Xenical Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics ................................................................................................................ 4

1.2 Geriatrics ................................................................................................................ 4

2 CONTRAINDICATIONS ................................................................................................. 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.1 Dosing Considerations ............................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 5

4.4 Administration ........................................................................................................ 5

4.5 Missed Dose ........................................................................................................... 5

5 OVERDOSAGE .............................................................................................................. 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 6

7 WARNINGS AND PRECAUTIONS .................................................................................. 6

7.1 Special Populations................................................................................................. 8

7.1.1 Pregnant Women ............................................................................................. 8

7.1.2 Breast-feeding .................................................................................................. 8

7.1.3 Pediatrics .......................................................................................................... 8

7.1.4 Geriatrics .......................................................................................................... 8

8 ADVERSE REACTIONS .................................................................................................. 8

8.1 Adverse Reaction Overview .................................................................................... 8

8.2 Clinical Trial Adverse Reactions .............................................................................. 8

8.2.1 Clinical Trial Adverse Reactions – Pediatrics .................................................. 13

8.5 Post-Market Adverse Reactions ........................................................................... 13

9 DRUG INTERACTIONS ................................................................................................ 14

9.2 Drug Interactions Overview .................................................................................. 14

9.3 Drug-Behavioural Interactions .............................................................................. 15

9.4 Drug-Drug Interactions ......................................................................................... 15

9.5 Drug-Food Interactions ......................................................................................... 19

9.6 Drug-Herb Interactions ......................................................................................... 19

9.7 Drug-Laboratory Test Interactions ........................................................................ 20

10 CLINICAL PHARMACOLOGY ....................................................................................... 20

10.1 Mechanism of Action ...................................................................................... 20

10.2 Pharmacodynamics ........................................................................................ 20

10.3 Pharmacokinetics ........................................................................................... 20

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 22

PART II: SCIENTIFIC INFORMATION ....................................................................................... 23

13 PHARMACEUTICAL INFORMATION ............................................................................ 23

14 CLINICAL TRIALS ........................................................................................................ 24

14.1 Clinical Trials by Indication ............................................................................. 24

14.2 Study Results .................................................................................................. 24

15 MICROBIOLOGY ........................................................................................................ 34

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 34

PATIENT MEDICATION INFORMATION .................................................................................. 43

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

XENICAL (orlistat), when used in conjunction with a mildly hypocaloric diet, is indicated for:

• obesity management including weight loss and weight maintenance;
• reducing the risk of weight regain in obese patients after prior weight loss.

These indications for the use of XENICAL apply to obese patients with a BMI* ≥ 30 kg/m² or a BMI ≥ 27 kg/m² in the presence of other risk factors (e.g. hypertension, type 2 diabetes, dyslipidemia, excess visceral fat).

The weight loss induced by the combination of XENICAL and a mildly hypocaloric diet results in an improvement of risk factors and comorbidities including hypercholesterolemia, impaired glucose tolerance, hyperinsulinemia, hypertension, reduction of visceral fat and waist circumference.

The weight loss induced by XENICAL improves glycemic control in diabetic patients and reduces the risk of developing type 2 diabetes in obese patients (BMI* ≥ 30 kg/m²) with impaired glucose tolerance. The effect of XENICAL on weight loss is adjunctive to that of diet and exercise.

XENICAL can be used in combination with anti-diabetic agents (sulfonylureas, metformin, insulin) to improve blood glucose control in overweight or obese type 2 diabetes patients who are inadequately controlled on diet, exercise, and one or more of a sulfonylurea, metformin, or insulin.

*The BMI is calculated by dividing weight in kilograms by height in metres squared.

1.1 Pediatrics

Pediatrics (< 12 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric patients below the age of 12 years. See 10.3 Pharmacokinetics, Special Populations and Conditions.

1.2 Geriatrics

Geriatrics (> 65 years of age): Clinical studies of XENICAL did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

2 CONTRAINDICATIONS

XENICAL (orlistat) is contraindicated in patients:

• with chronic malabsorption syndrome;
• with cholestasis;
• during pregnancy or breast-feeding (see 7.1.1 Pregnant Women and 7.1.2 Breast-feeding);
• who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• 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.
• 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 Mellitus in the New Millennium.
• Clinical investigations in patients with hepatic and/or renal impairment, elderly patients and children under the age of 12 have not been undertaken (see 10.3 Pharmacokinetics).
• Since Xenical has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, vitamin supplementation should be advised to ensure adequate nutrition. The vitamin supplement should be taken at least 2 hours before or after the administration of Xenical, such as at bedtime (see 7 WARNINGS AND PRECAUTIONS and 9.4 Drug-Drug Interactions).

4.2 Recommended Dose and Dosage Adjustment

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.

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.

Health Canada has not authorized an indication for pediatric use in patients less than 12 years of age (see 1 INDICATIONS and 10.3 Pharmacokinetics, Special Populations and Conditions).

4.4 Administration

XENICAL (orlistat) is administered orally with food (during a meal or up to 1 hour after the meal).

4.5 Missed Dose

If a dose is missed, it can be taken as soon as the patient remembers, provided this is within one hour of the last meal. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose. XENICAL cannot work properly if many doses are missed.

5 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 - Dosage Forms, Strengths, Composition and Packaging

Description

Each XENICAL 120 mg capsule contains 120 mg orlistat.

XENICAL 120 mg Capsules: turquoise cap and turquoise body with "XENICAL 120" printed in black ink.

XENICAL is supplied in blister packages in cartons of 84 capsules.

7 WARNINGS AND PRECAUTIONS

General

Patient Counselling Information: Patients should be advised to adhere to dietary guidelines. 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 4 DOSAGE AND ADMINISTRATION.

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 1 INDICATIONS for appropriate prescribing guidelines.

Patients should be advised to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene (see 4.1 Dosing Considerations and 9.4 Drug-Drug Interactions).

When using XENICAL in combination with insulin or oral hypoglycemic agents in patients with 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 (see 9.4 Drug-Drug Interactions).

XENICAL may interact with concomitant drugs including cyclosporine, levothyroxine, anticoagulants (e.g. warfarin), amiodarone, anticonvulsants, antidepressants, antipsychotics (including lithium), benzodiazepines and antiretrovirals (see 9.4 Drug-Drug Interactions).

Carcinogenesis and Mutagenesis

For animal data, refer to 16 NON-CLINICAL TOXICOLOGY.

Endocrine and Metabolism

Hypothyroidism and/or reduced control of hypothyroidism may occur. The mechanism may involve a decreased absorption of iodine salts and/or levothyroxine. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function (see 9.4 Drug-Drug Interactions).

Gastrointestinal

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

The possibility of experiencing gastrointestinal events (see 8 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.

Cases of rectal bleeding have been reported with XENICAL. Prescribers should investigate further in case of severe and/or persistent symptoms.

See also 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential.

Hepatic/Biliary/Pancreatic

There have been rare post-marketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with XENICAL with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light colored stools, or right upper quadrant pain) while taking XENICAL. When these symptoms occur, XENICAL should be discontinued immediately and liver function tests and ALT and AST levels obtained. See 10.3 Pharmacokinetics, Special Populations and Conditions.

Monitoring and Laboratory Tests

Diabetic patients treated with orlistat should have tests for fasting glucose and HbA1c as required.

Xenical may affect the absorption of concomitant medications requiring monitoring of plasma drug levels and/or clinical parameters (see 9.4 Drug-Drug Interactions).

Neurologic

Anticonvulsants: Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. These patients should be monitored for possible changes in the frequency and/or severity of convulsions (see 9.4 Drug-Drug Interactions).

Renal

Renal Calculi: Some patients may develop increased levels of urinary oxalate following treatment with XENICAL. Cases of hyperoxaluria and oxalate nephropathy with renal failure have been reported in patients treated with XENICAL. Caution should be exercised when prescribing XENICAL to patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis. See 10.3 Pharmacokinetics, Special Populations and Conditions.

Reproductive Health: Female and Male Potential

• Fertility

  The use of an additional contraceptive method is recommended to prevent possible failure of oral contraception that could occur in case of severe diarrhea (see 9.3 Drug-Behavioural Interactions).

7.1 Special Populations

7.1.1 Pregnant Women

XENICAL is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. 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. However, animal reproductive studies are not always predictive of human response.

There are no adequate and well-controlled studies of orlistat in pregnant women. See 2 CONTRAINDICATIONS.

7.1.2 Breast-feeding

XENICAL is contraindicated in nursing women. It is not known if orlistat is secreted in human milk. See 2 CONTRAINDICATIONS.

7.1.3 Pediatrics

Pediatrics (< 12 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric patients below the age of 12 years. See 10.3 Pharmacokinetics, Special Populations and Conditions.

7.1.4 Geriatrics

Geriatrics (> 65 years of age): Clinical studies of XENICAL did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Adverse reactions to XENICAL are largely gastrointestinal in nature and related to the pharmacologic effect of the drug on preventing the absorption of ingested fat. Commonly observed events are oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

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.)

Table 2 - Percentage of Patients with Commonly Observed GI Adverse Events (based on first- and second-year data) which Occurred with a Frequency of ≥ 5% in XENICAL 120 mg or Placebo

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.

In the 4-year double-blind, placebo-controlled XENDOS study, the incidence and duration of the commonly observed adverse reactions were comparable to those observed in the 1- and 2- year studies shown above.

Discontinuation of Treatment: In controlled obesity management clinical trials of 1-, and 2- year duration, 8.8% of patients treated with XENICAL discontinued treatment due to adverse events, compared to 5.0% of placebo treated patients. Similarly, in the 4-year XENDOS clinical trial, 8.0% and 4.0% of patients treated with XENICAL and placebo, respectively, discontinued treatment due to adverse events. 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.

Table 3 - Other Treatment-Emergent Adverse Events from Phase III Placebo-Controlled Obesity Management Clinical Trials – Year One Treatment

Table 4 - Other Treatment-Emergent Adverse Events from Phase III Placebo-Controlled Obesity Management Clinical Trials – Year Two Treatment

In the 4-year XENDOS study, the pattern and distribution of adverse events was similar to that reported for the 1- and 2-year studies. The total incidence of gastrointestinal related adverse events occurring in year 1 decreased progressively with each additional year of treatment, over the four-year period.

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 patients treated with XENICAL 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.

Weight loss induced by XENICAL is accompanied by improved metabolic control in type 2 diabetics which might allow or require reduction in the dose of hypoglycemic medication (see 7 WARNINGS AND PRECAUTIONS and 9.4 Drug-Drug Interactions).

* These values are the treatment difference between XENICAL and placebo.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

In clinical trials with XENICAL in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.

8.5 Post-Market Adverse Reactions

Endocrine disorders

Cases of hypothyroidism and/or reduced control of hypothyroidism have been reported in patients with no history of hypothyroidism and in patients treated concomitantly with levothyroxine (see 9.4 Drug-Drug Interactions).

Gastrointestinal disorders

Cases of rectal bleeding have been reported with XENICAL. Prescribers should investigate further in case of severe and/or persistent symptoms.

Pancreatitis has been reported with the use of XENICAL.

Cases of diverticulitis have been reported in patients treated with XENICAL.

Hepatobiliary disorders

Increase in liver transaminases and in alkaline phosphatase, and exceptional cases of hepatitis that may be serious have been reported during the post-marketing. There have been rare reports of serious liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with XENICAL observed in post-marketing surveillance with some of these cases resulting in liver transplant or death. Cases of jaundice and cholelithiasis with the use of XENICAL have been reported.

Immune system disorders

Rare cases of hypersensitivity have been reported. The main clinical symptoms were pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis.

Investigations

Reports of decreased prothrombin, increased international normalized ration (INR) and unbalanced anticoagulant treatment resulting in change of haemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants (see 9.4 Drug-Drug Interactions).

Nervous system disorders

Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs (see 9.4 Drug-Drug Interactions).

Renal and urinary disorders

Cases of hyperoxaluria and oxalate nephropathy with renal failure have been reported in patients treated with XENICAL (see 7 WARNINGS AND PRECAUTIONS, Renal).

Skin and subcutaneous tissue disorders

Very rare cases of bullous eruption have been reported.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Drug interaction studies with orlistat have been based on three criteria: 1) drugs related to orlistat-induced inhibition of fat absorption, which may reduce absorption of extremely lipophilic drugs and substances such as fat-soluble vitamins; 2) drugs with a narrow therapeutic index, such as digoxin and warfarin; and 3) concomitant medications likely to be used by the targeted patient population, such as hypolipidemic and antihypertensive drugs.

XENICAL (orlistat) inhibited the absorption of an oral pharmaceutical supplement of some fat-soluble vitamins and analogues such as β-carotene and vitamin E acetate. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A and nutritionally derived vitamin K is not known at this time.

XENICAL (orlistat) may decrease the absorption of antiepileptic drugs, leading to loss of seizure control.

XENICAL (orlistat) could negatively affect the efficacy of antidepressants, antipsychotics, benzodiazepines and antiretrovirals for HIV.

Data from a XENICAL (orlistat) and cyclosporine drug interactions study indicate a reduction of cyclosporine plasma levels when XENICAL (orlistat) was co-administered with cyclosporine.

Taking levothyroxine and XENICAL (orlistat) at the same time may reduce the blood levels of levothyroxine.

9.3 Drug-Behavioural Interactions

In a multiple-dose study in 30 normal weight subjects, co-administration 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.

Orlistat may indirectly reduce the availability of oral contraceptives and lead to unexpected pregnancies in some individual cases. An additional contraceptive method is recommended in case of severe diarrhea (see 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential).

9.4 Drug-Drug Interactions

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

Table 5 - Established or Potential Drug-Drug Interactions

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

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%.

10.2 Pharmacodynamics

Dose-response Relationship: A simple maximum effect (E_max) 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. E_max, 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.

10.3 Pharmacokinetics

Table 6 - Summary of Orlistat Pharmacokinetic Parameters in Adults

Absorption

Systemic exposure to orlistat is negligible. Following oral dosing with 360 mg ¹⁴C- orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were non-measurable (< 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 μM), without evidence of accumulation, and consistent with negligible absorption.

Distribution

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

Metabolism

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 β-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.

Special Populations and Conditions

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.

• Pediatrics: Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to slightly lower, compared to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in orlistat and placebo treatment groups, respectively.
• Hepatic Insufficiency: Clinical investigations in patients with hepatic impairment have not been undertaken.
• Renal Insufficiency: Clinical investigations in patients with renal impairment have not been undertaken.

Effect of Orlistat on Gastrointestinal and Systemic Physiological Processes:

Adults

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.

Pediatrics

In a 3-week study of 32 obese adolescents aged 12 to 16 years, XENICAL (120 mg, three times a day) did not significantly affect the balance of calcium, magnesium, phosphorous, zinc, or copper. The iron balance was decreased by 64.7 µmol/24 hours and 40.4 µmol/24 hours in orlistat and placebo treatment groups, respectively.

11 STORAGE, STABILITY AND DISPOSAL

XENICAL should be stored in its original package between 15-25°C. Keep the blister package in the XENICAL outer carton, in order to protect it from light and moisture. This medicine should not be used after the expiry date shown on the pack.

Keep out of reach and sight of children.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Physicochemical properties:

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Clinical Studies – Treatment of Obesity:

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.

An additional 4-year multicenter, double-blind, placebo-controlled study, the XENDOS study, assessed the effects of XENICAL on body weight, time to onset of type 2 diabetes, and comorbidities. The study included 3304 obese (BMI ≥ 30 kg/m²) patients.

In all the above studies, treatment with XENICAL and placebo designates treatment with XENICAL plus diet and placebo plus diet, respectively.

The observations regarding the effects on comorbidities during these trials are discussed in detail below.

14.2 Study Results

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 to all patients. 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:

Table 7 - Categorical Analysis of Weight Loss Following One Year of Treatment

* 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

Table 8 - Categorical Analysis of Weight Loss Following Two Full Years of Treatment

* 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, patients treated with XENICAL had lost 9.7%, compared with 6.6% for patients that received placebo (intent to treat). The findings were similar in the completers populations.

In the 4-year XENDOS trial, XENICAL was shown to be more effective than placebo in long-term weight control. Results showed that 73% of the patients treated with XENICAL lost ≥ 5% of baseline body weight after 1 year of treatment compared with 45% of the placebo-treated patients (p < 0.001). In addition, 41% of the patients treated with XENICAL lost ≥ 10% of body weight after 1 year compared with 21% of the placebo-treated patients (p < 0.001). Mean change in body weight was -10.56 kg for the XENICAL treatment group compared to -6.19 kg for the placebo treatment group at the end of the first year of treatment (p < 0.001). After 4 years of treatment, 44.8% and 21% of the patients treated with XENICAL lost ≥ 5 and ≥ 10% of body weight compared to 28.0% and 10% of the placebo-treated patients, respectively (p < 0.001). Mean change in body weight after 4 years of treatment was -5.75 kg for the XENICAL treatment group compared to -3.03 kg for the placebo treatment group (p < 0.001).

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 2^nd 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).

Effect on Comorbidities:

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. One, 2, and 4 years treatment 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, and maintained for each year throughout the entire 4-year treatment period.

The relative changes in risk factors associated with obesity following 4 years of therapy are summarized in the following table:

Table 9 - Mean Change in Risk Factors from Randomization Following 4-Years Treatment* (Population as Whole)

* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet

† ITT (LOCF)

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.

In the 4-year XENDOS study, the changes from randomization following 4-years of treatment in the population with abnormal lipid levels (LDL ≥ 3.362 mmol/L, HDL < 0.905 mmol/L, LDL:HDL ratio ≥ 3.5, triglycerides ≥ 2.54 mmol/L) were greater for XENICAL compared with placebo in respect to LDL (-14.86% vs -7.34%, p < 0.001), LDL/HDL (-0.87% vs -0.59%, p < 0.001), and triglycerides (-15.63% vs -13.92%, p = 0.562). HDL increased in the placebo group by 12.9% and in the XENICAL group by 11.6%

(p = 0.339). In the population with abnormal blood pressure at baseline (systolic ≥ 140 mmHg, diastolic ≥ 90 mmHg), the change in systolic blood pressure from baseline was greater for XENICAL than placebo (-11.44 mmHg vs -8.70 mmHg, p = 0.002). For patients with diastolic blood pressure ≥ 90 mmHg at baseline, the decrease in diastolic blood pressure in the XENICAL patients was -8.00 mmHg vs -6.26 mmHg in the placebo treated patients (p = 0.006). Fasting insulin decreased more in the XENICAL treatment group than the placebo treatment group (-47.02 pmol/L vs -37.47 pmol/L, p = 0.002) from randomization to year 4 in the population with abnormal baseline values (≥ 90 mmol/L).

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: -5.0% 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.

Table 10 - Impact of < 5% or ≥ 5% Weight Loss at 12 Weeks on Risk Factors following 1- and 2-Years Treatment with XENICAL

^a Percent change unless otherwise noted.

* 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.

** Number in brackets refers to the number of patients.

Onset of Type 2 Diabetes in Obese Patients (BMI ≥ 30 kg/m²):

In the 4-year XENDOS study, the effects of XENICAL in delaying the onset of type 2 diabetes were compared to placebo in obese patients who had either normal or impaired glucose tolerance at baseline.

Treatment with XENICAL, in combination with lifestyle changes, was shown to delay the onset of type 2 diabetes compared with treatment with placebo plus lifestyle changes (p < 0.01). A greater proportion of placebo-treated patients developed type 2 diabetes than did patients treated with XENICAL. At the end of the 4 years, the cumulative incidence rate for the development of type 2 diabetes was 9.04% for placebo and 6.15% for XENICAL. Over the 4-year treatment period, there was a 37.3% relative reduction in the risk of developing type 2 diabetes in the patients treated with XENICAL compared to the placebo group.

Table 11 - Cumulative Incidence of Diabetic Cases by Time of First Occurrence – ITT¹

¹ ITT: all eligible randomized patients with baseline and a follow-up efficacy assessment

^* p < 0.01, logrank test

A separate analysis was conducted in patients with impaired glucose tolerance (IGT) at baseline. In patients (ITT) with baseline IGT (placebo, n = 345; XENICAL, n = 352), treatment with XENICAL again was shown to delay the onset of type 2 diabetes compared with treatment with placebo. A greater proportion of placebo-treated patients developed diabetes than did patients treated with XENICAL. At the end of 4 years, the cumulative incidence rate of type 2 diabetes in patients with IGT at baseline was 28.77 % for placebo and 18.79% for XENICAL (p < 0.003). Over the 4-year treatment period, the relative risk of developing type 2 diabetes was reduced by 44.9% in the XENICAL group compared to the placebo group. In addition, treatment with XENICAL significantly reduced the progression to type 2 diabetes when diagnosed by repeat positive testing in patients with baseline IGT. Cumulative incidence rates after 4 years were 8.3% for XENICAL and 14.2% for placebo (p = 0.0171), corresponding to a 52% risk reduction.

Table 12 - Cumulative Incidence of Diabetic Cases by Time of First Occurrence – Patients with IGT at Baseline

^* p <0.01, logrank test

Glucose Tolerance in Obese Patients:

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:

Table 13 - The Percentage of Patients Improving to Normal or Deteriorating to Diabetic Status Following One or Two Years with XENICAL versus Placebo

* p < 0.01 and ** p = 0.059, Fisher’s Exact Test

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

¹ Treatment refers to orlistat plus diet or placebo plus diet.

Type 2 Diabetes:

Seven randomized, double-blind, placebo-controlled trials 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. An additional six-month trial was conducted to evaluate the metabolic effects of XENICAL combined with lifestyle intervention compared with lifestyle intervention alone in obese patients with type 2 diabetes.

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.

Table 14 - 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 Canadian Diabetes Association.

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

I 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).

N/D = Not done

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 patients treated with XENICAL 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.

In a six-month single centre, randomized, double-blind, placebo-controlled study in patients with type 2 diabetes, patients were randomized to receive XENICAL plus lifestyle intervention, or placebo plus lifestyle intervention. A significant improvement (p < 0.05) in insulin sensitivity was observed in the XENICAL group (+2.2 ± 0.4 mg.min-1.kg-1) compared with the placebo group (+1.2 ± 0.4 mg.min-1.kg-1), which was attributed to the significant decrease (p < 0.01) in fasting plasma free fatty acids observed in the XENICAL group (-154 ± 22 µmol/L) compared to the placebo group (-51 ± 33 µmol/L), after adjusted for effects of weight loss.

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 the table below. One year of therapy with XENICAL in combination with other antidiabetic medications resulted in statistically significant improvements in many of these risk factors.

Table 15 - Mean Change in Risk Factors from Randomization – Population with Abnormal Risk Factors¹

¹ Intent-to-treat population: observed data based on pooled data from 7 studies

² The 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.

Pediatric Clinical Studies:

The effects of XENICAL on body mass index (BMI) and weight loss were assessed in a 54-week multicenter, double-blind, placebo-controlled study in 539 obese adolescents (357 receiving XENICAL 120 mg three times a day, 182 receiving placebo), aged 12 to 16 years.

BMI was the primary efficacy parameter as it takes into account changes in height and body weight, which occur in growing children.

During the study, all patients were instructed to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after ingestion of XENICAL. All patients were also maintained on a well-balanced, reduced-calorie diet that was intended to provide 30% of calories from fat. In addition, all patients were placed on a behaviour modification program and offered exercise counselling.

Approximately 65% of patients in each treatment group completed the study.

Following one year of treatment, BMI decreased by an average of 0.55 kg/m² in the XENICAL-treated patients and increased by an average of 0.31 kg/m² in the placebo-treated patients (p = 0.001). The percentages of patients achieving 5% and 10% reduction in BMI and body weight after 52 weeks of treatment for the intent-to-treat population are presented below.

Table 16 - Percentages of Patients with ≥ 5% and ≥ 10% Decrease in Body Mass Index and Body Weight After 1-Year Treatment*

* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet

† Last observation carried forward

** BMI: placebo n = 178, XENICAL n = 347; Body Weight: placebo n = 180, XENICAL n = 348

In a subgroup of 152 XENICAL-treated and 77 placebo-treated patients from the 54-week study, changes in body composition measured by DEXA were similar in both treatment groups with the exception of fat mass, which was significantly reduced in patients treated with XENICAL compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p = 0.033).

Table 17 - Least Squares Mean Change from Baseline in DEXA¹ Total Body Assessments

¹ DEXA: Dual-Energy X-ray Absorptiometry

* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

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.

General Toxicology:

Table 18 - Acute Toxicity

* MNLD = Maximum Non-lethal Dose

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

The following abbreviations are used throughout Table 19, Table 20 and Table 21:

↑ (increased), ↓ (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).

Table 19 - Long-term Toxicology Studies

Carcinogenicity:

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.

Genotoxicity:

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.

Reproductive and Developmental Toxicology:

Table 20 - Reproduction and Teratology

Special Toxicology:

Table 21 - Special Toxicity Studies

¹DR = Dose Relate