ORLISTAT Drug Interactions: What You Need to Know

INTERACTIONS Cyclosporine: Reduction in cyclosporine plasma levels was observed when ORLISTAT was coadministered with cyclosporine. ( 7.1 ) Fat-soluble Vitamin Supplements and Analogues: All patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. ( 7.2 ) Levothyroxine: Patients treated concomitantly with ORLISTAT and levothyroxine should be monitored for changes in thyroid function. ( 7.3 ) Warfarin: Patients on chronic stable doses of warfarin who are prescribed ORLISTAT should be monitored closely for changes in coagulation parameters. ( 7.4 ) Amiodarone: A reduction in exposure to amiodarone was observed when ORLISTAT was co-administered. ( 7.5 )

Antiepileptic

Drugs: Convulsions have been reported in patients taking ORLISTAT with antiepileptic drugs. Patients should be monitored for possible changes in frequency or severity of convulsions. ( 7.6 )

Antiretroviral

Drugs: Loss of virological control has been reported in HIV-infected patients. Patients should be monitored frequently for changes in HIV RNA levels. ( 7.7 )

7.1 Cyclosporine Data from a ORLISTAT and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when ORLISTAT was coadministered with cyclosporine. ORLISTAT and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of ORLISTAT <span class="opacity-50 text-xs">[see Dosage and Administration (2) , and Warnings and Precautions (5.1) ]</span> .

7.2 Fat-soluble Vitamin Supplements and Analogues Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with ORLISTAT. ORLISTAT inhibited absorption of a vitamin E acetate supplement. The effect of ORLISTAT on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) , and Warnings and Precautions (5.1) ]</span> .

7.3 Levothyroxine Hypothyroidism has been reported in patients treated concomitantly with ORLISTAT and levothyroxine postmarketing. Patients treated concomitantly with ORLISTAT and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and ORLISTAT at least 4 hours apart <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> .

7.4 Anticoagulants including Warfarin Vitamin K absorption may be decreased with ORLISTAT. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with ORLISTAT and anticoagulants. Patients on chronic stable doses of warfarin or other anticoagulants who are prescribed ORLISTAT should be monitored closely for changes in coagulation parameters <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.5 Amiodarone A pharmacokinetic study, where amiodarone was orally administered during orlistat treatment, demonstrated a reduction in exposure to amiodarone and its metabolite, desethylamiodarone <span class="opacity-50 text-xs">[see Clinical Pharmocology (12.3) ]</span> . A reduced therapeutic effect of amiodarone is possible. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied.

7.6 Antiepileptic Drugs Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions.

7.7 Antiretroviral Drugs Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with antiretroviral drugs such as atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, and with the combinations lopinavir/ritonavir and emtricitabine/efavirenz/tenofovir disoproxil fumarate. The exact mechanism for this is unclear, but may include a drug-drug interaction that inhibits systemic absorption of the antiretroviral drug. HIV RNA levels should be frequently monitored in patients who take ORLISTAT while being treated for HIV infection. If there is a confirmed increase in HIV viral load, ORLISTAT should be discontinued.

ORLISTAT is contraindicated in: Pregnancy [see Use in Specific Populations (8.1) ] Patients with chronic malabsorption syndrome Patients with cholestasis Patients with known hypersensitivity to ORLISTAT or to any component of this product Pregnancy ( 4 , 8.1 ) Chronic malabsorption syndrome ( 4 ) Cholestasis ( 4 ) Known hypersensitivity to ORLISTAT or to any component of this product ( 4 )

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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2) , and Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> . Gastrointestinal events <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> may increase when ORLISTAT is taken with a diet high in fat (&gt;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.