Class: GI Drugs, Miscellaneous
VA Class: GA900
Chemical Name: [2S-[2α(R*),3β]]-1-[(3-hexyl-4-oxo-2-oxetanyl)-methyl]dodecyl-N-formyl-lLeucine
Molecular Formula: C29H53O5
CAS Number: 96829-58-2
Brands: Xenical
Special Alerts:
[Posted 05/26/2010] FDA notified healthcare professionals and patients that it has approved a revised label for orlistat (Xenical) to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication. The agency is also adding a new warning about rare reports of severe liver injury to the OTC Drug Facts label for orlistat (Alli).
Xenical and Alli are medications used for weight-loss that contain different strengths of the same active ingredient, orlistat. Orlistat 120 mg (Xenical) is available by prescription and orlistat 60 mg (Alli) is sold over-the-counter without a prescription. This new safety information, originally announced in August 2009, is based on FDA’s completed review of orlistat.
Healthcare professionals should weigh the benefits of weight-loss with the potential risks associated with orlistat before prescribing or recommending these medications to their patients; patients should stop use of orlistat and contact their healthcare professional if they develop the signs and symptoms of liver injury, including itching, yellow eyes or skin, dark urine, light-colored stools, or loss of appetite. For more information visit the FDA website at: and .
FDA notified healthcare professionals and patients that it is reviewing new safety information regarding reports of liver-related adverse events in patients taking orlistat (Xenical, Alli). Orlistat is marketed in the United States as a prescription product, Xenical, and as an over-the-counter (OTC) product, Alli. Between 1999 and October 2008, 32 reports of serious liver injury, including 6 cases of liver failure, in patients using orlistat were submitted to FDA’s Adverse Event Reporting System. The most commonly reported adverse events described in the 32 reports of serious liver injury were jaundice, weakness, and abdominal pain. FDA is reviewing other data on suspected cases of liver injury submitted by the manufacturers of orlistat, analysis of these data is ongoing and no definite association between liver injury and orlistat has been established at this time. FDA is not advising healthcare professionals to change their prescribing practices with orlistat. Consumers currently taking Xenical should continue to take it as prescribed and those using over-the-counter Alli should continue to use the product as directed.
FDA urges both healthcare professionals and consumers to report side effects from the use of orlistat (Alli and Xenical) to FDA’s MedWatch Adverse Event Reporting program at: . For more information visit the FDA website at: and .
Introduction
Reversible inhibitor of gastric and pancreatic lipases;1 2 4 5 6 8 9 10 11 12 13 14 18 19 21 22 exhibits antiobesity1 6 7 8 17 23 36 and antilipemic activity.1 3 4 5 6 7 8 20 36
Uses for Orlistat
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Obesity
Adjunct to caloric restriction, increased physical activity, and behavioral modification in the treatment of exogenous obesity; also used to reduce the risk of weight regain after initial loss.1 6 7 8 15 17 27 36
Use in patients with initial body mass index (BMI) of ≥30 kg/m2; also use in those with BMI of ≥27 kg/m2 in the presence of risk factor or disease (e.g., hypertension, diabetes mellitus, hyperlipidemia).1 15 27
Orlistat Dosage and Administration
Administration
Oral Administration
Administer orally 3 times daily, during (or up to 1 hour after) each main meal containing fat.1 8 19 20 23 27 However, efficacy apparently not affected by administering the drug up to 2 hours after midmeal.19 20
Omit orlistat dose if a meal occasionally is missed or contains no fat.1 27
Distribute daily fat (30% of calories), carbohydrate, and protein intake evenly over 3 main meals;1 27 administration of orlisatat with any one very high-fat meal increases potential for adverse GI effects.a
Manufacturer recommends use of vitamin supplement containing fat-soluble vitamins.1 Administer multivitamin ≥2 hours before or after orlistat; administer vitamin supplement at bedtime for convenience.1 8 27 37 (See Vitamin Supplementation under Cautions.)
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Adults
Obesity
Oral
120 mg 3 times daily with each main meal containing fat.1 6 7 8 17 23 27 36 No additional benefit with dosages >120 mg 3 times daily.1 23
Reassess weight management and therapy periodically.1 7 27 Safety and efficacy beyond 2 years not established in clinical studies.1 7 27 However, if effective for weight loss or maintenance and no serious adverse effects occur, may continue orlistat as long as clinically indicated.17
Cautions for Orlistat
Contraindications
Chronic malabsorption syndrome or cholestasis.1 27
Known hypersensitivity to orlistat or any ingredient in the formulation.1 27
Warnings/Precautions
Warnings
Obesity Evaluation
Rule out organic causes of obesity (e.g., hypothyroidism) before initiating orlistat therapy.1
Cyclosporine Interaction
Do not administer concomitantly with cyclosporine; administer cyclosporine 2 hours before or after orlistat.a (See Specific Drugs under Interactions.)
General Precautions
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Hyperoxaluria
Possible increased concentrations of urinary oxalate.a Caution in patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.1
Misuse Potential
Avoid use in inappropriate patient populations (e.g., those with anorexia nervosa or bulimia).1
Diabetes Mellitus
Weight loss may improve glycemic control; dose reductions or discontinuance of concomitant antidiabetic therapy (e.g., insulin, sulfonylureas, metformin) may be necessary.1 17 27
Dietary Guidelines
Adherence to dietary recommendations minimizes adverse GI effects related to fat intake, as well as contributing to weight loss.1 27
Vitamin Supplementation
Fat-soluble vitamin deficiency is unlikely but possible (see Specific Drugs under Interactions).7 8 17 25 26 27 Manufacturer considers routine (once daily) supplementation with fat-soluble vitamins (A,D, E, K) a prudent precaution (see Oral Administration under Dosage and Administration).1 27 37
Specific Populations
Pregnancy
Category B; use not recommended.1 27
Lactation
Not known whether orlistat is distributed into milk; use not recommended.1 27
Pediatric Use
Safety and efficacy not established in children <18 years of age.1 37
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1
Common Adverse Effects
Oily spotting,1 7 8 flatus with discharge,1 7 8 fecal urgency,1 7 8 fatty/oily stool,1 7 8 oily evacuation,1 8 increased defecation,1 7 8 fecal incontinence.1 7 8
Interactions for Orlistat
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
Alcohol | Interaction unlikely1 35 | |
Antidiabetic agents | Potential for improved glycemic control;1 17 29 glyburide pharmacokinetics and hypoglycemic effect unchanged in studya | Antidiabetic dosage reduction may be necessary1 17 29 |
Antilipemic agents | Possible additive antilipemic effects;1 pravastatin pharmacokinetics unaffecteda | |
Contraceptives, oral | Interaction unlikely1 33 | |
Cyclosporine | Decreased plasma cyclosporine concentrations1 27 | Administer cyclosporine ≥2 hours before or after orlistat; consider more frequent monitoring of cyclosporine concentrationsa |
Digoxin | Interaction unlikely1 30 | |
Nifedipine | Interaction unlikely with nifedipine extended-release tablets1 31 32 | |
Phenytoin | Interaction unlikely1 34 | |
Warfarin | Potential for reduced vitamin K absorption1 28 | Closely monitor coagulation parametersa |
Vitamins, fat-soluble (A, D, E, K) | Concentrations of fat-soluble vitamins decreased but remained within normal range in most individuals;7 8 17 25 26 36 30% decrease in β-carotene and 60% decrease in vitamin E acetate absorption;a effect on vitamins D, A, and nutritionally derived K unknowna | Supplementation needed only occasionally in clinical studies;7 8 17 25 26 36 however, manufacturer strongly recommends supplementation with fat-soluble vitaminsa |
Orlistat Pharmacokinetics
Absorption
Bioavailability
Systemic absorption of orlistat is minimal.1 6 21 22
Distribution
Plasma Protein Binding
>99% in vitro (lipoproteins and albumin).a
Elimination
Metabolism
Metabolized principally in intestinal wall to clinically unimportant metabolites.a
Elimination Route
Excreted principally in the feces (97%), mainly as unchanged drug (about 80%).1 6 21 22 a
Stability
Storage
Oral
Capsules
Tight containers at 25°C (may be exposed to 15–30°C).a
ActionsActions
Decreases intestinal lumen absorption of dietary fat (triacylglycerol) by reversibly inhibiting gastric and pancreatic lipase-mediated triglyceride hydrolysis,1 2 4 6 12 18 19 20 21 22 thereby decreasing intestinal concentrations of absorbable free fatty acids and monoglycerides.1 4 6 12
About one-third of dietary fat will not be absorbed at recommended dosages.1 6 12 18 19 20
Decreases concentrations of LDL1 3 4 5 6 7 8 20 36 and total1 4 5 6 7 8 20 36 cholesterol; variable effects on serum triglycerides1 3 4 5 6 7 20 and HDL cholesterol.3 4 6 7
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Provide patient a copy of manufacturer’s patient information.1 27
Importance of adherence to clinician’s dietary and, if applicable, exercise recommendations.1 15 17
Importance of distributing daily fat (30% of total daily calories), carbohydrate, and protein intake evenly over 3 main meals.1 27
Importance of omitting orlistat dose if meal contains no fat or is skipped.1 27
Importance of informing clinicians of any consistent problems absorbing food (chronic malabsorption), gallbladder problems, anorexia, or bulimia.27
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary supplements (including herbal preparations), particularly cyclosporine.27
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 27
Importance of informing patients of other precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 120 mg | Xenical (with povidone) | Roche |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Xenical 120MG Capsules (GENENTECH): 10/$53.99 or 20/$94.97
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Roche Laboratories Inc. Xenical (orlistat) capsules prescribing information. Nutley, NJ; 1999 May.
2. Hauptman JB, Jeunet FS, Hartmann D. Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18-0647 (tetrahydrolipstatin). Am J Clin Nutr. 1992; 55(Suppl):309S-13. [IDIS 290482] [PubMed 1728845]
3. Reitsma JB, Castro Cabezas M, de Bruin TW et al. Relationship between improved postprandial lipemia and low-density lipoprotein metabolism during treatment with tetrahydrolipstatin, a pancreatic lipase inhibitor. Metabolism. 1994; 43:293-8. [PubMed 8139476]
4. Tonstad S, Pometta D. Erkelens DW et al. The effect of the gastrointestinal lipase inhibitor, orlistat, on serum lipids and lipoproteins in patients with primary hyperlipidaemia. Eur J Clin Pharmacol. 1994; 46:405-10. [IDIS 333312] [PubMed 7957533]
5. Zavoral JH. Treatment with orlistat reduces cardiovascular risk in obese patients. J Hypertens. 1998; 16(12 Part 2):2013-7. [PubMed 9886891]
6. McNeely W, Benfield P. Orlistat. Drugs. 1998; 56:241-9. [PubMed 9711448]
7. Sjöström L, Rissanen A, Andersen T et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet. 1998; 352:167-72. [IDIS 407969] [PubMed 9683204]
8. Davidson MH, Hauptman J, DiGirolamo M et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. JAMA. 1999; 281:235-42. [IDIS 417495] [PubMed 9918478]
9. Borgstrom B. Mode of action of tetrahydrolipstatin: a derivative of the naturally occurring lipase inhibitor lipstatin. Biochim Biophys Acta. 1988; 962:308-16. [PubMed 3167082]
10. Hadvary P, Lengsfeld H, Wolfer H. Inhibition of pancreatic lipase in vitro by the covalent inhibitor tetrahydrolipstatin. Biochem J. 1988; 256:357-61. [PubMed 3223916]
11. Hadvary P, Sidler W, Meister W et al. The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase. J Biol Chem. 1991; 266:2021-7. [PubMed 1899234]
12. Guerciolini R. Mode of action of orlistat. Int J Obes Relat Metab Disord. 1997; 21(Suppl 3):12S-3.
13. Lookene A, Skottova N, Olivercrona G. Interactions of lipoprotein lipase with the active-site inhibitor tetrahydrolipstatin (Orlistat). Eur J Biochem. 1994; 222:395-403. [PubMed 8020477]
14. Pottoff AP, Haalck L, Spener F. Inhibition of lipases from Chromobacterium viscosum and Rhizopus oryzae by tetrahydrolipstatin. J Mass Spectrom. 1997; 32:739-49. [PubMed 9241856]
15. National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. 1998 Jun.
16. Froelich F, Hartmann D, Guezelhan C et al. Influence of orlistat on the regulation of gallbladder contraction in man: a randomized double-blind placebo-controlled crossover study. Dig Dis Sci. 1996; 41:2404-8. [IDIS 379327] [PubMed 9011450]
17. 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. [IDIS 411429] [PubMed 9702435]
18. Zhi J, Melia AT, Guerciolini MD et al. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther. 1994; 56:82-5. [IDIS 334194] [PubMed 8033498]
19. Hussain Y, Güzelham C, Odink J et al. Comparison of the inhibition of dietary fat absorption by full versus divided doses of orlistat. J Clin Pharmacol. 1994; 34:1121-5. [IDIS 339101] [PubMed 7876405]
20. Hartmann D, Hussain Y, Güzelhan C et al. Effect on dietary fat absorption of orlistat, adminstered at different times relative to meal intake. Br J Clin Pharmacol. 1993; 36:266-70. [IDIS 325097] [PubMed 9114915]
21. Zhi J, Melia AT, Funk C et al. Metabolic profiles of minimally absorbed orlistat in obese/overweight volunteers. J Clin Pharmacol. 1996; 36:1006-11. [IDIS 377092] [PubMed 8973989]
22. Zhi J, Melia AT, Eggers H et al. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol. 1995; 35:1103-8. [IDIS 356610] [PubMed 8626884]
23. Van Gaal LF, Broom JI, Enzi G et al et al. Efficacy and tolerability of orlistat in the treatment of obesity: a 6-month dose-ranging study. Eur J Clin Pharmacol. 1998; 54:125-32. [IDIS 405779] [PubMed 9626916]
24. Güzelhan C, Odink J, Niestijl Jansen-Zuidema JJ et al. Influence of dietary composition on the inhibition of fat absorption by orlistat. J Int Med Res. 1994; 22:255-65. [PubMed 7867870]
25. Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol. 1996; 36:647-53. [IDIS 370479] [PubMed 8844448]
26. Zhi J, Melia AT, Koss-Twardy SG et al. The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of β-carotene in healthy volunteers. J Clin Pharmacol. 1996; 36:152-9. [IDIS 364805] [PubMed 8852391]
27. Roche Laboratories Inc. Xenical (orlistat) capsules patient information. Nutley, NJ; 1999 April.
28. Zhi J, Melia AT, Guerciolini R et al. The effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol. 1996; 36:659-6. [IDIS 370481] [PubMed 8844450]
29. Zhi J, Melia AT, Koss-Twardy SG et al. The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. J Clin Pharmacol. 1995; 35:521-5. [IDIS 347823] [PubMed 7657854]
30. Melia AT, Zhi J, Koss-Twardy SG et al. The influence of reduced dietary fat absorption induced by orlistat on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol. 1995; 35:840-3. [IDIS 352910] [PubMed 8522642]
31. Melia AT, Mulligan TE, Zhi J. Lack of effect of orlistat on the bioavailability of a single dose of nifedipine extended-release tablets (Procardia XL) in healthy volunteers. J Clin Pharmacol. 1995; 35:840-3. [IDIS 352910] [PubMed 8522642]
32. Weber C, Tam YK, Schmidtke-Schrezenmeier G et al. Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antihypertensive drugs in healthy volunteers. Eur J Clin Pharmacol. 1996; 51:87-90. [IDIS 373196] [PubMed 8880057]
33. Hartmann D, Gzelhan C, Zuiderwijk PBM et al. Lack of interaction between orlistat and oral contraceptives. Eur J Clin Pharmacol. 1996; 50:421-4. [IDIS 370219] [PubMed 8839667]
34. Melia AT, Mulligan TE, Zhi J. The effect of orlistat on the pharmacokinetics of phenytoin in healthy volunteers. J Clin Pharmacol. 1996; 36:654-8. [IDIS 370480] [PubMed 8844449]
35. Melia AT, Zhi J, Zelasko R et al. The interaction of the lipase inhibitor orlistat with ethanol in healthy volunteers. Eur J Clin Pharmacol. 1998; 54:773-7. [IDIS 417963] [PubMed 9923583]
36. James WP, Avenell A, Broom J et al. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord. 1997; 21(Suppl 3):S24-30. [PubMed 9225173]
37. Roche Laboratories Inc, Nutley, NJ: Personal communication.
a. Roche Laboratories Inc. Xenical (orlistat) capsules prescribing information. Nutley, NJ; 2003 Dec.
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