Orlistat

1 INDICATIONS AND USAGE XENICAL is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. XENICAL is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m 2 or ≥27 kg/m 2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia). Table 1 illustrates body mass index (BMI) according to a variety of weights and heights. The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5 ' 5 " would have a BMI of 30. Table 1 Body Mass Index (BMI), kg/m 2 Conversion Factors: Weight in lbs ÷ 2.2 = weight in kilograms (kg) Height in inches × 0.0254 = height in meters (m) 1 foot = 12 inches XENICAL is a reversible inhibitor of gastrointestinal lipases indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. ( 1 ) XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. ( 1 ) Table 1

2 DOSAGE AND ADMINISTRATION One 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal). ( 2 ) Advise patients to take a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. ( 2 ) Distribute the daily intake of fat, carbohydrate, and protein over three main meals. ( 2 ) Advise patients to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. ( 2 ) Take the vitamin supplement at least 2 hours before or after the administration of XENICAL, such as at bedtime. ( 2 ) For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL. ( 2 ) For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart. ( 2 ) 2.1 Recommended Dosing The recommended dose of XENICAL is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal). The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of XENICAL can be omitted. Because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition [see Warnings and Precautions (5.1) ] . The vitamin supplement should be taken at least 2 hours before or after the administration of XENICAL, such as at bedtime. For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL. For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. Doses above 120 mg three times a day have not been shown to provide additional benefit. 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.

6 ADVERSE REACTIONS Most common treatment emergent adverse reactions (≥5% and at least twice that of placebo) include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact the Safety Call Center at 1-888-236-5445 or FDA at 1‑800‑FDA‑1088 (1-800-332-1088) or www.fda.gov/medwatch. 6.1 Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients. Commonly Observed (based on first year and second year data) Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of XENICAL in the seven 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 Commonly Observed Adverse Events Adverse Event Year 1 Year 2 XENICAL Treatment designates XENICAL three times a day plus diet or placebo plus diet % Patients (N=1913) Placebo % Patients (N=1466) XENICAL % Patients (N=613) Placebo % Patients (N=524) Oily Spotting Oily discharge may be clear or have a coloration such as orange or brown. 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 In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of GI adverse events associated with XENICAL treatment lasted for less than 1 week, and a majority lasted for no more than 4 weeks. However, GI adverse events may occur in some individuals over a period of 6 months or longer. Discontinuation of Treatment In controlled clinical trials, 8.8% of patients treated with XENICAL discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For XENICAL, the most common adverse events resulting in discontinuation of treatment were gastrointestinal. Other Adverse Clinical Events The following table lists other treatment-emergent adverse events from seven multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of ≥2% among patients treated with XENICAL 120 mg three times a day 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 Seven Placebo-Controlled Clinical Trials Body System/Adverse Event Year 1 Year 2 XENICAL Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet % Patients (N=1913) Placebo % Patients (N=1466) XENICAL % Patients (N=613) Placebo % Patients (N=524) – None reported at a frequency ≥2% and greater than placebo Gastrointestinal System Abdominal Pain/Discomfort 25.5 21.4 – – Nausea 8.1 7.3 3.6 2.7 Infectious Diarrhea 5.3 4.4 – – Rectal Pain/Discomfort 5.2 4.0 3.3 1.9 Tooth Disorder 4.3 3.1 2.9 2.3 Gingival Disorder 4.1 2.9 2.0 1.5 Vomiting 3.8 3.5 – – Respiratory System Influenza 39.7 36.2 – – Upper Respiratory Infection 38.1 32.8 26.1 25.8 Lower Respiratory Infection 7.8 6.6 – – Ear, Nose & Throat Symptoms 2.0 1.6 – – Musculoskeletal System Back Pain 13.9 12.1 – – Pain Lower Extremities – – 10.8 10.3 Arthritis 5.4 4.8 – – Myalgia 4.2 3.3 – – Joint Disorder 2.3 2.2 – – Tendonitis – – 2.0 1.9 Central Nervous System Headache 30.6 27.6 – – Dizziness 5.2 5.0 – – Body as a Whole Fatigue 7.2 6.4 3.1 1.7 Sleep Disorder 3.9 3.3 – – Skin & Appendages Rash 4.3 4.0 – – Dry Skin 2.1 1.4 – – Reproductive, Female Menstrual Irregularity 9.8 7.5 – – Vaginitis 3.8 3.6 2.6 1.9 Urinary System Urinary Tract Infection 7.5 7.3 5.9 4.8 Psychiatric Disorder Psychiatric Anxiety 4.7 2.9 2.8 2.1 Depression – – 3.4 2.5 Hearing & Vestibular Disorders Otitis 4.3 3.4 2.9 2.5 Cardiovascular Disorders Pedal Edema – – 2.8 1.9 Table 4 illustrates the percentage of adult patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in studies in which patients were not previously receiving vitamin supplementation. Table 4 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - First and Second Year) Placebo Treatment designates placebo plus diet or XENICAL plus diet XENICAL Vitamin A 1.0% 2.2% Vitamin D 6.6% 12.0% Vitamin E 1.0% 5.8% Beta-carotene 1.7% 6.1% Table 5 illustrates the percentage of adolescent patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study. Table 5 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Pediatric Patients With Normal Baseline Values All patients were treated with vitamin supplementation throughout the course of the study ) Placebo Treatment designates placebo plus diet or XENICAL plus diet XENICAL Vitamin A 0.0% 0.0% Vitamin D 0.7% 1.4% Vitamin E 0.0% 0.0% Beta-carotene 0.8% 1.5% In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period. In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed. Pediatric Patients 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of XENICAL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to XENICAL exposure. Rare cases of increase in transaminases and in alkaline phosphatase and hepatitis that may be serious have been reported. There have been reports of hepatic failure observed with the use of XENICAL in postmarketing surveillance, with some of these cases resulting in liver transplant or death [see Warnings and Precautions (5.2) ] . Rare cases of hypersensitivity have been reported with the use of XENICAL. Signs and symptoms have included pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption have been reported. Rare cases of leukocytoclastic vasculitis have been reported. Clinical signs include palpable purpura, maculopapular lesions, or bullous eruption. Acute oxalate nephropathy after treatment with XENICAL has been reported in patients with or at risk for renal disease [see Warnings and Precautions (5.3) ] . Pancreatitis has been reported with the use of XENICAL in postmarketing surveillance. No causal relationship or physiopathological mechanism between pancreatitis and obesity therapy has been definitively established. Lower gastrointestinal bleeding has been reported in patients treated with XENICAL. Most reports are nonserious; severe or persistent cases should be investigated further.

12.3 Pharmacokinetics Absorption Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14 C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal 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 an oral 14 C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed β-lactone ring product of orlistat) and M3 (sequential metabolite after M1's cleavage of the N-formyl leucine side-chain), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open β-lactone ring and extremely weak 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, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 eliminated at a slower rate (half-life approximately 13.5 hours). Elimination Following a single oral dose of 360 mg 14 C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion. Approximately 97% of the administered radioactivity was excreted in feces; 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 14 C-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. Specific Populations No pharmacokinetic study was conducted for specific populations such as geriatric, different races, and patients with renal and hepatic impairment. Drug Interactions Alcohol In a multiple-dose study in 30 normal-weight subjects, coadministration of XENICAL 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), or systemic exposure to orlistat. Amiodarone In a pharmacokinetic study conducted in healthy volunteers who received 120 mg orlistat three times daily for 13 days and a single dose of 120 mg orlistat on the morning of Day 14 co-administered with a single dose of 1200 mg amiodarone on Day 4, a 23 – 27% reduction in the systemic exposure to amiodarone and desethylamiodarone was observed [see Drug Interactions (7.5) ] . The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied. Cyclosporine In a multiple-dose study, coadministration of 50 mg cyclosporine twice daily with 120 mg XENICAL three times daily decreased cyclosporine AUC and C max by 31% and 25%, respectively. In the same study, administration of 50 mg cyclosporine twice daily three hours after the administration of 120 mg XENICAL three times daily decreased cyclosporine AUC and C max by 17% and 4%, respectively. Digoxin In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of XENICAL on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets) In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day 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 undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters.