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Continuing Education Activity

Orlistat is a medication used in the management of obesity. This activity reviews the indications, action, and contraindications of orlistat as a valuable agent in the treatment of obesity. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the care of patients with obesity.


  • Identify the mechanism of action of orlistat.
  • Describe the adverse effects of orlistat.
  • Outline the appropriate monitoring and toxicity of orlistat.
  • Review interprofessional team strategies for optimizing patient education regarding adverse effects and proper administration of orlistat for maximum efficacy.
Access free multiple choice questions on this topic.


Orlistat (tetrahydrolipstatin) is a United States Food and Drug Administration (FDA) approved anti-obesity medication. It is a saturated derivative of endogenous lipstatin isolated from Streptomyces toxytricini. FDA approved indications of orlistat include: 

  • Patients with obesity with a body mass index (BMI) of over 30 kg/m
  • Patients with a BMI greater than 27 kg/m and presence of risk factors including hypertension, diabetes, and dyslipidemias

The maximum benefit of orlistat occurs when used in conjunction with diet and exercise. The weight starts to decrease within two weeks of initiation of orlistat. Statistically, significant weight loss occurs when orlistat use is for greater than two months.[1] After six months of orlistat use, the mean weight loss is around 5.6 kg compared to 2.4 kg in the placebo group. Orlistat also causes a significant reduction in BMI, waist circumference, total cholesterol, and LDL levels.[2][3] In the XENDOS trial, orlistat has been found to have a statistically significant impact in reducing the incidence of diabetes in patients with impaired glucose tolerance.[4]

Mechanism of Action

Orlistat acts by reversibly inhibiting the gastric and pancreatic lipases. These lipases have an important role in the digestion of dietary fat. They work by breaking down the triglycerides into absorbable free fatty acids and monoglycerides. Orlistat covalently binds to the serine residues of active sites of lipases and inactivates them. The inactivation of lipases prevents the hydrolysis of triglycerides, and thus free fatty acids are not absorbed.[5] The primary action of orlistat is local lipase inhibition within the gut. Systemic absorption is not necessary for the activity of orlistat. At its recommended dosage, it inhibits dietary fat absorption by approximately 30%.


Orlistat is available in the oral tablets 60 mg (over the counter) and 120 mg (prescription product). The recommended orlistat prescription dose is 120 mg capsule orally thrice daily. The administration should be during or within 1 hour after the fat-containing meal. Doses of more than 120 mg have not shown any additional benefit. The recommendation is that the patient adheres to a nutritionally balanced, low-calorie diet with less than 30% calories from fat. If the patient misses the meal, they can omit the dose of orlistat. If the patient misses the dose of orlistat and it has been more than 2 hours past the fat-containing meal, then the patient can skip that dose since, by that time, most of the fat absorption has already occurred, and the medication would not work effectively. Since orlistat reduces the absorption of fat-soluble vitamins, patients should also take multivitamin supplements once daily, but their administration should be at a gap of more than 2 hours after the orlistat administration.[6]

Also, healthcare professionals need to rule out organic causes of obesity like hypothyroidism or Cushing syndrome before initiating orlistat therapy.

Pharmacokinetics [7]

  • Absorption: Orlistat acts mainly via its local effect in the gut, and systemic exposure to the medication is minimal.
  • Distribution: The majority (more than 99%) of the drug is bound to the plasma proteins (lipoproteins and albumin are the major binding proteins).
  • Metabolism: Orlistat metabolism is primarily within the intestinal wall.
  • Elimination: 95 to 97% of the medication is unabsorbed and gets excreted in feces.

Specific Population

  • Pregnancy: Orlistat should not be used in pregnant and breastfeeding mothers. It is a pregnancy category X drug.[8]
  • Pediatric population: No research has established safety and efficacy in the pediatric population. However, orlistat has been found to be safe and effective in adolescent patients with obesity.
  • Renal impairment: Orlistat is safe in patients with renal impairment.
  • Hepatobiliary disease: Orlistat use requires caution in patients with obstructed bile ducts and deranged liver function tests.

Adverse Effects

The side effects of orlistat include the following:

  • Gastrointestinal: The most common side effect of orlistat use is steatorrhea, which occurs because of the impaired absorption of dietary fat. Other side effects include fecal spotting, diarrhea, abdominal pain, and anal fissures. The gastrointestinal adverse effects decrease with ongoing orlistat therapy. These adverse effects can be minimized by following a hypocaloric and low-fat diet with less than 30% of the calories from fats.[9] Rarely, orlistat correlates with cholelithiasis, pancreatitis, and acute cholestatic hepatitis. However, orlistat has been shown to reverse steatosis in patients with non-alcoholic fatty liver disease (NAFLD).[10] Orlistat inhibits the absorption of fat-soluble vitamins and other fat-soluble nutrients. Patients should use a multivitamin tablet containing vitamin A, D, E, K, and beta-carotene once daily.[11]
  • Renal: Orlistat can increase the risk of acute kidney injury; this occurs because the unabsorbed fat binds with calcium in the intestinal lumen resulting in excessive oxalate, which is absorbed and deposited in the kidney leading to oxalate nephropathy and increased risk of renal stones.[12]
  • Musculoskeletal: Theoretically, orlistat can increase the risk of osteoporosis because of impaired absorption of calcium and vitamin D. 
  • Cancer: Animal studies have shown an increased risk of colorectal cancer with orlistat. However, in humans, no such association has been elucidated. Orlistat is known to inhibit the synthesis of fatty acid synthase (Fas) enzyme, which increases tumor growth. In addition, orlistat has been shown to have anti-neoplastic activity in ovarian cancer cells, breast cancer cells, and prostate cancer cells in various animal studies.

Few case reports have illustrated the association of orlistat use with hypertension, diabetic ketoacidosis, depression, cutaneous vasculitis, lichenoid eruptions, and vaginitis. However, a causal relationship between orlistat and these adverse effects remains unproven.

Drug Interactions [9]

  • Antiepileptics: Orlistat can reduce the absorption of lipophilic antiepileptics like lamotrigine, valproate, vigabatrin, and gabapentin, resulting in a decrease in their plasma concentration. In such cases, it is recommended to monitor antiepileptic medication levels.[13]
  • Amiodarone: Orlistat can reduce the absorption of amiodarone.[14]
  • Cyclosporine: Orlistat can also reduce the absorption of cyclosporine (immunosuppressant). Therefore, the recommendation is that the administration of these two medications should be at a gap of at least 2 hours. Also, the cyclosporine levels require monitoring in patients taking the medication along with orlistat.[15][16]
  • Levothyroxine: Orlistat can bind with levothyroxine in the gut and reduce its absorption, leading to decreased plasma concentration of levothyroxine and subsequent hypothyroidism. Thus, clinicians should advise patients to take levothyroxine and orlistat at least 4 hours apart.[17]
  • Warfarin: Using orlistat along with warfarin can result in prolonged prothrombin time and INR because orlistat reduces the absorption of vitamin K. Therefore, coagulation parameters require monitoring in patients taking these two medications together.[18]
  • Antiretroviral medications: Orlistat also reduces the absorption of antiretroviral drugs; monitoring of HIV viral load is necessary. If the HIV viral load increases, orlistat should be discontinued.[19]


Contraindications to orlistat include the following conditions[20][21]:

  • Hypersensitivity to orlistat or its constituents
  • Chronic malabsorption
  • Cholestasis
  • Anorexia and bulimia
  • Pregnancy
  • Severe renal impairment


  • It is necessary to monitor the body weight, body mass index (BMI), waist circumference, and lipid profile in patients taking orlistat.
  • The levels of cyclosporine, antiepileptics and HIV viral load require monitoring when using orlistat in conjunction with these medications.[9]
  • Patients with diabetes might need to adjust the dose of diabetes medicine, as weight loss can affect glycemic control.


There is no specific antidote for orlistat overdose. However, if a significant overdose of orlistat occurs, the patient should immediately come to the emergency department and be observed for 24 hours to provide supportive care.  There is a report of overdose with 5160 mg orlistat in a 28-month-old baby. The patient did not experience any adverse events and was discharged from the emergency room without any concerns.[22]

Enhancing Healthcare Team Outcomes

Obesity and its comorbidities have a significant burden on the healthcare system. Utilizing pharmacotherapy in the form of orlistat can reduce morbidity and mortality from obesity-related complications but should be employed judiciously.

Orlistat effectively lowers body weight, BMI, cholesterol levels, and waist circumference. It has also been shown to cause a modest decrease in blood pressure and improved glycemic control in patients with diabetes. Gastrointestinal adverse effects are the most common reason for discontinuation of the medication. In the proper clinical setting, the drug can be used to achieve weight loss goals and decrease obesity complications.

Clinicians need to be vigilant while prescribing orlistat, especially in patients with diabetes, epilepsy, HIV, and blood coagulation disorder. The clinical nurse is required to assist the medical team in educating the patient on the expected gastrointestinal effects of the drug. A specialized pharmacist is a key to optimizing therapy with this drug. The pharmacist is needed to assist the medical team in adjusting doses or timing of other medications when starting the patient on orlistat therapy to ensure their efficacy is not reduced. The pharmacist must educate the patient on proper dosing, timing, and frequency of therapy to minimize adverse outcomes. Dieticians should be involved in patient care, ensuring the patient has direction on a nutritionally balanced, low-calorie diet. A coordinated and collaborative interprofessional team of clinicians, pharmacists, nurses, physician assistants, and dieticians can improve the efficacy of orlistat therapy and achieve optimal patient results. [Level 5]

Review Questions


Jain SS, Ramanand SJ, Ramanand JB, Akat PB, Patwardhan MH, Joshi SR. Evaluation of efficacy and safety of orlistat in obese patients. Indian J Endocrinol Metab. 2011 Apr;15(2):99-104. [PMC free article: PMC3125014] [PubMed: 21731866]
Hollywood A, Ogden J. Taking Orlistat: Predicting Weight Loss over 6 Months. J Obes. 2011;2011:806896. [PMC free article: PMC2989378] [PubMed: 21113309]
Sjöström L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. 1998 Jul 18;352(9123):167-72. [PubMed: 9683204]
Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004 Jan;27(1):155-61. [PubMed: 14693982]
Guerciolini R. Mode of action of orlistat. Int J Obes Relat Metab Disord. 1997 Jun;21 Suppl 3:S12-23. [PubMed: 9225172]
Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy. 2000 Mar;20(3):270-9. [PMC free article: PMC6145169] [PubMed: 10730683]
McClendon KS, Riche DM, Uwaifo GI. Orlistat: current status in clinical therapeutics. Expert Opin Drug Saf. 2009 Nov;8(6):727-44. [PubMed: 19998527]
Stang J, Huffman LG. Position of the Academy of Nutrition and Dietetics: Obesity, Reproduction, and Pregnancy Outcomes. J Acad Nutr Diet. 2016 Apr;116(4):677-91. [PubMed: 27017177]
Filippatos TD, Derdemezis CS, Gazi IF, Nakou ES, Mikhailidis DP, Elisaf MS. Orlistat-associated adverse effects and drug interactions: a critical review. Drug Saf. 2008;31(1):53-65. [PubMed: 18095746]
Wang H, Wang L, Cheng Y, Xia Z, Liao Y, Cao J. Efficacy of orlistat in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomed Rep. 2018 Jul;9(1):90-96. [PMC free article: PMC6007047] [PubMed: 29930810]
McDuffie JR, Calis KA, Booth SL, Uwaifo GI, Yanovski JA. Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy. 2002 Jul;22(7):814-22. [PubMed: 12126214]
Humayun Y, Ball KC, Lewin JR, Lerant AA, Fülöp T. Acute oxalate nephropathy associated with orlistat. J Nephropathol. 2016 Apr;5(2):79-83. [PMC free article: PMC4844913] [PubMed: 27152294]
Bigham S, McGuigan C, MacDonald BK. Reduced absorption of lipophilic anti-epileptic medications when used concomitantly with the anti-obesity drug orlistat. Epilepsia. 2006 Dec;47(12):2207. [PubMed: 17201727]
Zhi J, Moore R, Kanitra L, Mulligan TE. Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers. J Clin Pharmacol. 2003 Apr;43(4):428-35. [PubMed: 12723464]
Nägele H, Petersen B, Bonacker U, Rödiger W. Effect of orlistat on blood cyclosporin concentration in an obese heart transplant patient. Eur J Clin Pharmacol. 1999 Nov;55(9):667-9. [PubMed: 10638396]
Asberg A. Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients. Drugs. 2003;63(4):367-78. [PubMed: 12558459]
Skelin M, Lucijanić T, Amidžić Klarić D, Rešić A, Bakula M, Liberati-Čizmek AM, Gharib H, Rahelić D. Factors Affecting Gastrointestinal Absorption of Levothyroxine: A Review. Clin Ther. 2017 Feb;39(2):378-403. [PubMed: 28153426]
MacWalter RS, Fraser HW, Armstrong KM. Orlistat enhances warfarin effect. Ann Pharmacother. 2003 Apr;37(4):510-2. [PubMed: 12659605]
Cope RJ, Fischetti BS, Kavanagh RK, Lepa TM, Sorbera MA. Safety and Efficacy of Weight-Loss Pharmacotherapy in Persons Living with HIV: A Review of the Literature and Potential Drug-Drug Interactions with Antiretroviral Therapy. Pharmacotherapy. 2019 Dec;39(12):1204-1215. [PubMed: 31602703]
Saunders KH, Shukla AP, Igel LI, Kumar RB, Aronne LJ. Pharmacotherapy for Obesity. Endocrinol Metab Clin North Am. 2016 Sep;45(3):521-38. [PubMed: 27519128]
MacConnachie AM. Orlistat (Xenical). Intensive Crit Care Nurs. 1999 Oct;15(5):298-9. [PubMed: 10808826]
O'Connor MB. An orlistat "overdose" in a child. Ir J Med Sci. 2010 Jun;179(2):315. [PubMed: 19763670]
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Bookshelf ID: NBK542202PMID: 31194359


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