Orlistat, sold under the brand nameXenical among others, is a medication used to treatobesity.[2] The effectiveness is modest with people losing about 2–3 kilograms (4.4–6.6 lb) more over the course of a year.[4] It reduces the risk oftype II diabetes in people who are obese similar to lifestyle changes.[5] It is taken by mouth.[2]
Orlistat was approved for medical use in Europe in 1998 and the United States in 1999.[2][6] It is available as ageneric medication.[1] In Australia, Europe, and the United States it is availablewithout a prescription.[7][2][8] In the United Kingdom 4 weeks of treatment costs about £25.[1] In the United States this amount costs about 80 USD.[9]
Medical uses
Orlistat is used for the treatment ofobesity. The amount of weight loss achieved with orlistat varies. In one-yearclinical trials, between 35.5% and 54.8% of subjects achieved a 5% or greater decrease in body mass, although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body fat.[10] After orlistat was stopped, asignificant number of subjects regained weight—up to 35% of the weight they had lost.[10] It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do.[5] Long-term use of orlistat also leads to a very modest reduction inblood pressure (mean reductions of 2.5 and 1.9mmHg insystolic anddiastolic blood pressure respectively).[11]
Dosage
It is taken at a dose of 120 mg three times per day with meals.[2]
The primaryside effects of the drug are gastrointestinal-related, and includesteatorrhea (oily, loose stools with excessiveflatus due to unabsorbed fats reaching the large intestine),fecal incontinence and frequent or urgent bowel movements.[12] To minimize these effects, foods with high fat content should be avoided; the manufacturer advises consumers to follow a low-fat, reduced-calorie diet. Oily stools and flatulence can be controlled by reducing the dietary fat content to somewhere in the region of 15 grams per meal.[13] The manual for Alli makes it clear that orlistat treatment involvesaversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.[14]
Side effects are most severe when beginning therapy and may decrease in frequency with time;[10] It has also been suggested that the decrease in side effects over time may be associated with long-term compliance with alow-fat diet.[15]
On 26 May 2010, theU.S. Food and Drug Administration (FDA) approved a revised label for Xenical to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication.[16]
An analysis of over 900 orlistat users in Ontario showed that their rate ofacute kidney injury was more than triple that of non-users.[17] The putative mechanism for this effect is postulated to be excessiveoxalate absorption from the gut and its subsequent deposition in the kidney, with excessive oxalate absorption being a known consequence of fat malabsorption.
An April 2013 study published in the British Medical Journal[18] looked at 94,695 patients receiving orlistat in the UK between 1999 and 2011. This study showed no evidence of an increased risk of liver injury during treatment. They concluded:
The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug.
Long-term
Despite a higher incidence ofbreast cancer amongst those taking orlistat in early, pooled clinical trial data—the analysis of which delayed FDA review of orlistat[19]—a two-year study published in 1999 found similar rates between orlistat and placebo (0.54% versus 0.51%), and evidence that tumors predated treatment in 3 of the 4 participants who had them.[20] There is evidence from anin vitro study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and themonoclonal antibodytrastuzumab, can inducecell death in breast cancer cells and block their growth.[21]
Fecal fat excretion promotescolon carcinogenesis. In 2006 the results of 30-day study were published indicating that orlistat at a dosage of 200 mg/kg chow administered to rats consuming a high-fat chow and receiving two 25 mg/kg doses of the potent carcinogen1,2-dimethylhydrazine produced significantly higher numbers ofaberrant crypt foci (ACF) colon lesions than did the carcinogen plus high-fat chow without orlistat.[22] ACF lesions are believed to be one of the earliest precursors ofcolon cancer.[23]
Precautions
Absorption offat-solublevitamins and other fat-soluble nutrients is inhibited by the use of orlistat. A multivitamin tablet containing vitaminsA,[24]D,E,K, andbeta-carotene should be taken once a day, at bedtime, when using orlistat.[10]
Interactions
Orlistat may reduce plasma levels ofciclosporin (also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), animmunosuppressive drug frequently used to preventtransplant rejection; the two drugs should therefore not be administered concomitantly.[10] Orlistat can also impair absorption of theantiarrhythmicamiodarone.[25] TheMHRA has recently suggested that Orlistat could theoretically reduce the absorption ofantiretroviralHIV medications.[26]
Orlistat works by inhibiting gastric and pancreaticlipases, theenzymes that break downtriglycerides in theintestine.[28][29] When lipase activity is blocked, triglycerides from the diet are nothydrolyzed into absorbable freefatty acids, and instead are excreted unchanged. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within theGI tract after an oral dose. The primary route of elimination is through thefeces.
Orlistat was also recently found toinhibit the thioesterase domain of fatty acid synthase (FAS), an enzyme involved in the proliferation of cancer cells but not normal cells. However, potential side effects of Orlistat, such as inhibition of other cellular off-targets or poor bioavailability, might hamper its application as an effective antitumor agent. One profiling study undertook a chemical proteomics approach to look for new cellular targets of orlistat, including its off-targets.[30] Orlistat also shows potential activity against theTrypanosoma brucei parasite.[31]
At the standard prescription dose of 120 mg three times daily, before meals, orlistat prevents approximately 30% of dietary fat from being absorbed.[32] Higher doses do not produce more potent effects.[10]
At times, such as in spring 2012, orlistat has come into short supply, with consequent price increases because of nonavailability of one of the drug's components.[35]
Legal status
Packaging of orlistat (Xenical) 120 mg capsules, as sold in Canada
Orlistat has historically been available by prescription only, and this situation continues inCanada. In Australia, theEuropean Union,[8] and the United States, certain formulations of orlistat have been approved for salewithout a prescription.
Australia and New Zealand
In Australia and New Zealand, orlistat has been available as a "Pharmacist Only Medicine since 2000.[36] In 2007 the Committee decided to keep orlistat as aSchedule 3 drug, but withdrew its authorization of direct-to-consumer Xenical advertising, stating this "increased pressure on pharmacists to provide orlistat to consumers...this in turn had the potential to result in inappropriate patterns of use".[37]
United States
On 23 January 2006, aU.S. Food and Drug Administration advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat, to be marketed under the name alli/ˈælaɪ/ byGlaxoSmithKline.[38] Approval was granted on 7 February 2007,[39] and alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.[40]Consumer advocacy organizationPublic Citizen opposed over-the-counter approval for orlistat.[41]
Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.[41][40]
Europe
On 21 January 2009, theEuropean Medicines Agency granted approval for the sale of orlistat without a prescription.[8]
At least since September 2017, tablets with 60 mg Orlistat can be freely sold in Swiss drugstores. Formulations with 120 mg per tablet require a prescription, but can be sold without one in pharmacies under an exemption rule, which is based on a list of easily diagnosable diseases.[42]
Generics
U.S. patent protection for Xenical, originally to end on 18 June 2004, was extended by five years (until 2009) by the U.S.Patent and Trademark Office. The extension was granted on 20 July 2002,[43] and expired on 18 June 2009.[44]
Generic orlistat is available in Iran under the brand Venustat manufactured by Aburaihan Pharmaceutical co., in India, under the brands Orlean (Eris), Vyfat, Olistat, Obelit, Orlica and Reeshape.[45] In Russia, orlistat is available under the brand names Xenical (Hoffmann–La Roche), Orsoten/Orsoten Slim (KRKA d. d.) and Xenalten (OBL-Pharm). In Austria, orlistat is available under the brand name Slimox. In Malaysia, orlistat is available under the brand name Cuvarlix and is marketed by Pharmaniaga.
Counterfeit products
In January 2010, theU.S. Food and Drug Administration issued an alert stating that some counterfeit versions of Alli sold over the Internet contain no orlistat, and instead contain the weight-loss drugsibutramine. The concentration of sibutramine in these counterfeit products is at least twice the amount recommended for weight loss.[46]
↑Zhi J, Melia AT, Eggers H, Joly R, Patel IH (1995). "Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers".J Clin Pharmacol.35 (11):1103–8.doi:10.1002/j.1552-4604.1995.tb04034.x.PMID8626884.S2CID23618845.
↑Siebenhofer, A; Jeitler, K; Horvath, K; Berghold, A; Posch, N; Meschik, J; Semlitsch, T (2 March 2016). "Long-term effects of weight-reducing drugs in people with hypertension".The Cochrane Database of Systematic Reviews.3: CD007654.doi:10.1002/14651858.CD007654.pub4.PMID26934640.
↑Garcia S, da Costa Barros L, Turatti A, Martinello F, Modiano P, Ribeiro-Silva A, de Oliveira Vespúcio M, Uyemura S (2006). "The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen".Cancer Lett.240 (2):221–4.doi:10.1016/j.canlet.2005.09.011.PMID16377080.
↑Takayama T, Katsuki S, Takahashi Y, Ohi M, Nojiri S, Sakamaki S, Kato J, Kogawa K, Miyake H, Niitsu Y (1998). "Aberrant crypt foci of the colon as precursors of adenoma and cancer".N Engl J Med.339 (18):1277–84.doi:10.1056/NEJM199810293391803.PMID9791143.
↑Zhi J, Moore R, Kanitra L, Mulligan TE (2003). "Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers".J Clin Pharmacol.43 (4):428–35.doi:10.1177/0091270003252236.PMID12723464.S2CID24389189.
↑PDB:2PX6;Pemble CW, Johnson LC, Kridel SJ, Lowther WT (August 2007). "Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat".Nat. Struct. Mol. Biol.14 (8):704–9.doi:10.1038/nsmb1265.PMID17618296.S2CID2105534.
↑Barbier P, Schneider F (1987). "Syntheses of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin".Helvetica Chimica Acta.70 (1):196–202.doi:10.1002/hlca.19870700124.
↑Jeanne Whalen (20 April 2012)."Glaxo Sells Bulk of Over-the-Counter Drugs".The Wall Street Journal.Archived from the original on 27 August 2016. Retrieved28 September 2021.Glaxo said the issue wasn't a lack of interested buyers, but manufacturing problems that have led to shortages of the diet pill and forced the company to delay the product's sale.Archived 27 August 2016 at theWayback Machine
↑"Scheduling of orlistat" (Press release). Australian Therapeutic Goods Administration. 22 February 2007. Archived fromthe original on 29 December 2007.
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