"Nov. 9, 2011 -- The FDA is again considering approval of an experimental weight loss drug it rejected a year ago over concerns about potential heart problems and birth defects in babies born to women who take the drug.
Concomitant Drug And Vitamin Use
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 simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 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.
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 betacarotene 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 2 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 2 : Incidence of Low Vitamin Values on Two or
More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline
Values - First and Second Year)
|*Treatment designates placebo plus diet or XENICAL plus diet|
Table 3 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 3 : Incidence of Low Vitamin Values on Two or
More Consecutive Visits (Pediatric Patients With Normal Baseline Values*)
|*All patients were treated with vitamin supplementation
throughout the course of the study
†Treatment designates placebo plus diet or XENICAL plus diet
Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin may be required in some patients [see Clinical Studies].
There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with XENICAL, with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking XENICAL. When these symptoms occur, XENICAL and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.
Increases In Urinary Oxalate
Some patients may develop increased levels of urinary oxalate following treatment with XENICAL. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing XENICAL to patients at risk for renal impairment and use with caution in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
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.
Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing XENICAL. 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.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION)
Information For Patients
Commonly Observed Adverse Events
Patients should be informed of the commonly-observed adverse events associated with the use of XENICAL which include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, fecal incontinence [see ADVERSE REACTIONS].
Potential Risks And Benefits
Patients should be informed of potential risks which include lowered absorption of fat-soluble vitamins and potential liver injury, increases in urinary oxalate, and cholelithiasis [see WARNINGS AND PRECAUTIONS]. Treatment with XENICAL may result in weight loss and improvement in obesity-related risk factors due to weight loss [see Clinical Studies].
Patients should be counseled to take XENICAL as directed with meals or up to one hour after a meal. Patients should also be advised to take multivitamin supplementation at least two hours before or after the administration of XENICAL, or at bedtime [see DOSAGE AND ADMINISTRATION].
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.
Use In Specific Populations
Pregnancy Category X
XENICAL is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.
Reproduction 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.
It is not known if XENICAL is present in human milk. Caution should be exercised when XENICAL is administered to a nursing woman.
Safety and effectiveness in pediatric patients below the age of 12 have not been established.
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 in the 54-week efficacy and safety study (64.8% female, 75% Caucasians, 18.8% Blacks, and 6.3% Other) 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 XENICAL 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 vitamin supplement should be taken at least 2 hours before or after XENICAL [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in XENICAL and placebo treatment groups, respectively.
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 [see Clinical Studies].
Prescribing Document Revised: October 2013This monograph has been modified to include the generic and brand name in many instances.
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