WARNINGS
Miscellaneous
Organic causes of obesity (eg, hypothyroidism) should be excluded before prescribing XENICAL.
Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Therefore, XENICAL and cyclosporine should not be coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 2 hours before or after XENICAL in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered.
PRECAUTIONS
General
Patients should be advised to adhere to dietary guidelines (see DOSAGE AND ADMINISTRATION). Gastrointestinal events (see ADVERSE REACTIONS) may increase when XENICAL 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 XENICAL is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.
Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene (see DOSAGE AND ADMINISTRATION). 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 XENICAL, such as at bedtime.
Table 9 illustrates the percentage of adult patients on XENICAL 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 9 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - First and Second Year) | Placebo
| XENICAL |
|---|
| Vitamin A | 1.0% | 2.2% |
| Vitamin D | 6.6% | 12.0% |
| Vitamin E | 1.0% | 5.8% |
| Beta-carotene | 1.7% | 6.1% |
Table 10 illustrates the percentage of adolescent patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study.
Table 10 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Pediatric Patients With Normal Baseline ValuesAll patients were treated with vitamin supplementation throughout the course of the study) | Placebo
| XENICAL |
|---|
| Vitamin A | 0.0% | 0.0% |
| Vitamin D | 0.7% | 1.4% |
| Vitamin E | 0.0% | 0.0% |
| Beta-carotene | 0.8% | 1.5% |
Some patients may develop increased levels of urinary oxalate following treatment with XENICAL. Caution should be exercised when prescribing XENICAL to patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
Weight-loss induction by XENICAL may be accompanied by improved metabolic control in diabetics, which might require a reduction in dose of oral hypoglycemic medication (eg, sulfonylureas, metformin) or insulin (see CLINICAL STUDIES).
Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of XENICAL for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to XENICAL and 1.8% (30/1655) for patients randomized to placebo. In this trial, the incidence of cholelithiasis was similar for XENICAL and placebo at similar amounts of weight loss. An increase in cholelithiasis with XENICAL was not seen in trials that were not evaluating the prevention of type 2 diabetes.
Misuse Potential
As with any weight-loss agent, the potential exists for misuse of XENICAL in inappropriate patient populations (eg, patients with anorexia nervosa or bulimia). See INDICATIONS AND USAGE for recommended prescribing guidelines.
Information for Patients
Patients should read the Patient Information before starting treatment with XENICAL and each time their prescription is renewed.
Drug Interactions
Alcohol
In a multiple-dose study in 30 normal-weight subjects, coadministration of XENICAL and 40 grams of alcohol (eg, approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat.
Cyclosporine
Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine (see WARNINGS).
Digoxin
In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin.
Fat-soluble Vitamin Supplements and Analogues
A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time.
Glyburide
In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide.
Levothyroxine
Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine postmarketing (see ADVERSE REACTIONS: Other Clinical Studies or Postmarketing Surveillance). Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and orlistat at least 4 hours apart.
Nifedipine (extended-release tablets)
In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets).
Oral Contraceptives
In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives.
Phenytoin
In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin.
Pravastatin
In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin.
Warfarin
In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters.
Carcinogenesis, Mutagenesis, 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 an 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 XENICAL in pregnant women. Because animal reproductive studies are not always predictive of human response, XENICAL is not recommended for use during pregnancy.
Nursing Mothers
It is not known if orlistat is secreted in human milk. Therefore, XENICAL should not be taken by nursing women.
Pediatric Use
The safety and efficacy of XENICAL have been evaluated in obese adolescent patients aged 12 to 16 years. Use of XENICAL in this age group is supported by evidence from adequate and well-controlled studies of XENICAL in adults with additional data from a 54-week efficacy and safety study and a 21-day mineral balance study in obese adolescent patients aged 12 to 16 years. Patients treated with XENICAL had a mean reduction in BMI of 0.55 kg/m2 compared with an average increase of 0.31 kg/m2 in placebo-treated patients (p=0.001). In both adolescent studies, adverse effects were generally similar to those described in adults and included fatty/oily stool, oily spotting, and oily evacuation. In a subgroup of 152 orlistat and 77 placebo patients from the 54-week study, changes in body composition measured by DEXA were similar in both treatment groups with the exception of fat mass, which was significantly reduced in patients treated with XENICAL compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p=0.033). Because XENICAL can interfere with the absorption of fat-soluble vitamins, all patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. The supplementshould be taken at least 2 hours before or after XENICAL (see CLINICAL PHARMACOLOGY: Other Short-term Studies; CLINICAL STUDIES: Pediatric Clinical Studies; ADVERSE REACTIONS: Pediatric Patients). XENICAL has not been studied in pediatric patients below the age of 12 years.
Geriatric Use
Clinical studies of XENICAL did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
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