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Orlistat (Oral-Local)

Primary: HS452

Commonly used brand name(s): Xenical.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.


Lipase inhibitor —



Obesity, exogenous (treatment)—Orlistat is indicated for the management of obesity in persons with an initial body mass index (BMI) ³ 30 kg per square meter of body surface area (kg/m 2), or a BMI ³ 27 kg/m2 when other risk factors (such as hypertension, diabetes, or dyslipidemia) are present. Orlistat should be used in conjunction with a reduced-calorie diet for management of obesity, including weight loss, weight maintenance, and reduction of the risk of weight gain following previous weight loss. Weight loss has been observed within 2 weeks of initiation of orlistat therapy{01}.
—Although the long-term effects of orlistat on morbidity and mortality associated with obesity have not been established, observational epidemiologic studies suggest that weight loss, if maintained, may produce health benefits for obese patients who have or are at risk of developing weight-related comorbidities, including cardiovascular disease, type 2 diabetes, certain forms of cancer, gallstones, and certain respiratory disorders{01}.

Acceptance not established
Although orlistat is used in obese type 2 diabetes patients, there is insufficient data to show that orlistat is beneficial as primary treatment of type 2 diabetes.{04}{05}{06}{07}{08}{09}{10}{11}{12}{13}


Physicochemical characteristics:
Molecular weight—

    Freely soluble in chloroform; very soluble in methanol and ethanol; practically insoluble in water.{01}

Mechanism of action/Effect:

Orlistat is a reversible inhibitor of intestinal lipases. In the lumen of the stomach and intestine, it bonds covalently with active serine residues of gastric and pancreatic lipases, making them unavailable to hydrolyze dietary triglycerides into absorbable fatty acids and monoglycerides. Because undigested triglycerides are not absorbed, a calorie deficit may occur, having a positive effect on weight control. Systemic absorption is minimal and is not needed for activity{01}.

At therapeutic doses, orlistat inhibits dietary fat absorption by approximately 30%{01}.

Other actions/effects:

Postprandial, cholecystokinin plasma concentrations were decreased after multiple doses of orlistat in two studies; however, two other studies have shown no difference from placebo{01}. No clinically significant changes in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reductions of gastric emptying time or gastric acidity were observed{01}. In addition, no effects on plasma triglyceride levels or systemic lipases were observed{01}.

Time to protective effect

Weight loss has been observed within 2 weeks of initiation of therapy{01}.


Systemic absorption of orlistat is minimal{01}.

Protein binding:

Very high (>99%){01}.


Believed to occur mainly within the gastrointestinal wall to form relatively inactive metabolites{01}.


1 to 2 hours{01}.

     Biliary, fecal— 97% (83% as unchanged drug){01}.

Precautions to Consider


Carcinogenicity studies in rats and mice showed no carcinogenic potential for orlistat at doses equivalent to 38 and 46 times the human daily dose calculated on an area under the concentration–time curve (AUC) basis of total drug-related material{01}.


Orlistat showed no detectable mutagenic or genotoxic activity in the Ames test, a mammalian forward mutation assay, an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay in rat hepatocytes in culture, and an in vivo mouse micronucleus test{01}.

There were no observable effects on fertility or reproduction in rats given doses of 400 mg per kg (mg/kg) per day (equivalent to 12 times the human dose on a mg per square meter of body surface area [mg/m 2] basis){01}.

Adequate and well-controlled studies in humans have not been done{01}. Orlistat is not recommended for use during pregnancy{01}

Rats and rabbits given doses up to 800 mg/kg per day showed no embryotoxicity or teratogenicity{01}. This dose is 23 and 47 times the daily human dose calculated on a mg/m 2 basis for rats and rabbits, respectively{01}. The incidence of dilated cerebral ventricles was increased in mid- and high-dose groups (6 and 23 times the daily human dose on a mg/m2 basis) of the rat teratology study{01}. However, this finding was not reproduced in subsequent, similar studies{01}.

FDA Pregnancy Category B{01}.


It is not known whether orlistat is distributed into human breast milk{01}.


Appropriate studies on the relationship of age to the effects of orlistat have not been performed in the pediatric population. Safety and efficacy have not been established{01}.


No information is available on the relationship of age to the effects of orlistat in geriatric patients{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Drug-drug interaction studies indicated that orlistat had no effect on the pharmacokinetics and/or pharmacodynamics of alcohol, digoxin, glyburide, nifedipine (extended-release tablets), oral contraceptives, phenytoin, or warfarin. Alcohol did not affect the pharmacodynamics of orlistat.{01}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Fat-soluble vitamins and analogues    (in a pharmacokinetic interaction study, concomitant administration of orlistat reduced the absorption of a vitamin E acetate supplement by approximately 60% and a beta-carotene supplement by approximately 30%; the effect on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known{01})

Pravastatin    (in a study of hypercholesterolemic subjects, the bioavailability and lipid-lowering effects of pravastatin were increased by coadministration of orlistat.{01})

Cyclosporine    ( preliminary data indicate that cyclosporine plasma concentrations may be reduced when orlistat is co-administered with cyclosporine; therefore, cyclosporine should be taken at least 2 hours before or after orlistat is administered; monitoring frequency of cyclosporine concentrations should be increased in patients on orlistat therapy{01}{03})

» Warfarin    (vitamin K status may be decreased with orlistat; patients on chronic warfarin therapy should be monitored closely for changes in coagulation parameters{01})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Oxalate, urine (increased levels may occur){01}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Chronic malabsorption{01}
» Cholestasis{01}
Risk-benefit should be considered when the following medical problems exist
Anorexia nervosa{01} or
Bulimia{01}    (increased risk of misuse{01})

» History of hyperoxaluria or calcium oxalate nephrolithiasis{01}    (increased risk of nephrolithiasis{01})

Sensitivity to orlistat {01}

Side/Adverse Effects

Note: Side effects caused by orlistat usually disappear within 2 to 3 days of discontinuing the medication {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
Influenza-like symptoms{01} (fever; chills; headache; bodyache)
upper respiratory tract infection{01} (runny nose; nasal congestion ; sneezing; sore throat; cough; fever)

Incidence less frequent
Lower respiratory tract infection{01} (cough; troubled breathing; tightness in chest; wheezing), tooth or gingival disorder{01} (tooth or gum problems)

Incidence rare
infectious diarrhea{01} (contagious diarrhea )
otitis{01} (change in hearing; earache; pain in ear)
urinary tract infection{01} (bloody or cloudy urine; difficult or painful urination; frequent urge to urinate)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Abdominal pain{01}
gastrointestinal symptoms{01}, including
fatty/oily stool{01} (oily bowel movements), fecal incontinence{01} (inability to hold bowel movement), fecal urgency{01} (immediate need to have bowel movement), flatus with discharge{01} (gas with leaky bowel movements), increased defecation{01} (increase in bowel movements), oily evacuation{01} (oily bowel movements), oily spotting{01} (oily spotting of underclothes)

Incidence less frequent
back pain{01}
menstrual irregularities{01} (menstrual changes)
rectal pain or discomfort{01}

Incidence rare
Arthritis{01} (joint pain)
dryness of skin{01}
fatigue{01} (unusual tiredness or weakness)
insomnia (trouble in sleeping)
myalgia{01} (muscle pain)
skin rash{01}

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
Doses of up to 400 mg three times a day for 15 days have produced no significant adverse effects{01}.

Treatment of overdose
Observe for 24 hours. Systemic effects attributable to the lipase-inhibiting properties of orlistat are expected to be rapidly reversible {01}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Orlistat (Oral-Local).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Importance of diet
» Using with a nutritionally balanced, calorie-restricted diet containing no more than 30% of calories as fat

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Not recommended for use during pregnancy

Breast-feeding—Not known if orlistat is excreted in human milk
Other medications, especially warfarin
Other medical problems, especially chronic malabsorption, cholestasis, history of hyperoxaluria or calcium oxalate nephrolithiasis

Proper use of this medication
» Taking with meals or within 1 hour of eating; omitting dose if a meal is missed or contains no fat

Importance of adhering to diet with less than 30% of calories as fat

Taking daily multivitamin supplement (that includes fat-soluble vitamins) at least 2 hours before or after orlistat

» Proper dosing
Skipping missed dose; continuing on regular schedule with next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress of therapy

For patients with diabetes: Improved metabolic control resulting from weight loss may require a reduction in oral hypoglycemic medication or insulin dose

» Medication may cause troublesome gastrointestinal effects, including oily spotting, flatus with discharge, fecal urgency, increased defecation, and fecal incontinence

Side/adverse effects
Signs of potential side effects, especially influenza-like symptoms; upper respiratory infection; lower respiratory infection; tooth or gingival disorder; infectious diarrhea; otitis; and urinary tract infection

General Dosing Information
Organic causes of obesity, such as hypothyroidism, should be excluded before orlistat therapy is started{01}.

Orlistat should be taken during fat-containing meals or up to 1 hour after the meal{01}. Doses in excess of 360 mg per day have not been shown to provide additional benefit{01}.

Weight loss has been observed within 2 weeks of initiation of therapy{01}.

Weight loss induced by orlistat may be accompanied by improved metabolic control in patients with diabetes, requiring reduction of hypoglycemic medication or insulin dose{01}.

Orlistat therapy should be used in conjunction with a nutritionally balanced, reduced-calorie diet that contains no more than 30% of calories as fat{01}. Higher fat levels increase the likelihood of side effects{01}. The daily intake of fat, protein, and carbohydrate should be distributed over three main meals{01}. If a meal is occasionally missed or contains no fat, the dose of orlistat should be omitted{01}.

Because orlistat reduces absorption of some fat-soluble vitamins and beta-carotene, patients should take a daily multivitamin supplement containing fat-soluble vitamins to prevent deficiency. The supplement should be taken at least 2 hours before or after the administration of orlistat{01}.

Oral Dosage Forms:


Usual adult dose
Obesity management
Oral, 120 mg three times a day, with each fat-containing meal{01}. The dose should be taken during fat-containing meals or up to 1 hour after the meal{01}.

Note: Doses in excess of 360 mg a day have not been shown to provide additional benefit{01}.

Usual adult prescribing limits
360 mg a day{01}.

Usual pediatric dose
Safety and efficacy have not been established{01}.

Strength(s) usually available

120 mg (Rx) [Xenical (microcrystalline cellulose ) (sodium starch glycolate) ( sodium lauryl sulfate) (povidone) (talc)]

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15° to 30°C (59° to 86°F). Store in a well-closed container{01}.

Developed: 11/22/1999
Revised: 06-28-02

  1. Xenical package insert (Roche Laboratories—US), Rev 5/99.
  1. Personal communication, Roche—US, 9/29/99.
  1. Manufacturer comment, 10/11/99.
  1. Reviewers' consensus on ballot of 5/2002.
  1. Heymsfield SB, Segal KR, Hauptman J, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med 2000;160:1321-6.
  1. Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 1998;21:1288-94.
  1. Sjostrom L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998;352:167-72.
  1. Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999;281:235-42.
  1. Hauptman J, Lucas C, Boldrin MN, et al. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med 2000;9:160-7.
  1. Miles JM, Aronne LJ, Hollander P, et al. Effect of orlistat in overweight and obese type 2 diabetes patients treated with metformin. Diabetes 2001;50:A442-3.
  1. Bray GA, Pi-Sunyer FX, Hollander P, et al. Effect of orlistat in overweight patients with type 2 diabetes receiving insulin therapy. Diabetes 2001;50:A107.
  1. Deerochanawong C. Effect of treatment with orlistat in overweight or obese Thai patients with type 2 diabetes. Diabetes 2001;50:A433.
  1. Halpern A. Latin-American multicentric study with orlistat in overweight or obese patients with type 2 diabetes. Diabetes 2001;50:A437.