CONTRAINDICATIONS
Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis,
and in patients with known hypersensitivity to orlistat or to any component of this
product.
WARNINGS
Miscellaneous: Organic causes of obesity (e.g., hypothyroidism) should be excluded
before prescribing orlistat.
PRECAUTIONS
General
Patients should be advised to adhere to dietary guidelines (see DOSAGE AND
ADMINISTRATION). Gastrointestinal events (see ADVERSE REACTIONS) may
increase when orlistat is taken with a diet high in fat (>30% total daily calories from fat).
The daily intake of fat should be distributed over three main meals. If orlistat is taken with
any one meal very high in fat, the possibility of gastrointestinal effects increases.
Patients should be counseled to take a multivitamin supplement that contains fat-soluble
vitamins to ensure adequate nutrition because orlistat has been shown to reduce the
absorption of some fat-soluble vitamins and beta-carotene. In addition, the levels of
vitamin D and beta-carotene may be low in obese patients compared with non-obese
subjects. The supplement should be taken once a day at least 2 hours before or after the
administration of orlistat, such as at bedtime.
TABLE 6 illustrates the percentage of patients on orlistat and placebo who developed a
low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in
studies in which patients were not previously receiving vitamin supplementation.
TABLE 6 Incidence of Low Vitamin Values on Two or More
Consecutive Visits (Nonsupplemented Patients With Normal Baseline
Values—First and Second Year)
Placebo*
Orlistat*
Vitamin A
1.0%
2.2%
Vitamin D
6.6%
12.0%
Vitamin E
1.0%
5.8%
Beta-carotene
1.7%
6.1%
* Treatment designates placebo plus diet or orlistat plus diet.
Some patients may develop increased levels of urinary oxalate following treatment with
orlistat. Caution should be exercised when prescribing orlistat to patients with a history of
hyperoxaluria or calcium oxalate nephrolithiasis.
Weight-loss induction by orlistat may be accompanied by improved metabolic control in
diabetics, which might require a reduction in dose of oral hypoglycemic medication (e.g.,
sulfonylureas, metformin) or insulin (see CLINICAL STUDIES).
Misuse Potential
As with any weight-loss agent, the potential exists for misuse of orlistat in inappropriate
patient populations (e.g., patients with anorexia nervosa or bulimia). See
INDICATIONS AND USAGE for recommended prescribing guidelines.
Information for the Patient
Patients should read the Patient Information before starting treatment with orlistat and
each time their prescription is renewed.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat
at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats,
these doses are 38 and 46 times the daily human dose calculated on a area under
concentration vs time curve basis of total drug-related material.
Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames
test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay
in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat
hepatocytes in culture, and an in vivo mouse micronucleus test.
When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study,
orlistat had no observable adverse effects. This dose is 12 times the daily human dose
calculated on a body surface area (mg/m2) basis.
Pregnancy, Teratogenic Effects, Pregnancy Category B
Teratogenicity studies were conducted in rats and rabbits at doses up to 800 mg/kg/day.
Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the
daily human dose calculated on a body surface area (mg/m2) basis for rats and rabbits,
respectively.
The incidence of dilated cerebral ventricles was increased in the mid- and high-dose
groups of the rat teratology study. These doses were 6 and 23 times the daily human
dose calculated on a body surface area (mg/m2) basis for the mid- and high-dose levels,
respectively. This finding was not reproduced in two additional rat teratology studies at
similar doses.
There are no adequate and well-controlled studies of orlistat in pregnant women.
Because animal reproductive studies are not always predictive of human response,
orlistat is not recommended for use during pregnancy.
Nursing Mothers
It is not known if orlistat is secreted in human milk. Therefore, orlistat should not be taken
by nursing women.
Pediatric Use
The safety and efficacy of orlistat in pediatric patients have not been established.
Geriatric Use
Clinical studies of orlistat did not include sufficient numbers of patients aged 65 years and
older to determine whether they respond differently from younger patients.