Orlistat

Orlistat
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Overview

Orlistat is an reversible inhibitor of gastrointestinal lipases that is FDA approved for the treatment of

• Obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet.
• Also indicated to reduce the risk for weight regain after prior weight loss. . Common adverse reactions include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence..

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.
• To reduce the risk for weight regain after prior weight loss.
• 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.

This image is provided by the National Library of Medicine.

Dosing

Parameter	Recommendation
Dose	One 120 mg capsule three times a day
Timing relative to meals	With each main meal containing fat, during or up to 1 hour after the meal
Missed or fat-free meal	Dose may be omitted if a meal is skipped or contains no fat
Maximum labeled benefit	Doses above 120 mg three times daily provide no additional benefit
Background diet	Nutritionally balanced, reduced-calorie diet with ~30% of calories from fat, distributed over three main meals
Multivitamin supplementation	Daily multivitamin containing fat-soluble vitamins (A, D, E, K, beta-carotene), taken ≥2 hours before or after orlistat (e.g., at bedtime)
Cyclosporine co-administration	Administer cyclosporine 3 hours after orlistat; do not co-administer simultaneously
Levothyroxine co-administration	Administer levothyroxine and orlistat ≥4 hours apart; monitor thyroid function
Onset of effect	Fecal fat excretion increases within 24–48 hours of starting therapy
Offset of effect	Fecal fat content returns to pretreatment levels within 48–72 hours of discontinuation
Dosage forms	120 mg capsules only (no other strengths)

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

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Orlistat in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Safety and effectiveness in patients under 12 years of age have not been established.

• In adolescents aged 12–16 years, orlistat has been evaluated using the same 120 mg three-times-daily adult dosing regimen, with the same multivitamin timing instructions.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding off-label guideline-supported use of orlistat in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding off-label non guideline-supported use of orlistat in pediatric patients.

Contraindications

ORLISTAT is contraindicated in:

• Pregnancy
• Patients with chronic malabsorption syndrome
• Patients with cholestasis
• Patients with known hypersensitivity to ORLISTAT or to any component of this product

Warnings

Drug Interactions

• ORLISTAT may interact with concomitant drugs including cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, and antiretroviral drugs.
• 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.

Decreased Vitamin Absorption

• Orlistat reduces absorption of some fat-soluble vitamins and beta-carotene; patients should be strongly encouraged to take a daily multivitamin containing fat-soluble vitamins, taken once a day at least 2 hours before or after orlistat (e.g., at bedtime).
• Vitamin D and beta-carotene levels may be lower in obese patients compared with non-obese subjects, making supplementation particularly important.

Liver Injury

• Rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure have occurred in patients treated with orlistat, with some cases resulting in liver transplant or death.
• Patients should be instructed to report any symptoms of hepatic dysfunction while taking orlistat, including anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain.
• If these symptoms occur, orlistat and other suspect medications should be discontinued immediately, and liver function tests (including ALT and AST levels) should be obtained.

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 those with renal impairment and those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
• Discontinue orlistat in patients who develop oxalate nephropathy.

Cholelithiasis

• Substantial weight loss can increase the risk of cholelithiasis.
• In a clinical trial of orlistat for the prevention of type 2 diabetes, cholelithiasis as an adverse event occurred in 2.9% (47/1649) of patients randomized to orlistat vs. 1.8% (30/1655) of 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% of total daily calories from fat).
• Daily fat intake should be distributed over three main meals; taking orlistat with any single meal very high in fat increases the possibility of gastrointestinal effects.

Adverse Reactions

Clinical Trials Experience

• 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

• Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events and are primarily a manifestation of the mechanism of action.
• The most frequently reported events were oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, and fecal incontinence.
• The first occurrence of these events was generally within 3 months of starting therapy.
• Approximately 50% of all GI adverse event episodes lasted less than 1 week, and a majority lasted 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

• Most common adverse events resulting in discontinuation of treatment were gastrointestinal.

Other Adverse Clinical Events

• Other treatment-emergent adverse events occurring at ≥2% incidence and greater than placebo, across body systems, included abdominal pain/discomfort, nausea, infectious diarrhea, rectal pain/discomfort, tooth disorder, gingival disorder, and vomiting (gastrointestinal); influenza and upper/lower respiratory infection (respiratory); back pain, arthritis, myalgia, joint disorder, and lower-extremity pain (musculoskeletal); headache and dizziness (central nervous system); fatigue and sleep disorder (body as a whole); rash and dry skin (skin); menstrual irregularity and vaginitis (female reproductive); urinary tract infection (urinary); anxiety and depression (psychiatric); otitis (hearing/vestibular); and pedal edema (cardiovascular).
• 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 post-approval 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 increased transaminases, increased alkaline phosphatase, and hepatitis that may be serious have been reported. There have been reports of hepatic failure in postmarketing surveillance, with some cases resulting in liver transplant or death.
• Rare cases of hypersensitivity have been reported, with signs and symptoms including pruritus, rash, urticaria, angioedema, bronchospasm, and anaphylaxis. Very rare cases of bullous eruption have been reported.
• Rare cases of leukocytoclastic vasculitis have been reported, with clinical signs including 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.
• Pancreatitis has been reported in postmarketing surveillance; no causal relationship or physiopathologic 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, but severe or persistent cases should be investigated further.

Drug Interactions

Drug/Class	Interaction	Recommendation
Cyclosporine	Reduces cyclosporine plasma levels	Do not coadminister simultaneously; administer cyclosporine 3 hours after orlistat
Fat-soluble vitamin supplements (beta-carotene, vitamin E)	Reduces absorption of beta-carotene and vitamin E acetate supplements; effect on vitamin D, vitamin A, and vitamin K not known	Separate dosing by ≥2 hours
Levothyroxine	Hypothyroidism reported postmarketing	Administer ≥4 hours apart; monitor thyroid function
Warfarin and other anticoagulants	Decreased vitamin K absorption; decreased prothrombin, increased INR, altered hemostatic parameters reported	Monitor coagulation parameters closely in patients on chronic stable anticoagulant doses
Amiodarone	Reduced systemic exposure to amiodarone and desethylamiodarone	Reduced therapeutic effect possible; not studied in patients on stable amiodarone therapy
Antiepileptic drugs	Convulsions reported	Monitor for changes in seizure frequency/severity
Antiretroviral drugs (e.g., atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir/ritonavir, efavirenz combinations)	Loss of virological control reported in HIV-infected patients	Monitor HIV RNA levels frequently; discontinue orlistat if viral load increase is confirmed

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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.
• Safety and efficacy have been evaluated in obese adolescent patients aged 12 to 16 years, supported by evidence from adequate and well-controlled adult studies plus a 54-week efficacy and safety study and a 21-day mineral balance study in this age group.
• In the 54-week study (64.8% female, 75% Caucasian, 18.8% Black, 6.3% Other), orlistat-treated patients had a mean BMI reduction of 0.55 kg/m² compared with an average increase of 0.31 kg/m² in placebo-treated patients (p=0.001).
• Adverse effects in both adolescent studies were generally similar to those seen in adults, including fatty/oily stool, oily spotting, and oily evacuation.
• In a DEXA substudy (152 orlistat, 77 placebo patients from the 54-week study), body composition changes were similar between groups except for fat mass, which was significantly reduced with orlistat compared with placebo (-2.5 kg vs. -0.6 kg, p=0.033).
• Because orlistat can interfere with absorption of fat-soluble vitamins, all patients should take a daily multivitamin containing vitamins A, D, E, K, and beta-carotene, 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 excretion was 27% of dietary intake in the orlistat group versus 7% in the placebo group.

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.

Race

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

Renal Impairment

• No pharmacokinetic study of orlistat has been conducted specifically in patients with renal impairment.
• Patients with renal impairment are at increased risk for oxalate nephropathy; monitor renal function when prescribing orlistat to these patients, as well as to those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
• Discontinue orlistat if oxalate nephropathy develops.
• Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported with orlistat use.

Hepatic Impairment

Hepatic Impairment

• No pharmacokinetic study of orlistat has been conducted specifically in patients with hepatic impairment.
• Orlistat has been associated with rare postmarketing reports of severe liver injury, including hepatocellular necrosis and acute hepatic failure, some resulting in liver transplant or death, in patients without pre-existing hepatic impairment.
• Patients should be instructed to report symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain); orlistat should be discontinued immediately if these occur, with liver function tests and ALT/AST levels obtained.
• Given the absence of pharmacokinetic data in hepatic impairment and the reported risk of drug-associated liver injury, orlistat should be used with caution in patients with pre-existing 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

• Orlistat is administered orally as a 120 mg capsule.
• Take one capsule three times a day with each main meal containing fat, during the meal or up to 1 hour after the meal.
• If a meal is occasionally missed, or a meal contains no fat, the dose of orlistat can be omitted.
• Distribute daily intake of fat, carbohydrate, and protein over three main meals; taking orlistat with any single meal very high in fat increases the likelihood of gastrointestinal effects.
• Doses above 120 mg three times a day have not been shown to provide additional benefit.
• Administer with a nutritionally balanced, reduced-calorie diet containing approximately 30% of calories from fat.
• Take a daily multivitamin containing fat-soluble vitamins (A, D, E, K, and beta-carotene) at least 2 hours before or after orlistat administration, such as at bedtime.

Monitoring

Note: The FDA label does not mandate a formal monitoring protocol (e.g., required laboratory testing schedule) for orlistat. The following table reflects clinically guided monitoring based on the risks and drug interactions described in the label, rather than FDA-mandated monitoring requirements.

Parameter	Trigger / Population	Monitoring Guidance
Renal function	Patients at increased risk for oxalate nephropathy (renal impairment, history of hyperoxaluria or calcium oxalate nephrolithiasis)	Monitor renal function; discontinue orlistat if oxalate nephropathy develops
Hepatic function	All patients	Instruct patients to report anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain; if these occur, discontinue orlistat immediately and obtain liver function tests, including ALT and AST
Glycemic control	Patients with diabetes mellitus	Monitor for need to reduce dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin as weight loss occurs
Thyroid function	Concomitant levothyroxine use	Monitor for changes in thyroid function
Coagulation parameters	Concomitant warfarin or other anticoagulants (chronic stable dose)	Monitor closely for changes in coagulation parameters
Seizure frequency/severity	Concomitant antiepileptic drug use	Monitor for possible changes in frequency or severity of convulsions
HIV RNA levels	Concomitant antiretroviral therapy in HIV-infected patients	Monitor frequently; discontinue orlistat if a confirmed increase in HIV viral load occurs
Cyclosporine levels	Concomitant cyclosporine use	Consider more frequent monitoring, given reduced cyclosporine plasma levels observed with concomitant orlistat

IV Compatibility

There is limited information regarding IV compatibility of orlistat.

Overdosage

• Single doses of orlistat up to 800 mg, and multiple doses of up to 400 mg three times a day for 15 days, have been studied in normal-weight and obese subjects without significant adverse findings.
• Should a significant orlistat overdose 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, consistent with orlistat's minimal systemic absorption and local mechanism of action in the gastrointestinal tract.

Pharmacology

Orlistat
Systematic (IUPAC) name
(S)-((S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate
Identifiers
CAS number	96829-58-2
ATC code	A08AB01
PubChem	3034010
DrugBank	DB01083
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	495.735 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	Negligible
Protein binding	>99%
Metabolism	In the GI tract
Half life	1 to 2 hours
Excretion	Fecal
Therapeutic considerations
Licence data	EU, US
Pregnancy cat.	B1(AU) X(US)
Legal status	Pharmacist Only (S3)(AU) P(UK) OTC(US)
Routes	Oral

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:

This image is provided by the National Library of Medicine.

• 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.

This image is provided by the National Library of Medicine.

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 µmole/24 hours and 40.4 µmole/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 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 14C-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 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.

This image is provided by the National Library of Medicine.

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.

This image is provided by the National Library of Medicine.

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.

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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%.

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• 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).

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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.

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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.

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• In addition, orlistat (n=162) compared to placebo (n=159) was associated with significant lowering for total cholesterol (-1.0% vs +9.0%, p≤0.05), LDL-cholesterol (-3.0% vs +10.0%, p≤0.05), LDL/HDL ratio (-0.26 vs -0.02, p≤0.05) and triglycerides (+2.54% vs +16.2%, p≤0.05), 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.

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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 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.

Orlistat should not be used after the given expiration date.

Images

Drug Images

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Patient Counseling Information

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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

orlistat

Look-Alike Drug Names

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

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.