'Xenical' (orlistat) is a reversible inhibitor of lipases. It exerts its therapeutic activity non- systemically in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit has a positive effect on weight loss, maintenance and prevention of weight regain. Systemic absorption of the drug is therefore not needed for activity. At the recommended dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.

Pharmacokinetics

14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were nonmeasurable (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/mL or 0.02 :M), without evidence of accumulation, and consistent with negligible absorption. Studies in rats and dogs indicated that the absolute bioavailability of orlistat in plasma is <2% at oral doses up to 1000 mg/kg/day.

In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.

Metabolism: Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on a 14C -orlistat mass balance study in obese patients, of the minute fraction of the radio-labelled dose that was absorbed systemically, the presence of two metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open $- lactone ring and extremely weak systemic lipase inhibitory activity (1000- and 2500- fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady-state plasma levels of M1, but not M3, increased in proportion to orlistat doses. Elimination: Following a single oral dose of 360 mg 14C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Approximately 97% of the administered radioactivity was excreted in feces and 83% of that was found to be unchanged orlistat. The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg 14C-orlistat. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours. Orlistat, M1 and M3 metabolites were also subject to biliary excretion.

Because the drug is minimally absorbed, with no defined pharmacokinetics, studies in special populations (geriatric, pediatric, different races, patients with renal and hepatic insufficiency) were not conducted.

In several studies of up to 6-weeks duration, the effects of orlistat on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of orlistat in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effect on plasma triglyceride levels, systemic lipases or balance of six minerals (calcium, magnesium, phosphorus, zinc, copper and iron) were observed with administration of orlistat in these studies.

CONTRAINDICATIONS

'Xenical' (orlistat) is contraindicated in patients with chronic malabsorption syndrome, cholestasis and in patients with known hypersensitivity to 'Xenical' or to any component of this product.

WARNINGS

No serious adverse reactions or safety hazards related to the use of 'Xenical' (orlistat) have been reported to date during large, long-term clinical trials (up to 2 years) (see PRECAUTIONS and ADVERSE REACTIONS).

PRECAUTIONS

A reduction in cyclosporine plasma levels has been observed when 'Xenical' (orlistat) is co-administered. Therefore, it is recommended to monitor cyclosporine plasma levels more frequently than usual if 'Xenical' is co-administered (see DRUG INTERACTIONS).

Patients should be advised to adhere to dietary guidelines (see DOSAGE AND ADMINISTRATION).

Diabetic patients treated with orlistat should have tests for fasting glucose and HbA1c as required. The possibility of experiencing gastrointestinal events (see ADVERSE REACTIONS) may increase when 'Xenical' is taken with a diet high in fat (e.g. in a 2000 Calorie/day diet, a diet high in fat would contain >30% calories from fat, which equates to >67g fat). The daily intake of fat should be distributed over three main meals. If 'Xenical' is taken with any one meal very high in fat, the possibility of gastrointestinal effects may increase. 'Xenical' only inhibits the absorption of dietary fat. Patients should be advised that if the resulting caloric reduction is compensated by an increase in calories from protein or carbohydrates, the expected weight loss will not occur. As with any weight-loss agent, the potential exists for misuse of 'Xenical' in inappropriate patient populations (e.g. patients with anorexia nervosa or bulimia). See the INDICATIONS AND CLINICAL USE section for appropriate prescribing guidelines. When using 'Xenical' in combination with insulin or oral hypoglycemic agents in the treatment of type 2 diabetes, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to the patient, family members, caregiver or others. Use in Pregnant and Lactating Women: Teratogenicity studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 22 and 43 times the daily human dose calculated, on a body surface area (mg/m2) basis, for rats and rabbits, respectively. There are no adequate and well-controlled studies of orlistat in pregnant women. Because animal reproductive studies are not always predictive of human response, 'Xenical' should be used during pregnancy only if the benefit clearly outweighs any potential harm. It is not known if orlistat is secreted in human milk. Therefore, 'Xenical' should not be used by nursing women unless the benefit to the mother clearly outweighs any potential for harm to the nursing infant. Use in Children: The safety and efficacy of 'Xenical' in pediatric patients (# 17 years) have not been established.

Some patients may develop increased levels of urinary oxalate following treatment with 'Xenical'. Caution should be exercised when prescribing 'Xenical' to patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.

'Xenical' should be used with caution in patients with pre-existing disease of the large bowel or rectum.

Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study with $- carotene showed a 30% reduction in $-carotene supplement absorption when concomitantly administered with 'Xenical'. 'Xenical' inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A and nutritionally derived vitamin K is not known at this time. Obesity management studies indicated that some patients required vitamin D supplementation with a multivitamin to achieve desirable blood levels. The decreases in vitamin D were modest (measured by 25-OH-D) and were not associated with any changes in vitamin D metabolism, as evidenced by total or ionized calcium and parathyroid levels. Clinical studies did not reveal any interference with blood coagulation that would indicate vitamin K deficiency. During obesity management studies, there were decreases in the levels of some fat soluble vitamins and $-carotene based on the pharmacologic action of the drug. The vast majority of patients in up to two full years of treatment had vitamin levels that stayed well within normal range, and there was no evidence of clinical sequelae. The vitamin status of obese patients in general and patients on a weight control regimen including 'Xenical' pharmacotherapy may be low. Therefore patients should be counselled to take a multivitamin which includes fat-soluble vitamins and $-carotene to ensure adequate nutrition. The supplement should be taken at least two hours before or after the administration of 'Xenical', or at bedtime.

As treatment with orlistat may potentially impair the GI absorption of vitamin K, close monitoring of the coagulation parameters is recommended when oral anticoagulants are co- administered (see DRUG INTERACTIONS).

(Extended-Release Tablets): In 17 normal weight subjects receiving 'Xenical' 120 mg tid for 6 days, 'Xenical' did not alter the bioavailability of nifedipine extended-release tablets.

At 50 mg tid for 7-8 days, orlistat did not significantly alter the pharmacokinetics of atenolol, captopril, furosemide and nifedipine retard.

In a pharmacokinetic (PK) study, oral administration of amiodarone during orlistat treatment demonstrated a 25 - 30% reduction in the systemic exposure to amiodarone and desethylamiodarone. Due to the complex pharmacokinetics of amiodarone, the clinical effects of this is unclear. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied. A potential reduced therapeutic effect of amiodarone is possible.

Weight loss induced by 'Xenical' is accompanied by improved metabolic control in non-insulin dependent diabetics, which might allow or require reduction in dose of oral hypoglycemic medication (e.g. sulfonylureas).

In 12 normal weight subjects receiving 'Xenical' 80 mg tid for 4 1/3 days, 'Xenical' did not alter the pharmacokinetics or pharmacodynamics (blood-glucose-lowering) of glyburide.

Metformin: In 20 normal weight subjects receiving 'Xenical' 120 mg tid for 6 days in a two way crossover study, 'Xenical' did not alter the pharmacokinetics of metformin.

Drug interaction studies were performed with 'Xenical' and a number of drugs with a narrow therapeutic index. 'Xenical' had no inhibitory effects on pharmacokinetic or pharmacodynamic parameters of the following drugs:

In 12 normal weight subjects receiving 'Xenical' 120 mg tid for 7 days, 'Xenical' did not alter the pharmacokinetics of a single 300-mg dose of phenytoin.

Warfarin: In 12 normal weight subjects, administration of 'Xenical' 120 mg tid for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although Vitamin K nutritional status parameters (ratios of vitamin K1 epoxide to vitamin K1 and undercarboxylated osteocalcin to osteocalcin) were also unaltered by orlistat, treatment with orlistat may potentially impair the GI absorption of vitamin K. Close monitoring of the coagulation parameters, including international normalised ratio (INR) values, is recommended when oral anticoagulants are co-administered (see PRECAUTIONS).

In 12 normal weight subjects receiving 'Xenical' 120 mg tid for 6 days, 'Xenical' did not alter the pharmacokinetics of a single dose of digoxin.

In a multiple-dose study in 30 normal weight subjects, coadministration of orlistat and 40 grams of alcohol (e.g. approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), and systemic exposure to orlistat.

A reduction in cyclosporine plasma levels has been observed when 'Xenical' is co- administered. Therefore, it is recommended to monitor cyclosporine plasma levels more frequently than usual if 'Xenical' is co-administered.

In 20 normal weight female subjects, the treatment of 'Xenical' 120 mg tid for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives.

In 24 normal weight, mildly hypercholesterolemic subjects receiving 'Xenical' 120 mg tid for 6 days in a two way cross-over study, 'Xenical' did not affect the pharmacokinetics or pharmacodynamics of pravastatin.

ADVERSE REACTIONS

Treatment of Obesity:

Commonly Observed:

(based on first year and second year data - 120 mg versus placebo):

Gastrointestinal symptoms are the most commonly observed treatment-emergent adverse events associated with the use of 'Xenical' (orlistat) in double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of $ 5% and an incidence in the 'Xenical' 120 mg group that is at least twice that of placebo.)

Adverse Event	Year One		Year Two
	Xenical (% patients) (n=1913)	Placebo (% patients) (n=1466)	Xenical (% patients) (n=613)	Placebo (% patients) (n=524)
Oily Spotting	26.6	1.3	4.4	0.2
Flatus with Discharge	23.9	1.4	2.1	0.2
Fecal Urgency	22.1	6.7	2.8	1.7
Fatty/Oily Stool	20.0	2.9	5.5	0.6
Oily Evacuation	11.9	0.8	2.3	0.2
Increased Defecation	10.8	4.1	2.6	0.8
Fecal Incontinence	7.7	0.9	1.8	0.2

These and other commonly observed adverse reactions were generally mild and transient, and decreased during the second year of treatment. Events occurred early in treatment (within 3 months) and most patients experienced only one episode. Only 3% experienced more than two episodes of any one adverse event. The incidence of these effects is directly related to the amount of dietary fat ingested and increases or decreases with the fat content of the diet. Patients should be counselled as to the possibility of the occurrence of gastrointestinal effects and how to minimize them, such as reinforcing the diet, particularly the percentage of fat it contains. Consumption of a diet low in fat (<30%) will decrease the likelihood of experiencing the gastrointestinal effects. The occurrence of gastrointestinal effects may actually help demonstrate to patients that the medication is working and help them monitor and regulate their fat intake.

Discontinuation of Treatment:

In controlled obesity management clinical trials, 8.8% of patients treated with 'Xenical' discontinued treatment due to adverse events, compared to 5.0% of placebo treated patients. For 'Xenical', the most common adverse events resulting in discontinuation of treatment were gastrointestinal.

Incidence in Controlled Obesity Management Clinical Trials: The following tables list other treatment-emergent adverse events from seven Phase III, multicenter, double-blind, placebo- controlled clinical trials that occurred at a frequency of $1% among patients treated with 'Xenical' 120 mg tid and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.

Other Treatment-Emergent Adverse Events From Phase III Placebo-Controlled Obesity Management Clinical Trials Year One Treatment
Body System / Adverse Event	'Xenical' % Patients (n=1913)	Placebo % Patients (n=1466)
Gastrointestinal System	25.5	21.4
Abdominal Pain/Discomfort	25.5	21.4
Flatulence	16.0	13.1
Liquid Stools	15.8	11.4
Stools Soft	8.8	6.8
Nausea	8.1	7.3
Infectious Diarrhea	5.3	4.4
Rectal Pain/Discomfort	5.2	4.0
Tooth Disorder	4.3	3.1
Gingival Disorder	4.1	2.9
Vomiting	3.8	3.5
Oral Mucosa Disorder	1.5	0.5
Feces Discoloured	1.1	0.3
Respiratory System Disorder	38.1	32.8
Upper Respiratory Infection	38.1	32.8
Lower Respiratory Infection	7.8	6.6
Ear, Nose and Throat Symptoms	2.0	1.6
Asthma	1.8	0.8
Resistance Mechanism Influenza	39.7	36.2
Other Treatment-Emergent Adverse Events From Phase III Placebo-Controlled Obesity Management Clinical Trials Year One Treatment
Body System / Adverse Event	'Xenical' % Patients (n=1913)	Placebo % Patients (n=1466)
Musculoskeletal System
Back Pain	13.9	12.1
Arthritis	5.4	4.8
Myalgia	4.2	3.3
Joint Disorder	2.3	2.2
Tendonitis	1.9	1.7
Injury (Nonspecific)	1.0	0.5
Central Nervous System	30.6	27.6
Headache	30.6	27.6
Dizziness	5.2	5.0
Paresthesia	1.2	0.8
Body as a Whole	7.2	6.4
Fatigue	7.2	6.4
Surgical Procedure	5.5	4.9
Sleep Disorder	3.9	3.3
Body Temperature Abnormal	2.1	1.5
Anxiety	1.2	0.8
Skin and Appendages	4.3	4.0
Rash	4.3	4.0
Dry Skin	2.1	1.4
Hair Thinning	1.8	1.4
Infection	1.8	1.2
Acne	1.6	1.2
Nail Disorder	1.4	1.1
Insect Bites	1.2	1.0
Urticaria	1.1	0.9
Reproductive Disorders, Female	9.8	7.5
Menstrual Irregularity	9.8	7.5
Vaginitis	3.8	3.6
Urinary System Urinary Tract Infection	7.5	7.3
Psychiatric Disorders Psychiatric Anxiety	4.7	2.9
Hearing and Vestibular Disorders Otitis	4.3	3.4
Cardiovascular Disorders Pedal Edema	1.2	1.1
Other Treatment-Emergent Adverse Events From Phase III Placebo-Controlled Obesity Management Clinical Trials Year One Treatment
Body System / Adverse Event	'Xenical' % Patients (n=1913)	Placebo % Patients (n=1466)
Vascular (Extracardiac) Vein Disorder	1.3	1.0
Other Treatment-Emergent Adverse Events From Phase III Placebo- Controlled Obesity Management Clinical Trials Year Two Treatment
Body System / Adverse Event	'Xenical' % Patients (n=613)	Placebo % Patients (n=524)
Gastrointestinal System	4.4	3.2
Flatulence	4.4	3.2
Rectal Pain/Discomfort	3.3	1.9
Stools Soft	2.9	2.5
Nausea	3.6	2.7
Tooth Disorder	2.9	2.3
Gingival Disorder	2.0	1.5
Respiratory System Upper Respiratory Infection	26.1	25.8
Musculoskeletal System Pain Lower Extremities Tendonitis Muscle Cramps Bone Fracture	10.8 2.0 1.1 1.0	10.3 1.9 0.8 0.8
Body as a Whole	3.1	1.7
Fatigue	3.1	1.7
Body Temperature Abnormal	1.5	1.1
Injury	1.6	1.1
Pain	1.5	1.3
Allergic Reaction	1.1	1.0
Skin and Appendages Pruritus	1.1	0.8
Reproductive, Female	2.6	1.9
Vaginitis	2.6	1.9
Breast Disorder	1.6	1.0
Menopausal Syndrome	1.3	1.0
Urinary System Disorders Urinary Tract Infection	5.9	4.8
Psychiatric Disorder	2.8	2.1
Psychiatric Anxiety	2.8	2.1
Depression	3.4	2.5
Hearing and Vestibular Disorders Otitis	2.9	2.5
Cardiovascular Disorders Pedal Edema	2.8	1.9

Trials in Patients with Type 2 Diabetes:

Commonly observed adverse events:

Mild and transient gastrointestinal effects of the same type as those seen in the obesity management trials were observed in the double-blind, placebo-controlled clinical trials for type 2 diabetes management. However, the overall difference in incidence of these adverse events between 'Xenical' treated patients and patients receiving placebo was generally less than in the overall obesity trials. Marked decreases were seen in the trials in patients with type 2 diabetes in the incidence of oily spotting, fecal urgency and flatus with discharge (15.8%, 10.5%, 9.4%) *, compared to those for obesity management (25.3%, 15.4% and 22.5% respectively) *. Recurrence also decreased in the diabetes trials: 4% of the patients experienced more than one episode of each gastrointestinal event compared to 6% in the obesity trials. The 2 sets of trials were not run concurrently and thus may not be directly comparable.

Of the other treatment-emergent adverse events reported in the diabetes trials, all were similar in type and generally occurred at a lower incidence compared to those of the obesity management trials, with the exception of cough (2.8% in 'Xenical' vs 2.4% in placebo), abdominal distension (5.8% vs 4.1%) and hypoglycemia (13.2% vs 9.5%). The majority of hypoglycemic events were mild to moderate in intensity and most patients could control the symptoms themselves. Only two patients in the placebo treatment group and three patients in the orlistat treatment group had hypoglycemic events that would be considered severe.

Post-Marketing Experience:

Rare cases of hypersensitivity have been reported. The main clinical symptoms were pruritus, rash, urticaria, angioedema and anaphylaxis. Very rare cases of bullous eruption, increase in transaminases and in alkaline phosphatase, and exceptional cases of hepatitis that may be serious have been reported during the post-marketing. No causal relationship or physicopathological mechanism between hepatitis and orlistat therapy have been established.

Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of haemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.

* These values are the treatment difference between 'Xenical' and placebo.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Single doses of 800 mg 'Xenical' (orlistat) and multiple doses of up to 400 mg tid for 15 days have been studied in normal weight and obese subjects without significant adverse findings. In addition, doses of 240 mg tid have been administered to obese patients for 6 months without a significant increase in adverse findings. Orlistat overdose cases received during post-marketing reported either no adverse events or adverse events that are similar to those reported with the recommended dose. Should a significant overdose of 'Xenical' occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, any systemic effects attributable to the lipase- inhibiting properties of orlistat should be rapidly reversible.

DOSAGE AND ADMINISTRATION

The recommended dose of 'Xenical' (orlistat) is one 120 mg capsule three times daily with each main meal (during or up to 1 hour after the meal). If a meal is occasionally missed or contains no fat, the dose of 'Xenical' may be omitted. The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains no more than 30% of calories from fat. The daily intake of fat, carbohydrate and protein should be distributed over three main meals (see PRECAUTIONS, Fat Soluble Vitamin Supplements and Analogues). For patients with type 2 diabetes, the reduced calorie diet should be consistent with the dietary recommendations of the Canadian Diabetes Association Guidelines for the Nutritional Management of Diabetes Mellitis in the New Millennium. Doses above 120 mg three times daily have not been shown to provide additional benefit. No dose adjustment is necessary for the geriatric patient. Based on fecal fat measurements, the effect of 'Xenical' is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours. The safety and efficacy of 'Xenical' has not been determined beyond 2 years.

PHARMACEUTICAL INFORMATION DRUG SUBSTANCE

Proper Name: Orlistat Chemical Name: (S)-2-Formylamino-4-methyl-pentanoic acid (S)-1-[(2S,3S)-3-hexyl- 4-oxo-oxetan-2-ylmethyl]-dodecyl ester Molecular Formula: C29H53NO5 Molecular Weight: 495.75 Structural Formula:

C 6 H 1 3 Physical Form: Orlistat is a white to almost white fine crystalline powder or fine crystalline powder with lumps Solubility: Water - <0.001g/100 ml pKa: No value within physiological range Partition co-efficient: log P=4.40 (octanol/water) Melting Point: Approximately 44 BC

DOSAGE FORM

Composition:

Each 'Xenical' 120 mg capsule contains 120 mg orlistat. Non-medicinal ingredients (alphabetical order): gelatin, indigo carmine, microcrystalline cellulose, povidone K30, sodium lauryl sulphate, sodium starch glycolate, talc, titanium dioxide.

Stability and Storage Recommendations:

'Xenical' should be stored between 15-25/C. Protect from moisture. This medicine should not be used after the expiry date shown on the pack.

AVAILABILITY

'Xenical' 120mg Capsules: turquoise cap and turquoise body with "ROCHE XENICAL 120" printed in black ink. 'Xenical' is supplied in blister packages in cartons of 84 capsules.

INFORMATION FOR THE PATIENT

You have been prescribed Xenical(r) (pronounced Zen-e-cal) by your doctor. Reading this information can help you learn about 'Xenical' (orlistat) and how to make this medicine work best for you. If you have any questions after reading this information, speak with your doctor or pharmacist.

What is 'Xenical'?

'Xenical' is a prescription medicine when, combined with a mildly reduced calorie diet, can help you lose weight and keep it off. Weight loss occurs because 'Xenical' blocks the absorption of some of the fat you eat.

'Xenical' taken in combination with diabetes medications such as insulin, metformin and/or a sulfonylurea (like glyburide) may help you manage your type 2 diabetes by lowering your blood sugar.

Each capsule contains 120 mg of the active ingredient orlistat. The capsules also contain non- medicinal or inactive ingredients. These are:

microcrystalline cellulose, povidone, sodium starch glycolate, sodium lauryl sulphate, talc. The capsule shell contains:

What is 'Xenical' used for?

Xenical is used along with a mildly reduced calorie diet to assist in weight loss and to maintain the weight loss in obese patients and overweight patients who have health risk factors such as type 2 diabetes, high blood pressure, and blood lipid problems. The weight loss will contribute to lowering the blood pressure and cholesterol and blood sugar levels. Even a modest weight loss of 5-10% can lower your risk of developing health problems.

How does 'Xenical' work?

'Xenical' is a fat blocker. Fats from foods need to be broken down before they can be absorbed into the body. To break down fat, your body uses enzymes, called lipases. 'Xenical', when taken with meals, prevents these enzymes from working. This blocks the absorption of about one third (30%) of the fat in food. The fat that is not absorbed passes out of the body in bowel movements, called stools. When you absorb less fat, you take in fewer calories, which leads to weight loss.

Taking 'Xenical' can help you reach a healthier weight. This medicine works best when you take it as directed (see "How should Xenical be taken? ", below), eat less fat and become more physically active.

'Xenical' does not suppress or change your appetite. It does not affect the brain like other medicines used for weight loss. Less than 1% of 'Xenical' is absorbed and the rest leaves the body in the stool.

Who should take 'Xenical'? Weight Management

adults with a BMI * of 27 to 29 who have health problems, such as type 2 diabetes, high blood pressure, high cholesterol or a large waist measurement.

Diabetes Management: adults with type 2 diabetes who are overweight (BMI * of 27 or greater).

* BMI is a simple measurement to estimate how overweight a person is. See your doctor to have your BMI measured.

Children under 17 years of age should not take 'Xenical'. This medicine has not been studied in this age group.

What should you tell your doctor before you start taking 'Xenical'?

you have ever had a bad reaction to orlistat ('Xenical') or any of the inactive ingredients

C you are taking diabetes medicines such as insulin, metformin and/or a sulfonylurea C you are taking any other medicines including those not prescribed by your doctor C you always have problems absorbing your food (chronic malabsorption syndrome) C you have bowel or rectal problems

This information will help your doctor and you decide whether you should use 'Xenical', and what extra care may need to be taken while you are on the medicine.

How should 'Xenical' be taken?

Your doctor has prescribed 'Xenical' after carefully studying your case. Other people may not benefit from taking this medicine, even though their problems may seem similar to yours. Do not give your 'Xenical' to anyone else.

Take one capsule (120 mg) during or just following each main meal (breakfast, lunch and dinner). Swallow the capsule whole along with some water. Take the capsule no later than 1 hour after the meal is eaten.

For example, if you just finished eating lunch at 12:30 p.m., you should take your lunchtime dose before 1:30 p.m.

'Xenical' should be taken with a mildly reduced calorie diet that contains no more than 30% of calories from fat as recommended by your doctor, dietitian or other healthcare professional.

'Xenical' can reduce the absorption of fat-soluble vitamins and beta-carotene. In clinical studies, most people's vitamin and beta-carotene levels were within the normal range. However, your doctor may tell you to take a daily multivitamin supplement while taking 'Xenical'. If he or she does, you should take your multivitamin two hours before or after your 'Xenical' capsule, or at bedtime.

If you occasionally miss a main meal or if your meal contains no fat, do not take your 'Xenical' capsule.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

You will not lose more weight or lose it more quickly if you take more 'Xenical' capsules than your doctor has instructed.

If You Have Type 2 Diabetes: The same dosage recommendations apply as for weight management. Your reduced calorie diet should be consistent with the dietary recommendations of the Canadian Diabetes Association Guidelines for the Nutritional Management of Diabetes Mellitis in the New Millennium. You should talk with your doctor about diabetes medications you may be taking, as this dosage might need to be lowered.

What should you do if you forget a dose of 'Xenical'?

If you forget to take a dose, it can be taken up to one hour after a meal and still be effective. Do not take double the amount if you miss one dose. 'Xenical' cannot work properly if many doses are missed.

What else should you remember while you are taking 'Xenical'?

As 'Xenical' works by partially blocking dietary fat absorption, the expected weight loss will not occur if you replace the fat calories with carbohydrates or protein.

Eat foods from all food groups (for example, see "Canada's Food Guide to Healthy Eating").

If you have to go to the hospital or if you are given a new prescription medicine, you should tell the doctor(s) that you are taking 'Xenical'.

Losing weight can affect the dose of other medicines you need, such as those for diabetes, high blood pressure or high cholesterol. Your doctor may need to adjust the doses of your other medicines. He or she may ask you to have regular blood tests to check your blood sugar and/or cholesterol level.

If you have type 2 diabetes, you should follow the dietary recommendations of the Canadian Diabetes Association and test blood sugar and HbA1c levels regularly.

What are the possible unwanted effects of 'Xenical'?

Unwanted effects are possible with all medicines. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking 'Xenical'.

The most common possible side effects from 'Xenical' are directly related to the way 'Xenical' works. By blocking the absorption of some dietary fat, it is likely that you will experience some change in bowel habits. These effects are generally mild and transient (occur for a short period of time). They can increase if you eat high fat foods. In clinical studies, only 3% of people experienced one of these effects more than twice: oily spotting gas with discharge

Due to the presence of undigested fat, the oil in your bowel movement may be clear, orange or brown in colour. These bowel changes are a natural effect of blocking the fat from being absorbed and indicate that 'Xenical' is working.

Unwanted side effects are more likely to occur if you eat meals that contain large amounts of fat.

Sticking to a diet that contains no more than 30% of calories from fat in each meal will reduce side effects.

Some unwanted side effects may go away during treatment as your body adjusts to the medicine.

Experience shows that changes in bowel habits in patients with type 2 diabetes occurred less frequently than in patients taking 'Xenical' for weight management. Also, symptoms of hypoglycemia (low blood sugar) may occur, such as: sweating dizziness shakiness hunger confusion Talk to your doctor for advice about how you can help avoid these symptoms and whether the dosage of the diabetes medications you may be taking might need to be lowered or discontinued.

If you are concerned about these or any other unexpected effects while on 'Xenical', talk with your doctor or pharmacist.

How should this product be stored?

C Store 'Xenical' in its original labelled container at room temperature (between 15-25degC) and protect it from moisture.

PHARMACOLOGY

Animal Pharmacology

No effect on arterial blood pressure, heart rate and gross spontaneous behaviour was observed in conscious dogs after either oral or intravenous administration of orlistat at doses of 1 g/kg and 1, 3 and 10 mg/kg, respectively. In preclinical models, orlistat demonstrated potent anti-obesity and some hypolipemic properties. These therapeutic effects are attributable to the inhibitory action of orlistat on digestive lipases in the gastrointestinal lumen which results in the reduction of fat and cholesterol absorption. Orlistat increased the fecal concentration of unesterified fatty acids and diglycerides in animal studies, but decreased levels of bile acids. This effect differs from that observed following an increase in dietary fat alone, in which case bile acids also increased. Increased exposure of the colonic mucosa to fatty acids and diglycerides did not lead to histopathological observations indicative of pre-neoplastic alterations (see Toxicology section).

Human Pharmacology

Dose-response Relationship: A simple maximum effect (Emax) model was used to define the dose- response curve of the relationship between 'Xenical' (orlistat) daily dose and fecal fat excretion as representative of gastrointestinal lipase inhibition. Emax, the maximum attainable intensity of effect produced by 'Xenical' and presented as percentage of ingested fat excreted, was 37% +- 2 (SE). The dose-response curve demonstrated a steep portion for doses up to 400 mg daily, followed by a plateau for higher doses. In a dose which was above that recommended for therapy (360 mg -120 mg tid), the percentage increase was minimal.

: The effects of 'Xenical' on weight loss, weight maintenance, weight regain and on a number of comorbidities were assessed in seven multicenter, double-blind, placebo-controlled clinical trials of 1-to 2-years duration. During the first year of therapy, weight loss and weight maintenance were assessed. During the second year of therapy, some studies assessed continued weight loss and weight maintenance and others assessed the effect of orlistat on weight regain. These studies included over 2800 patients treated with 'Xenical' and 1400 patients treated with placebo. The observations regarding the effects on comorbidities during these trials are discussed in detail below.

Efficacy Results: Weight Loss and Prevention of Weight Regain: During the weight loss and weight maintenance period, a well-balanced, mildly hypocaloric diet that provided 30% of calories from fat was recommended. The diet was calculated using initial body weight to provide a caloric deficit of 500-800 calories per day, which represents an average caloric decrease of 20%. The percentages of patients achieving a $5% and $10% weight loss after 1 and 2 years treatment from two representative studies (BM14119C and BM14149) are summarized in the following tables:

Categorical Analysis of Weight Loss Following One-Year of Treatment
Study Number	Intent to Treat Population	Completers Population
	$ 5% Weight Loss	$ 10% Weight Loss	$ 5% Weight Loss	$ 10% Weight Loss
	Xenical	Placebo	P Value	Xenical	Placebo	P Value	Xenical	Placebo	P Value	Xenical	Placebo	P value
BM 14119C *	68.5%	49.1%	< 0.05	38.8 %	17.6%	< 0.05	77.2%	57.4%	< 0.05	46.9%	21.3%	< 0.05
BM 14149 * *	62.5%	43.6%	0.001	38.3%	18.8%	0.001	77.3%	57.3%	0.001	49.7%	25.7%	0.001

Intent to treat population: placebo n=340, Xenical n=343; completers population placebo n=249, Xenical n=271

* * Intent to treat population: placebo n=234, Xenical n=240: completers population: placebo n=136, Xenical n=163

Categorical Analysis of Weight Loss Following Two Full Years Treatment
Study Number	Intent to Treat Population	Completers Population
	$ 5% Weight Loss	$ 10% Weight Loss	$ 5% Weight Loss	$ 10% Weight Loss
	Xenical	Placebo	P Value	Xenical	Placebo	P Value	Xenical	Placebo	P Value	Xenical	Placebo	P value
BM 14119C *	57.1%	37.4%	0.006	33.8%	14.6%	0.006	58.4%	40.9%	0.006	38.6%	15.1%	0.006
BM 14149 * *	51.7%	30.3%	<0.001	24.2%	13.2%	<0.001	65.7%	37.8%	<0.001	30.8%	22.0%	<0.001

Intent to treat population: placebo n=123, Xenical n=133; Completers population n=93 placebo, Xenical n=101

* Intent to treat population: placebo n=234, Xenical n=240: placebo n=127 , Xenical n=146

At the end of 52 weeks of double-blind treatment in study BM14119C, mean weight loss for the placebo treated patients was 6.1% and 10.2% in Xenical treated patients (intent to treat analysis). In study BM 14149, Xenical treated patients had lost 9.7%, compared with 6.6% for patients that received placebo (intent to treat). The findings were similar in the completers populations. Prevention of Weight Regain Following One Year of Weight Loss: Studies NM14185 and BM14119C were designed to evaluate the effects of Xenical compared to placebo in reducing weight regain in year-2 after previous weight loss achieved by prior treatment with Xenical in year 1. The diet utilized during the 2nd year prevention of weight regain portion of the studies was a weight maintenance diet, rather than a weight loss diet, and patients received less nutritional counselling than patients in the first year. In study BM14119C, patients treated with placebo regained 52% of the weight they had previously lost while patients treated with Xenical regained only 26% of the weight they had previously lost (p<0.001). In study, NM14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with Xenical regained only 35% of the weight they had lost (p<0.001).

At the recommended therapeutic dose of 'Xenical', the inhibition of the absorption of approximately one-third of dietary fat produces meaningful weight loss and reduces risk factors. At the same time, this effect allows absorption of adequate amounts of dietary fat and other nutrients that are essential for the maintenance of good health. Both one and two year therapy (clinical trials) with 'Xenical' resulted in statistically significant improvements in many risk factors associated with obesity compared to placebo treatment. The statistically significant improvement of risk factors included fasting glucose and fasting insulin, total cholesterol, LDL-cholesterol, LDL/HDL ratio, waist and hip circumference. Statistically significant improvements over placebo in systolic and diastolic blood pressure were also observed after one year of treatment. Only diastolic blood pressure was reduced following two years of 'Xenical' treatment relative to placebo.

Subpopulations with Abnormal Baseline Risk Factors: Patient subpopulations with the following abnormal baseline risk factors at randomization also showed statistically significant reductions in the following abnormal values relative to patients receiving placebo following one or two years treatment with 'Xenical'; Metabolic: LDL-cholesterol $3.362 mmol/L, LDL/HDL ratio $3.5 (year 1 only), fasting insulin $120 pmol/L. Cardiovascular: systolic BP$140 mm Hg and Diastolic BP <90mm Hg (year 1 only). Anthropometric: waist circumference >100 cm. Predictors of Response: An analysis was performed with two of the European studies (BM14119C and BM14149) to determine if early response to Xenical treatment predicts long-term weight maintenance and health benefits. It was found that patients that lost $5% of body weight at during the first 12 weeks of drug therapy achieved significantly greater weight loss after 2 years than those who lost <5% (-11.9% vs -4.7%, respectively, p=0.0001). Similarly, patients that lost $5% of their body weight during the first 12 weeks of drug treatment achieved significantly greater weight loss after 1-year of treatment, compared to patients that lost <5% (-14.5% vs -6.9%, respectively, p=0.0001). Weight loss at the end of one and two years treatment was also greater in patients that lost $5% weight at 12 weeks and $10% body weight at 6 months, compared to those patients that lost <10% at six months (year 1: -17.7% vs -11.9%; year 2: -15.0% vs -9.33%, respectively). The impact on risk factors based on whether patients achieved 5% weight loss at 12 weeks is shown in the table below for both 1 and 2 years treatment.

Impact of <5% or $5% Weight Loss at 12 Weeks on Risk Factors following 1 and 2 Years Treatment with Xenical
Years on Therapy	Risk Factor a	12 week weight loss	P value *
		<5%	$ 5%
Year 1	Total cholesterol	-8.25 (111) * *	-14.87 (102)	0.0002
LDL cholesterol	-10.06 (111)	-18.69 (102)	0.0003
HDL cholesterol	1.48 (111)	4.77 (102)	n.s
Triglycerides	-1.98 (111)	-14.66 (102)	0.004
Systolic blood pressure (mm Hg)	-7.48 (116)	-10.88 (104)	n.s
Diastolic blood pressure (mm	-4.37 (116)	-7.65 (104)	0.013

Year 2	Total cholesterol	-4.87 (111)	-10.67 (98)	0.0014
LDL cholesterol	-4.83 (111)	-11.30 (98)	0.015
HDL cholesterol	5.06 (111)	8.38 (98)	n.s
Triglycerides	3.27 (111)	-16.18 (98)	0.000
Systolic blood pressure (mm Hg)	-3.66 (116)	-9.45 (104)	0.005
Diastolic BP (mm Hg)	-2.24 (116)	-5.37 (104)	0.017

* P value refers to the comparison of Xenical treated patients that lost either greater than or less than 5% weight loss at 12 weeks, not to patients treated with placebo.

Two-year studies that included oral glucose tolerance tests were conducted in obese patients whose baseline oral glucose tolerance test (OGTT) status at randomization was either normal, impaired or diabetic. The progression from a normal OGTT at randomization to a diabetic or impaired OGTT following two years treatment with 'Xenical' (n=251) or placebo (n=207) were compared. Following treatment with 'Xenical', 0.0% and 7.2 % of the patients progressed from normal to diabetic and impaired OGTT respectively, compared to 1.9 % and 12.6% of the placebo group respectively (p=0.01).

In patients found to have an impaired OGTT at baseline, the percent of patients improving to normal or deteriorating to diabetic status following one or two years of treatment with 'Xenical' compared to placebo are presented below and the difference between treatment groups was significant:

* * * OGTT status in mmol/L at 120 min: normal <7.77; impaired $7.77 and <11.1; diabetic $11.1.

of one- year (4 trials) and six-months (3 trials) duration were conducted to evaluate the use of 'Xenical' in combination with sulfonylureas, metformin or insulin in overweight and obese patients with type 2 diabetes. During these studies, patients were maintained on a well-balanced, reduced-calorie diet consistent with the dietary recommendations of the Canadian Diabetes Association.

One year Results:

Maximum improvements in fasting glucose were observed as early as two weeks of initiation of therapy. Improvements in weight loss were observed as early as four weeks of initiation of therapy. Improvements in HbA1c were seen at the time of the first assessment point at twelve weeks.

A total of 1729 overweight and obese patients with type 2 diabetes participated in four double-blind, placebo-controlled one-year studies conducted to assess the efficacy of 'Xenical' in combination with antidiabetic agents such as insulin, metformin and sulfonylureas. In these studies 'Xenical' and diet, used in combination with antidiabetic agents, showed significant reductions in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG) and body weight compared to placebo and diet used in combination with antidiabetic agents.

Mean Changes in Glycemic Control Parameters and Body Weight in Patients With Type 2 Diabetes, 1-Year Studies *

*The diet utilized during the studies was a reduced-calorie diet consistent with the dietary recommendations of the

p<0.05 based on statistical analysis XENICAL compared to placebo (least squares mean)

p<0.01 based on statistical analysis XENICAL compared to placebo (least squares mean) p<0.01, Cochran-Mantel-Haenszel

Results were not statistically significant likely due to the study design in which the dose and antidiabetic

medication could be changed during the conduct of the study depending on the glycemic control response. Reanalysis of this study excluding the assessments done after any change in antidiabetic therapy resulted in a mean decrease from baseline in HbA1c of -0.73% in the XENICAL group and -0.36% in the placebo group (p<0.01).

Orlistat has an additional glucose-lowering effect in obese and overweight type 2 diabetic patients receiving antidiabetic medication separate from its effect on body weight. An analysis of pooled data from patients who completed one year of treatment was conducted for HbA1c in patients losing #1% of their baseline body weight. The mean change in body weight from baseline in these patients was +1.35 kg in the 'Xenical'-treated patients and + 1.53 kg in the placebo treatment group; however, patients receiving orlistat had a significantly greater mean decrease in HbA1c compared to the placebo treatment group (-0.29% vs +0.14%, p<0.0008), respectively. 'Xenical' in combination with antidiabetic agents had favourable effects on lipids, blood pressure and waist circumference, risk factors associated with type 2 diabetes and excess body weight. The changes from randomization following treatment in the type 2 diabetic population with abnormal baseline lipid levels, blood pressure and waist circumference (pooled data for 7 clinical trials) are summarized in Table 3. One year of therapy with Xenical- in combination with other antidiabetic medications resulted in statistically significant improvements in many of these risk factors.

Table 3 Mean Change in Risk Factors From Randomisation - Population with Abnormal Risk Factors1

2The diet utilized during the studies was a reduced-calorie diet consistent with the dietary recommendations of the American Diabetes Association; ++$102 cm for males and $88 cm for females at baseline.

Six-Month Results:

A total of 779 overweight and obese patients with type 2 diabetes participated in three double-blind, placebo controlled 24-week studies also conducted to assess the efficacy of 'Xenical' in combination with antidiabetic agents. In these studies, improvements similar to those for the one-year results were observed in glycemic control, weight loss and effects on risk factors were also observed.

This was a pyramiding dose toxicity study; doses were escalated daily. The female dog received approximately 972 mg as a final dose.

Multiple Dose Toxicity and Reproduction and Teratology Studies

-See Tabular Summaries which follow The following abbreviations are used throughout these tables (and the Special Toxicity Tabulations); 8(increased), 9 (decreased), ALP (alkaline phosphatase), ALT (alanine aminotransferase), AUC (area under the curve), BW (body weight), clin.obs (clinical observations-in life), clin.path (clinical pathology), diet.admix (dietary admixture), DR (drug related), emul (emulsion), F (female), food cons. (food consumption), Histopath. (histopathology), M (male), met.act. (metabolic activation), min. (minutes), MNLD (maximum non-lethal dose), mos. (months), NOAE [no-observed-adverse-effect(s)], org.wt (organ weight), pp-hyptri (post-prandial hypertriglyceridemia).

Carcinogenicity Studies

LONG-TERM TOXICOLOGY STUDIES
Species	Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg/d)	Duration (weeks)	Principal Findings
Mouse	Ibm: MORO (SPF) (high dose & control: 15 all others: 10)	p.o. (diet admix)	0, 10, 65, 400, 2500	13	Mortality : NOAE Clin. Obs. : DR incr. food cons. in M @ 400 & 2500 and in F @ all doses Hematology: not done Clin. Path. : DR decr. in plasma cholesterol @ 65 & higher; DR incr. in plasma triglycerides @ 65 & higher (400 @ - 2500); DR decr. in hepatic vitamins A & E conc. Necropsy: NOAE Organ Wt. : NOAE Histopath. : NOAE
Species	Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg/d)	Duration (weeks)	Principal Findings
Rat	Fu-albino (10 + 4 for toxicokin.)	p.o. (diet admix)	0, 50, 150, 450	13	Mortality: NOAE Clin. Obs. : incr. food intake @ all doses Ophthalmoscopy: NOAE Hematology: 20-25%. decr. in WBC @ 450 after 13 wks; lipemic plasma @ 150 & 450 Clin. Path. : after 13 wks - bilirubin & cholesterol 2-3 X incr. @ 450; DR incr. triglycerides (27 X @ 450); decr. hepatic Vit A ( - 60%) & Vit E ( - 60-75%) @ 450 Urinalysis: NOAE Necropsy: NOAE Organ Wt. : incr. ( - 10%). liver in F @ 450; incr. ( - 10-20%) adrenal in M+F @ 450 Histopath. : NOAE

LONG -TERM TOXICOLOGY
Species	Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg/d)	Duration (weeks)	Principal Findings
Rat	Fu-albino (20)	p.o. (diet admix)	0, 250, 500, 1000, 2500	13	Mortality: NOAE Clin. Obs. : ~ 13-14% decr. B.W. gain @ 2500; incr. food intake @ all doses Ophthalmoscopy: NOAE Hematology: NOAE Clin. Path. : DR incr. pp-hyptri. @ $ 500 (7-25 X @ 2500); DR incr. (2-9 X) bilirubin @ $ 500; incr. fecal total lipid (75-80% of intake) @ all doses; decr. hepatic vitamins A & E ( - 60%) @ all doses despite supplement (M >F); Urinalysis: NOAE Necropsy: NOAE Organ Wt. : DR incr. in F adrenal wt. incr. M adrenal wt. @ 1000 & 2500 Histopath. : fatty change, vacuolation, and/or + fat stain in bone marrow, lumen of heart vessels, hepatocytes, or adrenal glands primarily @ 1000 & 2500 Toxicokinetics: DR incr. @ wk. 5.: Male: 20, 68, 225, 1470 ng/ml Female: 32, 91, 311, 1050 ng/ml
Species	Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg/d)	Duration (weeks)	Principal Findings
Rat	Fu-albino (26)	p.o. (diet admix)	0, 5, 25, 125	52	Mortality: NOAE Clin. Obs. : DR incr. food cons. @ 25 & 125; dark coloured feces @ 25 & 125 Ophthalmoscopy NOAE Hematology: NOAE Clin. Path. : decr. % -amylase & incr. BUN @ 125; plasma levels of vit. A decr. @ 125 in M (9- 20%) and a DR decr. in plasma vit. E M & F; DR decr. in hepatic vit. A & E; +-hypertriglyceridemia @ 125; DR incr. in total fecal fat
					Urinalysis: NOAE Necropsy: NOAE Organ Wt. : NOAE Histopath. : NOAE Toxicokinetics: no unchanged drug detected in plasma @ 5 or 25; up to 64 ng/ml detected at week 51 @ 125.

REPRODUCTION AND TERATOLOGY
Study	Species Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg/d)	Duration (days)	Principal Findings
Segment I	Rat	p.o.	0, 25, 100,	M: 70 prior to &	No parental mortality; decr. wt. gain in males @ 400; plasma triglycerides incr.
Fu-albino	(gavage)	400	during mating	in males @ 100 (51%) and 400 (111%)
(32)		Parents: NOAE with respect to fertility or reproductive performance
F: 14 prior to, and	Progeny: no morphological or functional impairment observed
during mating,
gestation, &
lactation
Segment II	Rat	p.o.	0, 50, 200,	Days 7-16 of	Dams: NOAE
Fu-albino	(gavage)	800	gestation	Progeny: slight statistically significant increase in resorptions in hysterectomy
(36, F only)	(day of mating =	subgroup (10.9%) but not in the delivery sub-group and within the range of
day 1)	normal (0-23.5%; mean = 8.1%) for the laboratory
Dose-related increase in the incidence of dilated cerebral ventricles statistically
significant at the high dose (1, 2, 4, & 7 @ 0, 50, 200, & 800, respectively)
Segment II	Rat Fu-albino (30, F only)	p.o. (gavage)	0, 800	Days 6-15 of gestation (day of mating = day 0)	Dams: B.W. gain during gestation days 6-16 decr. ~ 16% for the treated group Progeny: NOAE
Study	Species Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg/d)	Duration (days)	Principal Findings
Segment II	Rat	p.o.	Ro 18-	Days 6-15 of	Ro 18-0647/002
Crl:CD (r) BR	(gavage)	0647/002:	gestation
VAF/Plus (r)	0, 50, 250,	(day of mating =	Dams: NOAE
(25, F only)	800	day 0)	Progeny: NOAE
	Ro 18-0647/008
Ro 18-
0647/008:	Dams: NOAE
0, 50, 250,	Progeny: NOAE
800
Segment	Rat	p.o.	0, 25, 100,	Day 15 of	Dams: slight impairment of B.W. gain @ 400 during late gestation and lactation
III	Fu-albino	(gavage)	400	gestation through	Progeny: slight impairment of B.W. gain @ 400 during lactation period
(24, F only)	day 22 of	F1-Generation: NOAE with respect to physical or functional development
lactation
Segment II	Rabbit	p.o.	0, 100, 300,	Days 7-19 of	Dams: NOAE
Swiss hare	(gavage)	800	gestation	Progeny: NOAE
(20, F only)
(Day of mating =
gestation day 1)

Two- year oral (dietary admix) carcinogenicity studies were conducted in mice and rats at high doses of 1500 and 1000 mg/kg/day, respectively; female mice were terminated after 94 weeks of dosing because of excessive intercurrent mortality that did not distinguish treated from control animals. The incidence and nature of gross findings at necropsy and of neoplastic lesions did not distinguish treated from control mice or rats. Toxicokinetic analyses conducted at the termination of the studies showed that the systemic exposure to orlistat was 100 to 1000 times higher in mice and rats, respectively, than that observed in patients during phase III clinical trials receiving 120 mg tid, the recommended therapeutic dose of orlistat.

Mutagenicity

The mutagenic potential of orlistat was investigated in the following short-term assays; Ames Test, with and without metabolic activation (tester strains TA97, TA98, TA100, TA102, TA1535, TA1537, TA1538), mammalian cell (V79/HPRT) gene mutation assay with and without metabolic activation, unscheduled DNA synthesis in primary cultures of rat hepatocytes, clastogenesis in vitro in human peripheral lymphocytes with and without metabolic activation, chromosome aberration assay (mouse micronucleus test) in vivo. No evidence of mutagenicity or genotoxicity was associated with orlistat in any of the assays.

Baseline OGTT Status Intent to Treat Population	Patients Normal * * * Post- Treatment	Patients Diabetic * * * Post-Treatment
Impaired * * *	one year of treatment	one year of treatment
Placebo n=48	45.8%	10.4%
Orlistat *, 1 n=115	72.2%	2.6%

Impaired * * *	2 years of treatment	2 years of treatment
Placebo n=40	50.0 %	7.5%
Orlistat * *, 1 n=60	71.7%	1.7%

Study Numbers:	M37047 XENICAL/Insulin Study		M37048 XENICAL/Metformin Study		M37002 XENICAL/ Sulfonylurea Study		M14336 XENICAL/ Sulfonylurea Study

Parameters:	XENICAL N=266	Placebo N=269	XENICAL N=250	Placebo N=254	XENICAL N=189	Placebo N=180	XENICAL N=162	Placebo N=159
HbA1c (%)	9.0	9.0	8.9	8.8	8.3	8.2	7.5	7.5
Baseline (mean)
Mean Change from Baseline	-0.62 ++	-0.27	-0.75 SS	-0.41	-0.62 ++	-0.06	-0.14 ++	+0.32
% Patients with Reduction in HbA1c	52 ++	40	61 ++	43	54 ++	33	44 ++	20
$ 0.5% decrease in HbA1c
$ 1.0% decrease in HbA1c	32 +	22	46 ++	29	33 +	22	22 ++	11
FPG (mmol/L)	10.9	11.2	11.6	11.1	10.2	9.8	7.9	7.9
Baseline (mean)
Mean Change from Baseline	-1.63 +	-1.08	-2.02 ++	-0.69	-0.95 ++	+0.34	+0.04 ++	+0.73
PPG (mmol/L)	-	-	-	-	12.6	12.3	-	-
Baseline (mean)
Mean Change from Baseline	N/D	N/D	N/D	N/D	-1.13 ++	+0.36	N/D	N/D
Decrease in antidiabetic med	41	31	17	8.2	10	9	42	30
% Patients, Orlistat vs placebo
Increase in antidiabetic med.	15	32	12	22	14	18	7	18
% Patients, Orlistat vs placebo
Weight (kg)	102.0	101.8	102.2	101.2	97.6	96.5	97.5	97.5
Baseline (mean)
Mean Change from Baseline	-3.89 ++	-1.27	-4.66 ++	-1.82	-3.49 ++	-1.46	-3.83 ++	-1.35

Risk Factor - Value at Randomization	Xenical 120 mg + Diet 2 + Antidiabetic Medications			Placebo +Diet 2 + Antidiabetic Medications
Lipids:	N	Baseline Mean	Mean Change From Baseline	N	Baseline Mean	Mean Change From Baseline	P Value
LDL-Cholesterol $ 3.362 mmol/L	496	4.12	-11.56%	462	4.09	-2.13%	0.0000
HDL-Cholesterol < 0.905 mmol/L	298	0.77	+14.18%	301	0.78	+19.19%	0.0287
LDL/HDL $ 3.5	368	4.43	-0.81	343	4.45	-0.61	0.0210
Triglycerides $ 2.54 mmol/L	335	4.11	-6.42%	328	4.17	-3.94%	0.5913
Blood Pressure:
Systolic Blood Pressure $ 130 mm Hg	813	143.36	-6.08	781	143.30	-4.41	0.0251
Diastolic Blood Pressure $ 80 mm Hg	814	86.42	-4.53	776	86.47	-3.77	0.0772
Anthropometric:
Waist Circumference, cm ++	1008	111.39	-4.82	968	111.53	-2.41	0.0000

- 38 -
Acute Toxicity					TOXICOLOGY
Species	Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg)	Obs. Period (days)	Principal Findings *
Mouse	Fu-albino	p.o.	5000	14	MNLD = > 5000 mg/kg; no observed clinical adverse effects
	(10)	(gavage)
	Fu-albino	i.v.	0, 100	14	MNLD = > 100 mg/kg; short-lived (1-4 min.) CNS depression following both vehicle and
	(10)	(25 ml/kg)			test article
	Fu-albino	i.v.	0, 150	14	MNLD = > 150mg/kg; no observed clinical adverse effects
	(5)	(3 ml/kg)
Rat	Fu-albino	p.o.	5000	14	MNLD = > 5000 mg/kg; no observed clinical adverse effects
	(5)	(gavage)
	Fu-albino	p.o.	3000	14	MNLD = > 3000 mg/kg; no observed clinical adverse effects; plasma levels of unchanged
	(5)	(gavage)			drug were BLQ
	Fu-albino	i.v.	0, 100	14	MNLD = > 100 mg/kg; short-lived (1-4 min.) CNS depression following both vehicle and
	(5)	(10 ml/kg)			test article
	Fu-albino	i.v.	0, 150	14	MNLD = > 150 mg/kg; no observed clinical adverse effects
	(5)	(3 ml/kg)

Species	Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg)	Obs. Period (days)	Principal Findings *
Rat (2-week old)	Crl:CD (r) B R (5)	p.o. (gavage)	0, 2000	14	MNLD = > 2000 mg/kg; no observed clinical adverse effects
Dog	Beagle (1)	p.o. (capsule)	50, 100, 200, 400, 600, 800, & 1000 +	1 day following last dose	MNLD = > 1000 mg/kg; no observed clinical adverse effects

Study	Species & Strain (#/sex/grp.)	Route of Admin.	Doses (mg/kg/day)	Duration	Principal Findings
Effect(s) on fecal lipid parameters & colonic cell proliferation	Rat Wistar (6/dose; M only)	p.o. (diet admix) Note: 40% of calories from fat & 0.1% Ca ++ (synthetic diet)	0, 8.5, 116	9 days	Low Dose: 24% inhib. of fat absorption; incr. alk. phosphatase in fecal water, increased cytolytic activity in fecal water; incr. (20 X) free fatty acids in feces; decr. conc. of bile acids in fecal water; 2.5-fold increase in colonic epithelial proliferation High Dose: $ 56% inhibition of fat absorption; fecal lipid parameters not adequately assessed due to marked "oily leakage" from rectum ; 10-fold increase in colonic epithelial proliferation
As above	Rat Wistar (6/dose; M only)	As above	0, 8.5, 25, 127	10 days	DR 1 8 fecal fat excretion: +29, +58, +>75%; DR 8 thymidine incorporation into DNA in colonic mucosa: 1.9- 2.4-, 5.0-fold; no colonic hypertrophy or hyperplasia; effects reversed after discontinuation of treatment.

Control # 078996

PRODUCT MONOGRAPH

Xenical(r) (orlistat) Capsules 120 mg

THERAPEUTIC CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY

Pharmacokinetics

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

WARNINGS

PRECAUTIONS

ADVERSE REACTIONS

SYMPTOMS AND TREATMENT OF OVERDOSAGE

DOSAGE AND ADMINISTRATION

PHARMACEUTICAL INFORMATION DRUG SUBSTANCE

DOSAGE FORM

Composition:

Stability and Storage Recommendations:

AVAILABILITY

INFORMATION FOR THE PATIENT

What is 'Xenical'?

What is 'Xenical' used for?

How does 'Xenical' work?

Who should take 'Xenical'? Weight Management

What should you tell your doctor before you start taking 'Xenical'?

How should 'Xenical' be taken?

What should you do if you forget a dose of 'Xenical'?

What else should you remember while you are taking 'Xenical'?

What are the possible unwanted effects of 'Xenical'?

How should this product be stored?

PHARMACOLOGY

Animal Pharmacology

Human Pharmacology

One year Results:

Mean Changes in Glycemic Control Parameters and Body Weight in Patients With Type 2 Diabetes, 1-Year Studies *

Table 3 Mean Change in Risk Factors From Randomisation - Population with Abnormal Risk Factors1

Six-Month Results:

Multiple Dose Toxicity and Reproduction and Teratology Studies

Carcinogenicity Studies

Mutagenicity

Special Toxicity Studies

SPECIAL TOXICITY STUDIES

SPECIAL TOXICITY STUDIES

SPECIAL TOXICITY STUDIES

BIBLIOGRAPHY