg	56.5 +- 21.1 (12)	43.6 +- 13.0 (14)	41.0 +- 11.2 (11)
Vd/f (L), 1 mg	10.6 +- 1.8 (12)	-	-
2 mg	12.6 +- 2.9 (12)	-	-
4 mg	15.7 +- 5.4 (12)	20.8 +- 11.3 (12)	40.2 +- 22.3 (12)
8 mg	20.9 +- 6.9 (12)	18.9 +- 14.1 (14)	33.8 +- 12.6 (11)
t 1/2 (h), 1 mg	1.2 +- 0.5 (12)	-	-
2 mg	1.3 +- 0.4 (12)	-	-
4 mg	1.5 +- 0.5 (12)	5.30 +- 2.54 (12)	8.82 +- 4.36 (12)
8 mg	1.5 +- 0.4 (12)	4.69 +- 2.61 (14)	9.63 +- 2.63 (11)

PART I: HEALTH PROFESSIONAL INFORMATION 3