Orlistat
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Orlistat, sold under the brand name Xenical among others, is a medication used to treat obesity. Its primary function is preventing the absorption of fats from the human diet by acting as a lipase inhibitor, thereby reducing caloric intake. It is intended for use in conjunction with a healthcare provider-supervised reduced-calorie diet.<ref name="Xenical FDA label"/>
Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini.<ref name="OriginalSynth">Template:Cite journal</ref> However, due to its relative simplicity and stability, orlistat was chosen over lipstatin for development as an anti-obesity drug.<ref name="LipstatinSynth">Template:Cite journal</ref>
The effectiveness of orlistat in promoting weight loss is definite but modest. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about Template:Convert more than those not taking the drug over the course of a year.<ref name=Padwal>Template:Cite journal</ref> Orlistat also modestly reduces blood pressure and appears to prevent the onset of type 2 diabetes, whether from the weight loss itself or other effects. It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do.<ref name=BMJ2007>Template:Cite journal</ref>
Benefits aside, however, orlistat is noted for its gastrointestinal side effects (sometimes referred to as treatment effects), which can include steatorrhea (oily, loose stools). They decrease with time, however, and are the most frequently reported adverse effects of the drug.<ref name="Xenical FDA label" /> In Australia, the United States and the European Union, orlistat is available for sale without a prescription.<ref>Template:Cite web</ref> Over-the-counter approval was controversial in the United States, with consumer advocacy group Public Citizen repeatedly opposing it on safety and efficacy grounds.<ref name="WP2" /> Generic formulations of orlistat are available in some countries. In Australia it has been listed as an S3 medication, available from a pharmacist without a prescription, since 2000.<ref name=TGAauth/> Template:TOC limit
Medical uses
Orlistat is used for the treatment of obesity. The amount of weight loss achieved with orlistat varies. In one-year clinical 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.<ref name="Xenical FDA label" /> After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost.<ref name="Xenical FDA label" /> It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do.<ref name=BMJ2007/> Long-term use of orlistat also leads to a very modest reduction in blood pressure (mean reductions of 2.5 and 1.9 mmHg in systolic and diastolic blood pressure respectively).<ref>Template:Cite journal</ref>
Contraindications
Orlistat is contraindicated in:<ref name="Xenical FDA label" />
- Malabsorption
- Hypersensitivity to orlistat
- Reduced gallbladder function (e.g. after cholecystectomy)
- Pregnancy and breastfeeding
- Anorexia and Bulimia
- Use caution with: obstructed bile duct, impaired liver function, and pancreatic disease
Side effects
The primary side effects of the drug are gastrointestinal-related, and include steatorrhea (oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine), fecal incontinence and frequent or urgent bowel movements.<ref>Template:Cite web</ref> 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.<ref name=GSKPressRelease>Template:Cite press release</ref> The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.<ref>From page 12 of the Alli Companion Guide, 2007 edition: "They can be an incentive to keep from eating more fat than you really intend to."</ref>
Side effects are most severe when beginning therapy and may decrease in frequency with time;<ref name="Xenical FDA label" /> It has also been suggested that the decrease in side effects over time may be associated with long-term compliance with a low-fat diet.<ref name=ManciniHalpern2006>Template:Cite journal</ref>
On 26 May 2010, the U.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.<ref>Template:Cite web</ref>
An analysis of over 900 orlistat users in Ontario showed that their rate of acute kidney injury was more than triple that of non-users.<ref>Template:Cite journal</ref>
A study from 2013 looked at 94,695 participants receiving orlistat in the UK between 1999 and 2011.<ref name="pmid 23585064">Template:Cite journal</ref> The study showed no evidence of an increased risk of liver injury during treatment.<ref name="pmid 23585064" /> They concluded:<ref name="pmid 23585064" />
Long-term
Despite a higher incidence of breast cancer amongst those taking orlistat in early, pooled clinical trial data—the analysis of which delayed FDA review of orlistat<ref>Template:Cite news</ref>—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.<ref>Template:Cite journal</ref> There is evidence from an in vitro study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and the monoclonal antibody trastuzumab, can induce cell death in breast cancer cells and block their growth.<ref name="Menendez et al.">Template:Cite journal</ref>
Fecal fat excretion promotes colon 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 carcinogen 1,2-dimethylhydrazine produced significantly higher numbers of aberrant crypt foci (ACF) colon lesions than did the carcinogen plus high-fat chow without orlistat.<ref name="Garcia et al.">Template:Cite journal</ref> ACF lesions are believed to be one of the earliest precursors of colon cancer.<ref>Template:Cite journal</ref>
Precautions
Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat.<ref name="Xenical FDA label" />
Interactions
Orlistat may reduce plasma levels of ciclosporin (also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), an immunosuppressive drug frequently used to prevent transplant rejection; the two drugs should therefore not be administered concomitantly.<ref name="Xenical FDA label" /> Orlistat can also impair absorption of the antiarrhythmic amiodarone.<ref>Template:Cite journal</ref> The Medicines and Healthcare products Regulatory Agency (MHRA) has suggested the possibility that orlistat could reduce the absorption of antiretroviral HIV medications.<ref>Template:Cite web</ref>
The opioid receptor agonist loperamide assists with stool consistency in individuals taking orlistat. Continence problems caused by how orlistat blocks the absorption of fat were found to be improved with loperamide intervention.<ref>Template:Cite journal</ref>
Mechanism of action
Orlistat works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and instead are excreted unchanged. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces.
Orlistat was also found to inhibit 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.<ref>Template:Cite journal</ref> Orlistat also shows potential activity against the Trypanosoma brucei parasite.<ref>Template:Cite journal</ref>
Orlistat prevents approximately 30% of dietary fat from being absorbed.<ref name="PDR">Template:Cite book</ref>
Legal status
Orlistat is available both with and without a prescription.<ref name=BBC /><ref name="Xenical FDA label" /><ref name="Alli FDA label" /><ref>Template:Cite web</ref>
Australia and New Zealand
In Australia and New Zealand, orlistat is available as a "Pharmacist Only Medicine".<ref name=TGAauth>Template:Cite web</ref> In 2007, the Committee decided to keep orlistat as a Schedule 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".<ref name=TGApr>Template:Cite press release</ref>
United States
Orlistat was initially approved by the U.S. Food and Drug Administration in April 1999 as a prescription-only medication.<ref name="Stolberg 1999">Template:Cite web</ref> On 23 January 2006, an FDA advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat, to be sold under the brand name Alli by GlaxoSmithKline.<ref name="WP">Template:Cite news</ref> Approval was granted on 7 February 2007,<ref>Template:Cite press release</ref> and Alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.<ref name="NYT">Template:Cite news</ref> Consumer advocacy organization Public Citizen opposed over-the-counter approval for orlistat.<ref name="WP2">Template:Cite news</ref>
Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.<ref name="WP2" /><ref name="NYT" />
European Union and Switzerland
On 21 January 2009, the European Medicines Agency granted approval for the sale of orlistat without a prescription.<ref name=BBC>Template:Cite news</ref><ref>Template:Cite press release</ref>
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.<ref>http://www.compendium.ch Template:Webarchive, directory of drugs approved in Switzerland</ref>
Generic formulations
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,<ref>Template:Cite web</ref> and expired on 18 June 2009.<ref>"Drug Patent Expirations in June 2009". DrugPatentWatch.com, in Template:Cite web</ref>
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.<ref>Template:Cite news</ref> 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. In the Philippines orlistat is available under the brand name RedoXfat Plus manufactured by ATC Healthcare
Society and culture
Cost
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.<ref>Template:Cite news</ref>
Counterfeit products
In January 2010, the U.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 drug sibutramine. The concentration of sibutramine in these counterfeit products is at least twice the amount recommended for weight loss.<ref>Template:Cite news</ref>
References
Further reading
External links
Template:Antiobesity preparations Template:Cannabinoid receptor modulators Template:Xenobiotic-sensing receptor modulators Template:GlaxoSmithKline Template:Portal bar