Chapter Updates

Content Update for Chapter 27, "Overweight and Obesity"

FDA Approval of OTC Orlistat

The following information updates and supplements text in Chapter 27, “Overweight and Obesity,” in the Handbook of Nonprescription Drugs, 15th Edition.

Orlistat

Orlistat was approved by the Food and Drug Administration (FDA) as a prescription weight loss medication (Xenical) in 1999 and as a nonprescription weight loss medication (alli) in 2007.1 The prescription strength of orlistat is approved for use in patients 12 years of age and older, whereas the nonprescription medication is approved for only those 18 years and older.

GlaxoSmithKline Consumer Healthcare provides free support to those using alli through an individually tailored online plan called myalliplan (www.myalli.com). The alli Starter Pack provides reference guides to help patients follow the program as well as information for joining the online plan.

Mechanism of Action  Orlistat aids in weight loss by decreasing absorption of dietary fats. It inhibits gastric and pancreatic lipases, and specifically reduces absorption of fat by inhibiting hydrolysis of triglycerides.2

Indications  The drug is recommended for use along with a reduced-calorie, low-fat diet, and exercise program. The product labeling for the prescription product states that the drug is indicated for obese patients with a body mass index (BMI) > 30 kg/m2, or for patients with a BMI > 27 kg/m2 who also demonstrate risk factors such as diabetes, hypertension, or dyslipidemia. Interestingly, the labeling for the nonprescription product simply states that the drug is for use in overweight adults, which by the standard definition would be persons with a BMI > 25 kg/m2.

Dosage  Prescription strength orlistat is recommended at a dosage of 120 mg 3 times a day before meals containing fat; at this dosage it inhibits dietary fat absorption by about 30% through inhibition of gastric and pancreatic lipase.2,3 The nonprescription form of the drug is recommended at a dosage of 60 mg 3 times a day before meals containing fat; therefore, its inhibition of fast absorption may be less. Because of its mechanism of action, there is no need to give the drug with a fat-free meal.

Of the plethora of published studies, most have utilized the 120 mg dosage in combination with a reduced-calorie diet and have reported modest weight losses, especially during the first 6 months of therapy. This dosage may also be useful for weight loss maintenance following initial weight loss. In one of the few full-text studies published to date with the 60 mg nonprescription dose, weight loss after 16 weeks in the active drug group was significantly greater than in patients receiving placebo (3.05 kg vs. 1.90 kg; P < 0.001.)4 The nonprescription product labeling notes that most patients lost 5 to 10 pounds (about 2 to 5 kg) over 6 months in clinical trials. Patients receiving orlistat in the this study had significantly greater reductions in low-density lipoprotein (LDL) cholesterol and blood pressure compared with the placebo group. These beneficial effects are consistent with data utilizing the 120 mg dosage; the effects on lipid levels may be independent of weight loss, whereas the changes in blood pressure are probably largely due to weight loss. One-year data, published to date in only abstract form, showed persistent beneficial effects of the 60 mg dosage on weight loss and LDL cholesterol outcomes.5 Orlistat in the 120 mg dosage has been shown to be effective in preventing and delaying development of type 2 diabetes over a 4-year period in patients with impaired glucose tolerance.6

Safety Considerations  Related to its mechanism of action in decreasing fat absorption, orlistat may decrease absorption of fat-soluble vitamins. Therefore, it is recommended that patients taking this medication take a multivitamin once daily at bedtime or separated by at least two hours of an orlistat dose. The adverse effect profile of orlistat is also largely driven by its mechanism of action; the drug is minimally absorbed and therefore exhibits little effect in terms of systemic toxicity. Common gastrointestinal side effects include:

Decreasing the amount of ingested fat can minimize these effects. These side effects are expected to be less common with the nonprescription dosage compared with the prescription dosage, and they generally resolve within a few weeks of initiating therapy.

Drug interactions with orlistat would be predicted to be unlikely because of  the drug’s limited absorption. A theoretical concern exists when a patient is taking both orlistat and warfarin because of the potential for orlistat to decrease vitamin K absorption; close monitoring of the international normalized ratio would be recommended in a patient taking these medications concomitantly. Orlistat therapy should be avoided in patients receiving cyclosporine, as reductions in cyclosporine plasma concentrations have been noted with concomitant administration. Patients with malabsorption disorders should avoid taking orlistat, and patients with a history of thyroid disease, cholelithiasis, nephrolithiasis, or pancreatitis should consult their primary care provider before taking orlistat. In addition, the package label advises patients taking medication to treat diabetes to consult a doctor or pharmacists before using alli.

There has been some concern regarding potential associations between orlistat and development of breast cancer and colon cancer. A petition from Public Citizen in 2006 asked FDA to remove prescription orlistat from the market or to at least consider these associations when deliberating approval of nonprescription orlistat. After consideration of the data, FDA ruled that the preponderance of evidence favored the beneficial effects of orlistat over the potential harm.7

Nonprescription orlistat may be useful as an adjunct to lifestyle changes in helping patients lose modest amounts of weight. Patients should be aware that this is not a “miracle pill,” and that results will be more favorable when this agent is combined with a reduced calorie, low-fat diet and increased physical activity. They should also be aware that the gastrointestinal side effects of the medication are likely to be exacerbated by concomitant ingestion of a low-carbohydrate, high-fat diet.

There is also some concern that this nonprescription agent may be misused, particularly by adolescents; it would be prudent for pharmacists to watch for adolescents purchasing this medication.

References

  1. FDA approval letter for Orlistat NDA 21-887. Rockville, MD: US Food and Drug Administration; February 7, 2007. Available at: http://www.fda.gov/cder/foi/appletter/2007/021887s000ltr.pdf. Accessed June 26, 2007.
  2. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord. 1993;17:241-4.
  3. Orlistat for obesity. Med Lett Drugs Ther. 1999; 41(1055):55-6.     
  4. Anderson JW, Schwartz SM, Hauptman J, et al.     Low-dose orlistat effects on body weight of mildly to moderately overweight individuals: a 16-week, double-blind, placebo-controlled trial. Ann Pharmacother. 2006;40:1717-23.
  5. Low-dose orlistat data show weight loss, improved lipids and blood pressure. Available at: http://www.medscape.com/viewarticle/544285. Accessed June 26, 2007.
  6. Torgerson JS, Hauptman J, Boldrin MN, et al. 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;27:155-61.
  7. Remove from the market, the prescription version of Xenical (Orlistat, Roche Pharmaceuticals). Available at: http://www.fda.gov/ohrms/dockets/dockets/06p0154/06p0154.htm. Accessed June 26, 2007.