ORLISTAT: 6,498 Adverse Event Reports & Safety Profile

XENICAL (orlistat) is a gastrointestinal lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats. Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Its empirical formula is C 29 H 53 NO 5 , and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm. The structure is: Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no p K a within the physiological pH range. XENICAL is available for oral administration as a turquoise hard-gelatin capsule. The capsule is imprinted with black. Each capsule contains a pellet formulation consisting of 120 mg of the active ingredient, orlistat, as well as the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. The capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink containing pharmaceutical grade shellac, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide. chemical structure

AND USAGE ORLISTAT is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. ORLISTAT is also indicated to reduce the risk for weight regain after prior weight loss. ORLISTAT 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 ORLISTAT 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 ) ORLISTAT is also indicated to reduce the risk for weight regain after prior weight loss. ( 1 )

Table

1

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 ORLISTAT, such as at bedtime. ( 2 ) For patients receiving both ORLISTAT and cyclosporine therapy, administer cyclosporine 3 hours after ORLISTAT. ( 2 ) For patients receiving both ORLISTAT and levothyroxine therapy, administer levothyroxine and ORLISTAT at least 4 hours apart. ( 2 )

2.1 Recommended Dosing The recommended dose of ORLISTAT 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 ORLISTAT can be omitted. Because ORLISTAT 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . The vitamin supplement should be taken at least 2 hours before or after the administration of ORLISTAT, such as at bedtime. For patients receiving both ORLISTAT and cyclosporine therapy, administer cyclosporine 3 hours after ORLISTAT. For patients receiving both ORLISTAT and levothyroxine therapy, administer levothyroxine and ORLISTAT at least 4 hours apart. Patients treated concomitantly with ORLISTAT 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 ORLISTAT 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.

ORLISTAT is contraindicated in: Pregnancy [see Use in Specific Populations (8.1) ] Patients with chronic malabsorption syndrome Patients with cholestasis Patients with known hypersensitivity to ORLISTAT or to any component of this product Pregnancy ( 4 , 8.1 ) Chronic malabsorption syndrome ( 4 ) Cholestasis ( 4 ) Known hypersensitivity to ORLISTAT or to any component of this product ( 4 )

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 1-877-778-8969 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 ORLISTAT 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 ORLISTAT 120 mg group that is at least twice that of placebo.)

Table

2 Commonly Observed Adverse Events Adverse Event Year 1 Year 2 Orlistat Treatment designates ORLISTAT three times a day plus diet or placebo plus diet % Patients (N=1913) Placebo % Patients (N=1466) Orlistat % 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 ORLISTAT 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 ORLISTAT discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For ORLISTAT, 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 ORLISTAT 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 Orlistat Treatment designates ORLISTAT 120 mg three times a day plus diet or placebo plus diet % Patients (N=1913) Placebo % Patients (N=1466) Orlistat % 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 &amp; 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 &amp; 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 &amp; 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 ORLISTAT 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 ORLISTAT plus diet Orlistat 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 ORLISTAT 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 ORLISTAT plus diet Orlistat 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 ORLISTAT 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 ORLISTAT. 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 ORLISTAT 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 ORLISTAT in postmarketing surveillance, with some of these cases resulting in liver transplant or death <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Rare cases of hypersensitivity have been reported with the use of ORLISTAT. 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 ORLISTAT has been reported in patients with or at risk for renal disease <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . Pancreatitis has been reported with the use of ORLISTAT 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 ORLISTAT. Most reports are nonserious; severe or persistent cases should be investigated further.

AND PRECAUTIONS ORLISTAT has drug interactions and can decrease vitamin absorption. ( 5.1 , 7 ) Take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition. ( 5.1 ) Rare cases of severe liver injury with hepatocellular necrosis or acute hepatic failure have been reported. ( 5.2 ) Patients may develop oxalate nephrolithiasis and oxalate nephropathy following treatment with ORLISTAT. Monitor renal function in patients at risk for renal insufficiency. Discontinue ORLISTAT if oxalate nephropathy develops. ( 5.3 ) Substantial weight loss can increase the risk of cholelithiasis. ( 5.4 ) Exclude organic causes of obesity (eg, hypothyroidism) before prescribing ORLISTAT. ( 5.5 ) Gastrointestinal events may increase when ORLISTAT is taken with a diet high in fat (>30% total daily calories from fat). ( 5.5 )

5.1 Drug Interactions and Decreased Vitamin Absorption ORLISTAT may interact with concomitant drugs including cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, and antiretroviral drugs <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Data from a ORLISTAT and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when ORLISTAT was coadministered with cyclosporine. Therefore, ORLISTAT and cyclosporine should not be simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 hours before or after ORLISTAT in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered. Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because ORLISTAT has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene <span class="opacity-50 text-xs">[see Dosage and Administration (2) , and Adverse Reactions (6.1) ]</span> . In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The supplement should be taken once a day at least 2 hours before or after the administration of ORLISTAT, such as at bedtime. Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin may be required in some patients <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> .

5.2 Liver Injury There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with ORLISTAT, 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 ORLISTAT. When these symptoms occur, ORLISTAT and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.

5.3 Oxalate Nephrolithiasis and Oxalate Nephropathy with Renal Failure Some patients may develop increased levels of urinary oxalate following treatment with ORLISTAT. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing ORLISTAT to patients at increased risk for oxalate nephropathy, including patients with renal impairment and in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis. Discontinue ORLISTAT in patients who develop oxalate nephropathy.

5.4 Cholelithiasis Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of ORLISTAT for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to ORLISTAT and 1.8% (30/1655) for patients randomized to placebo.

5.5 Miscellaneous Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing ORLISTAT. Patients should be advised to adhere to dietary guidelines <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> . Gastrointestinal events <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> may increase when ORLISTAT is taken with a diet high in fat (&gt;30% total daily calories from fat). The daily intake of fat should be distributed over three main meals. If ORLISTAT is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.

INTERACTIONS Cyclosporine: Reduction in cyclosporine plasma levels was observed when ORLISTAT was coadministered with cyclosporine. ( 7.1 ) Fat-soluble Vitamin Supplements and Analogues: All patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. ( 7.2 ) Levothyroxine: Patients treated concomitantly with ORLISTAT and levothyroxine should be monitored for changes in thyroid function. ( 7.3 ) Warfarin: Patients on chronic stable doses of warfarin who are prescribed ORLISTAT should be monitored closely for changes in coagulation parameters. ( 7.4 ) Amiodarone: A reduction in exposure to amiodarone was observed when ORLISTAT was co-administered. ( 7.5 )

Antiepileptic

Drugs: Convulsions have been reported in patients taking ORLISTAT with antiepileptic drugs. Patients should be monitored for possible changes in frequency or severity of convulsions. ( 7.6 )

Antiretroviral

Drugs: Loss of virological control has been reported in HIV-infected patients. Patients should be monitored frequently for changes in HIV RNA levels. ( 7.7 )

7.1 Cyclosporine Data from a ORLISTAT and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when ORLISTAT was coadministered with cyclosporine. ORLISTAT and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of ORLISTAT <span class="opacity-50 text-xs">[see Dosage and Administration (2) , and Warnings and Precautions (5.1) ]</span> .

7.2 Fat-soluble Vitamin Supplements and Analogues Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with ORLISTAT. ORLISTAT inhibited absorption of a vitamin E acetate supplement. The effect of ORLISTAT on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) , and Warnings and Precautions (5.1) ]</span> .

7.3 Levothyroxine Hypothyroidism has been reported in patients treated concomitantly with ORLISTAT and levothyroxine postmarketing. Patients treated concomitantly with ORLISTAT and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and ORLISTAT at least 4 hours apart <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> .

7.4 Anticoagulants including Warfarin Vitamin K absorption may be decreased with ORLISTAT. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with ORLISTAT and anticoagulants. Patients on chronic stable doses of warfarin or other anticoagulants who are prescribed ORLISTAT should be monitored closely for changes in coagulation parameters <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.5 Amiodarone A pharmacokinetic study, where amiodarone was orally administered during orlistat treatment, demonstrated a reduction in exposure to amiodarone and its metabolite, desethylamiodarone <span class="opacity-50 text-xs">[see Clinical Pharmocology (12.3) ]</span> . A reduced therapeutic effect of amiodarone is possible. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied.

7.6 Antiepileptic Drugs Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions.

7.7 Antiretroviral Drugs Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with antiretroviral drugs such as atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, and with the combinations lopinavir/ritonavir and emtricitabine/efavirenz/tenofovir disoproxil fumarate. The exact mechanism for this is unclear, but may include a drug-drug interaction that inhibits systemic absorption of the antiretroviral drug. HIV RNA levels should be frequently monitored in patients who take ORLISTAT while being treated for HIV infection. If there is a confirmed increase in HIV viral load, ORLISTAT should be discontinued.

Active ingredient (in each sealed capsule)

Orlistat

60 mg

Inactive ingredients FD&C Blue No. 2, edible ink, gelatin, iron oxide, microcrystalline cellulose, povidone, sodium lauryl sulfate, sodium starch glycolate, talc, titanium dioxide