Orlistat

Orlistat (marketed under the trade name Xenical by Roche; or over-the-counter as alli^[2] by GlaxoSmithKline (pronounced /ˈælaɪ/, like the English word "ally")—also known as tetrahydrolipstatin—is a drug designed to treat obesity.^[3] Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. It is intended for use in conjunction with a physician-supervised reduced-calorie diet.

Orlistat is the saturated derivative of lipstatin—a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini.^[4] However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.^[5]

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Pharmacology

Orlistat works by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. 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.

At the standard prescription dose of 120 mg three times daily before meals, orlistat prevents approximately 30% of dietary fat from being absorbed,^[6] and about 25% at the standard over-the-counter dose of 60 mg.^[7][8] Higher doses do not produce more potent effects.^[9]

Efficacy

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 mass.^[9] After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost.^[9] Despite this relatively small body mass effect, there was a 37% reduction in the incidence of type 2 diabetes,^[10] a significant difference. This study (XENDOS) proved that the side effect profile of orlistat remained the same up to 4 years. Respondents who lost 5% of their initial body weight in the first three months plus 2.5 gm in the first 4 weeks prior to the study, lost 16.4% of their weight at the end of one year.

Side effects

The primary side effects of the drug are gastrointestinal-related. Side effects are most severe when beginning therapy, and decrease in frequency with time; in clinical trials, nearly half of side effects lasted less than a week, but some may persist for over six months.^[11] Because orlistat's main effect is to prevent dietary fat from being absorbed, the fat is excreted unchanged in the faeces and so the stool may become oily or loose (steatorrhea). Increased flatulence is also common. Bowel movements may become frequent or urgent, and rare occurrences of fecal incontinence have been seen in clinical trials; the manufacturer website of alli recommends to users "[...] Until you have a sense of any treatment effects, it's probably a smart idea to wear dark pants, and bring a change of clothes with you to work".^[12][13] 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,^[14] and it has been suggested that the decrease in side effects over time may be associated to long-term compliance with a low-fat diet.^[15]

Because of this side effect, the US consumer group, Prescription Access Litigation (PAL) awarded its first 2007 Bitter Pill Award to GlaxoSmithKline for alli, the 'With Allies Like This, Who Needs Enemas?' Award.^[16][17]

Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. A multivitamin tablet containing vitamins A, D, E, K, and beta-carotene should be taken once a day, at least 2 hours before or after taking the drug.^[11]

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—,^[18] 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.^[19] 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 actually induce cell death in breast cancer cells and block their growth.^[20]

A 2006 animal study linked orlistat with aberrant crypt foci (ACF), lesions found in the colon which are believed to be one of the earliest precursors of colon cancer.^[21][22]

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.^[11] Orlistat can also impair absorption of the antiarrhythmic amiodarone.^[23]

Contraindications

Orlistat is contraindicated in:^[11]

• Malabsorption
• Hypersensitivity to Orlistat
• Reduced gallbladder function (e.g. after cholecystectomy)
• Pregnancy and breastfeeding
• Use Caution with: Obstructed bile duct, impaired liver function, and pancreatic disease

Availability

In most areas, such as the United Kingdom, France, and Canada, orlistat is available by prescription only. In Australia and the United States, certain formulations of orlistat have been approved for sale without a prescription.

Australia

In Australia, orlistat is currently available over-the-counter in 120 mg size (84 capsules to the pack). Initially available only with a prescription, it was reclassified as a "Pharmacist Only Medicine" in October 2003. In late 2006, the Australian Consumers' Association complained that Roche was inappropriately advertising the drug to teenagers, and Roche was forced to withdraw its ads.^[24] The Association filed further complaints^[24] with the Therapeutic Goods Administration—TGA, Australia's regulatory authority for healthcare products—and the TGA's Scheduling Committee agreed to convene on February 20, 2007, to discuss possible revoking of orlistat's over-the-counter status.^[25] The Committee ultimately 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".^[26] Xenical has recently began being advertised direct-to-customers again.

United States

On January 23, 2006, a U.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 by GlaxoSmithKline.^[27] Approval was granted on February 7, 2007,^[28] and alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.^[29] Consumer advocacy organization Public Citizen, through its Health Research Group, opposed over-the-counter approval for orlistat, calling it "the height of recklessness" and "a dangerous mistake" due to questionable benefits and possible adverse effects.^[30]

Alli became available in the U.S. in June of 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.^[29][30]

Generic formulations

As of 2007, no generic formulations of orlistat are legally available in the United States. U.S. patent protection for Xenical, originally to end on June 18, 2004, was extended by five years (until 2009) by the U.S. Patent and Trademark Office. The extension was granted on July 20, 2002.^[31]

References