Orlistat

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# Overview
Orlistat is an antiobesity drug that is FDA approved for the treatment of obesity including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet.   Common adverse reactions include oily spotting, flatus with discharge,fecal urgency,fatty/oily stool,oily evacuation,
increased defecation, fecal incontinence, abdominal pain/discomfort, nausea,  influenza, back pain, rash.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- 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/m2 or 27 kg/m2 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.

# 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. 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.

# DOSAGE FORMS AND STRENGTHS
- Orlistat 120 mg turquoise capsules imprinted with ROCHE and orlistat 120 in black ink.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use

# Indications and  Dosing
- Concomitant nutritionally-balanced meal with 30% calories from fat is recommended
- Concomitant daily multivitamin supplement is recommended
- Obesity: 120 mg orally 3 times daily during or within 1 hour of each fat-containing meal
- Obesity: over-the-counter dose: 60 mg ORALLY 3 times daily during or within 1 hour of each fat-containing meal

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Orlistat in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Orlistat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use

# Indications and Dosing
- Concomitant nutritionally-balanced meal with 30% calories from fat is recommended.
- Concomitant daily multivitamin supplement is recommended.
- Obesity: (12 to 16 years) 120 mg ORALLY 3 times daily during or within 1 hour of each fat-containing meal.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Orlistat in pediatric patients.

# Contraindications
- Pregnancy
- Patients with chronic malabsorption syndrome
- Patients with cholestasis
- Patients with known hypersensitivity to orlistat or to any component of this product

# Warnings

# Concomitant Drug and Vitamin Use
- 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. 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.
- TABLE 2 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 3 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.
- 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

# 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.

# Increases in Urinary Oxalate
- 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 risk for renal impairment and use with caution in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.

# 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.

# Miscellaneous
- Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing orlistat.
- Patients should be advised to adhere to dietary guidelines. Gastrointestinal events  may increase when orlistat is taken with a diet high in fat (>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.

# Adverse Reactions

## Clinical Trials Experience

# 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.)
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.
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.

## 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.
- Cases of reduced concentrations of cyclosporine have been reported when cyclosporine was co-administered with orlistat.
- 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.
- 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.
- Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine.
- Acute oxalate nephropathy after treatment with orlistat has been reported in patients with or at risk for renal disease.
- 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 non serious; severe or persistent cases should be investigated further.
- Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs.

# Drug Interactions
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.
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
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 .
Warfarin
Vitamin K absorption may be decreased with orlistat. Patients on chronic stable doses of warfarin who are prescribed orlistat should be monitored closely for changes in coagulation parameters.
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

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Category X
Orlistat is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.
Animal Data
Reproduction studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/m2) basis for rats and rabbits, respectively.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Orlistat in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Orlistat during labor and delivery.

### Nursing Mothers
It is not known if orlistat is present in human milk. Caution should be exercised when orlistat is administered to a nursing woman.

### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
- The safety and efficacy of orlistat have been evaluated in obese adolescent patients aged 12 to 16 years. Use of orlistat in this age group is supported by evidence from adequate and well-controlled studies of orlistat in adults with additional data from a 54-week efficacy and safety study and a 21-day mineral balance study in obese adolescent patients aged 12 to 16 years. Patients treated with orlistat in the 54-week efficacy and safety study (64.8% female, 75% Caucasians, 18.8% Blacks, and 6.3% Other) had a mean reduction in BMI of 0.55 kg/m2 compared with an average increase of 0.31 kg/m2 in placebo-treated patients (p=0.001). In both adolescent studies, adverse effects were generally similar to those described in adults and included fatty/oily stool, oily spotting, and oily evacuation. In a subgroup of 152 orlistat and 77 placebo 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 orlistat compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p=0.033). Because orlistat can interfere with the absorption of fat-soluble vitamins, all patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. The vitamin supplement should be taken at least 2 hours before or after orlistat .
- Plasma concentrations of orlistat and its metabolites M1 and M3 were similar 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.

### Geriatic Use
Clinical studies of orlistat did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

### Gender
There is no FDA guidance on the use of Orlistat with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Orlistat with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Orlistat in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Orlistat in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Orlistat in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Orlistat in patients who are immunocompromised.

### Others

# Administration and Monitoring

### Administration
Oral

### Monitoring
There is limited information regarding Orlistat Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Orlistat and IV administrations.

# Overdosage
Single doses of 800 mg orlistat and multiple doses of up to 600 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.
Should a significant overdose of orlistat occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible.

# Pharmacology

## Mechanism of Action
- Orlistat is a reversible inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue 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 may have a positive effect on weight control.

## Structure
- Orlistat (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 C29H53NO5, 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 pKa within the physiological pH range.
- Orlistat 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, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide.

## Pharmacodynamics
'Dose-response Relationship'
The dose-response relationship for orlistat in human volunteers is shown in FIGURE 1. The effect is the percentage of ingested fat excreted, referred to as fecal fat excretion percentage. Both individual data (open circles) and the curve predicted for the population with the maximum-effect model (continuous line) are shown in FIGURE 1.
At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.
Ethanol does not affect orlistat's effect on preventing the absorption of fat.
'Other Short-term Studies'
- Adults
In several studies of up to 6-weeks duration, the effects of therapeutic doses 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 effects on plasma triglyceride levels or systemic lipases were observed with the administration of orlistat in these studies. In a 3-week study of 28 healthy male volunteers, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron.
- Pediatrics
In a 3-week study of 32 obese adolescents aged 12 to 16 years, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 mole/24 hours and 40.4 mole/24 hours in orlistat and placebo treatment groups, respectively.

## Pharmacokinetics
Absorption
Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-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 M), 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 14C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed -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 -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 14C-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 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.
Specific Populations
No pharmacokinetic study was conducted for specific populations such as geriatric, different races, and patients with renal and hepatic impairment.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats, these doses are 38 and 46 times the daily human dose calculated on an area under concentration vs time curve basis of total drug-related material.
- Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat hepatocytes in culture, and an in vivo mouse micronucleus test.
- When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study, orlistat had no observable adverse effects. This dose is 12 times the daily human dose calculated on a body surface area (mg/m2) basis.

# Clinical Studies
- The long-term effects of XENICAL on morbidity and mortality associated with obesity have not been established.
- The effects of orlistat on weight loss, weight maintenance, and weight regain and on a number of comorbidities (eg, type 2 diabetes, lipids, blood pressure) were assessed in the 4-year XENDOS study and in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, the studies of 2-year duration assessed weight loss and weight maintenance. 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 orlistat and 1400 patients treated with placebo (age range 17-78 years, 80.2% women, 91.0% Caucasians, 5.7% Blacks, 2.3% Hispanics, 0.1% Other). The majority of these patients had obesity-related risk factors and comorbidities. In the XENDOS study, which included 3304 patients (age range 30-58 years, 55% women, 99% Caucasians, 1% other), the time to onset of type 2 diabetes was assessed in addition to weight management. In all these studies, treatment with orlistat and placebo designates treatment with orlistat plus diet and placebo plus diet, respectively.
- During the weight loss and weight maintenance period, a well-balanced, reduced-calorie diet that was intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat was recommended to all patients. In addition, all patients were offered nutritional counseling.

## One-year Results: Weight Loss, Weight Maintenance, and Risk Factors
Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 1 year of treatment in the intent-to-treat population was 13.4 lbs in the patients treated with orlistat and 5.8 lbs in the placebo-treated patients. After 1 year of treatment, the mean percent weight loss difference between orlistat-treated patients and placebo-treated patients was 3%. One thousand seventy two (69%) patients treated with orlistat and 701 (63%) patients treated with placebo completed 1 year of treatment. Of the patients who completed 1 year of treatment, 57% of the patients treated with orlistat (120 mg three times a day) and 31% of the placebo-treated patients lost at least 5% of their baseline body weight.
The percentages of patients achieving 5% and 10% weight loss after 1 year in five large multicenter studies for the intent-to-treat populations are presented in TABLE 6.
The relative changes in risk factors associated with obesity following 1 year of therapy with orlistat and placebo are presented for the population as a whole and for the population with abnormal values at randomization.
Population as a Whole
The changes in metabolic, cardiovascular and anthropometric risk factors associated with obesity based on pooled data for five clinical studies, regardless of the patient's risk factor status at randomization, are presented in TABLE 7. One year of therapy with orlistat resulted in relative improvement in several risk factors.
Population With Abnormal Risk Factors at Randomization
The changes from randomization following 1-year treatment in the population with abnormal lipid levels (LDL 130 mg/dL, LDL/HDL 3.5, HDL <35 mg/dL) were greater for orlistat compared to placebo with respect to LDL-cholesterol (-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by 20.1% and in the orlistat group by 18.8%. In the population with abnormal blood pressure at baseline (systolic BP 140 mm Hg), the change in SBP from randomization to 1 year was greater for orlistat (-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure 90 mm Hg, orlistat patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg. Fasting insulin decreased more for orlistat than placebo (-39 vs -16 pmol/L) from randomization to 1 year in the population with abnormal baseline values (120 pmol/L). A greater reduction in waist circumference for orlistat vs placebo (-7.29 vs -4.53 cm) was observed in the population with abnormal baseline values (100 cm).

## Effect on Weight Regain
- Three studies were designed to evaluate the effects of orlistat compared to placebo in reducing weight regain after a previous weight loss achieved following either diet alone (one study, 14302) or prior treatment with orlistat (two studies, 14119C and 14185). The diet utilized during the 1-year weight regain portion of the studies was a weight-maintenance diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in weight-loss studies. For studies 14119C and 14185, patients' previous weight loss was due to 1 year of treatment with orlistat in conjunction with a mildly hypocaloric diet. Study 14302 was conducted to evaluate the effects of 1 year of treatment with orlistat on weight regain in patients who had lost 8% or more of their body weight in the previous 6 months on diet alone.
- In study 14119C, patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with orlistat regained 26% of the weight they had previously lost (p<0.001). In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with orlistat regained 35% of the weight they had lost (p<0.001). In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with orlistat regained 32% of the weight that they had lost (p<0.001)

## Two-year Results: Long-term Weight Control and Risk Factors
- The treatment effects of orlistat were examined for 2 years in four of the five 1-year weight management clinical studies previously discussed (see TABLE 6). At the end of year 1, the patients' diets were reviewed and changed where necessary. The diet prescribed in the second year was designed to maintain patient's current weight. Orlistat was shown to be more effective than placebo in long-term weight control in four large, multicenter, 2-year double-blind, placebo-controlled studies.
- Pooled data from four clinical studies indicate that 74% of all patients treated with 120 mg three times a day of orlistat and 76% of patients treated with placebo completed 2 years of the same therapy. Pooled data from four clinical studies indicate that the mean weight loss difference between orlistat 120 mg three times a day and placebo treatment groups at year 2 in those patients who completed 1 year of treatment (ITT LOCF) was 3%. In the same studies cited in the One-year Results (see TABLE 6), the percentages of patients achieving a 5% and 10% weight loss after 2 years are shown in TABLE 8.
The relative changes in risk factors associated with obesity following 2 years of therapy were also assessed in the population as a whole and the population with abnormal risk factors at randomization.
Population as a Whole
The relative differences in risk factors between treatment with orlistat and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, LDL/HDL ratio, triglycerides, fasting glucose, fasting insulin, diastolic blood pressure, waist circumference, and hip circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.
Population With Abnormal Risk Factors at Randomization
The relative differences in risk factors between treatment with orlistat and placebo were similar to the results following 1 year of therapy for LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for LDL/HDL ratio and isolated systolic blood pressure were less than that observed in the year one results.

## Four-year Results: Long-term Weight Control and Risk Factors
- In the 4-year double-blind, placebo-controlled XENDOS study, the effects of orlistat in delaying the onset of type 2 diabetes and on body weight were compared to placebo in 3304 obese patients who had either normal or impaired glucose tolerance at baseline. Thirty-four percent of the 1655 patients who were randomized to the placebo group and 52% of the 1649 patients who were randomized to the orlistat group completed the 4-year study.
- At the end of the study, the mean percent weight loss in the placebo group was -2.75% compared with -5.17% in the orlistat group (p<0.001) (see FIGURE 2). Forty-five percent of the placebo patients and 73% of the orlistat patients lost 5% of their baseline body weight, and 21% of the placebo patients and 41% of the orlistat patients lost 10% of their baseline body weight following the first year of treatment. Following 4 years of treatment, 28% of the placebo patients and 45% of the orlistat patients lost 5% of their baseline body weight and 10% of the placebo patients and 21% of the orlistat patients lost 10% of their baseline body weight. After 4 years of treatment, the mean % difference in weight loss between orlistat treated patients and placebo was 2.5%.
- ITT LOCF study population
- The relative changes from baseline in risk factors associated with obesity following 4 years of therapy were assessed in the XENDOS study population (see TABLE 9).
Onset of Type 2 Diabetes in Obese Patients
- In the XENDOS trial, in the overall population, orlistat delayed the onset of type 2 diabetes such that at the end of four years of treatment the cumulative incidence rate of diabetes was 8.3% for the placebo group compared to 5.5% for the orlistat group, p=0.01 (see TABLE 10). This finding was driven by a statistically-significant reduction in the incidence of developing type 2 diabetes in those patients who had impaired glucose tolerance at baseline (TABLE 10 and FIGURE 3). Orlistat did not reduce the risk for the development of diabetes in patients with normal glucose tolerance at baseline.
- The effect of orlistat to delay the onset of type 2 diabetes in obese patients with IGT is presumably due to weight loss, and not to any independent effects of the drug on glucose or insulin metabolism. The effect of orlistat on weight loss is adjunctive to diet and exercise.

## Study of Patients With Type 2 Diabetes
- A 1-year double-blind, placebo-controlled study in type 2 diabetics (N=321) stabilized on sulfonylureas was conducted. Thirty percent of patients treated with XENICAL achieved at least a 5% or greater reduction in body weight from randomization compared to 13% of the placebo-treated patients (p<0.001). TABLE 11 describes the changes over 1 year of treatment with orlistat compared to placebo, in sulfonylurea usage and dose reduction as well as in hemoglobin HbA1c, fasting glucose, and insulin.
- In addition, orlistat (n=162) compared to placebo (n=159) was associated with significant lowering for total cholesterol (-1.0% vs +9.0%, p0.05), LDL-cholesterol (-3.0% vs +10.0%, p0.05), LDL/HDL ratio (-0.26 vs -0.02, p0.05) and triglycerides (+2.54% vs +16.2%, p0.05), respectively. For HDL cholesterol, there was a +6.49% increase on orlistat and +8.6% increase on placebo, p>0.05. Systolic blood pressure increased by +0.61 mm Hg on orlistat and increased by +4.33 mm Hg on placebo, p>0.05. Diastolic blood pressure decreased by -0.47 mm Hg for orlistat and by -0.5 mm Hg for placebo, p>0.05

## Glucose Tolerance in Obese Patients
- Two-year studies that included oral glucose tolerance tests were conducted in obese patients not previously diagnosed or treated for type 2 diabetes and 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 2 years of treatment with orlistat (n=251) or placebo (n=207) were compared. Following treatment with orlistat, 0.0% and 7.2% of the patients progressed from normal to diabetic and normal to impaired, respectively, compared to 1.9% and 12.6% of the placebo treatment group, respectively.
- In patients found to have an impaired OGTT at randomization, the percent of patients improving to normal or deteriorating to diabetic status following 1 and 2 years of treatment with orlistat compared to placebo are presented. After 1 year of treatment, 45.8% of the placebo patients and 73% of the orlistat patients had a normal oral glucose tolerance test while 10.4% of the placebo patients and 2.6% of the orlistat patients became diabetic. After 2 years of treatment, 50% of the placebo patients and 71.7% of the orlistat patients had a normal oral glucose tolerance test while 7.5% of placebo patients were found to be diabetic and 1.7% of orlistat patients were found to be diabetic after treatment.

## Pediatric Clinical Studies
- The effects of orlistat 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 orlistat 120 mg three times a day, 182 receiving placebo), aged 12 to 16 years. All study participants had a baseline BMI that was 2 units greater than the US weighted mean for the 95th percentile based on age and gender. Body mass index was the primary efficacy parameter because 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 orlistat. 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 behavior modification program and offered exercise counseling.
- 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 orlistat-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 in TABLE 12.

# How Supplied
XENICAL is a turquoise, hard-gelatin capsule containing pellets of powder.
Orlistat 120 mg Capsules: Turquoise, two-piece, No. 1 opaque hard-gelatin capsule imprinted with ROCHE and XENICAL 120 in black ink  bottle of 90 (NDC 0004-0257-52).

## Storage
Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) . Keep bottle tightly closed.
Orlistat should not be used after the given expiration date.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

# Precautions with Alcohol
Alcohol-Orlistat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
-rlistat

# Look-Alike Drug Names
There is limited information regarding Orlistat Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price