warnings and cautions
5 WARNINGS AND PRECAUTIONS ORLISTAT has drug interactions and can decrease vitamin absorption. ( 5.1 , 7 ) Take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition. ( 5.1 ) Rare cases of severe liver injury with hepatocellular necrosis or acute hepatic failure have been reported. ( 5.2 ) Patients may develop oxalate nephrolithiasis and oxalate nephropathy following treatment with ORLISTAT. Monitor renal function in patients at risk for renal insufficiency. Discontinue ORLISTAT if oxalate nephropathy develops. ( 5.3 ) Substantial weight loss can increase the risk of cholelithiasis. ( 5.4 ) Exclude organic causes of obesity (eg, hypothyroidism) before prescribing ORLISTAT. ( 5.5 ) Gastrointestinal events may increase when ORLISTAT is taken with a diet high in fat (>30% total daily calories from fat). ( 5.5 ) 5.1 Drug Interactions and Decreased Vitamin Absorption ORLISTAT may interact with concomitant drugs including cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, and antiretroviral drugs [see Drug Interactions (7) ]. Data from a ORLISTAT and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when ORLISTAT was coadministered with cyclosporine. Therefore, ORLISTAT 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 ORLISTAT 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 ORLISTAT has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene [see Dosage and Administration (2) , and Adverse Reactions (6.1) ] . 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. 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 (14) ] . 5.2 Liver Injury There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with ORLISTAT, 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 ORLISTAT. When these symptoms occur, ORLISTAT and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained. 5.3 Oxalate Nephrolithiasis and Oxalate Nephropathy with Renal Failure Some patients may develop increased levels of urinary oxalate following treatment with ORLISTAT. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing ORLISTAT to patients at increased risk for oxalate nephropathy, including patients with renal impairment and in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis. Discontinue ORLISTAT in patients who develop oxalate nephropathy. 5.4 Cholelithiasis Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of ORLISTAT for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to ORLISTAT and 1.8% (30/1655) for patients randomized to placebo. 5.5 Miscellaneous Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing ORLISTAT. Patients should be advised to adhere to dietary guidelines [see Dosage and Administration (2) ] . Gastrointestinal events [see Adverse Reactions (6.1) ] 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.