BOSENTAN

WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risk of hepatotoxicity, bosentan tablets are available only through a restricted program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS). Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.2) ]. Hepatotoxicity In clinical studies, bosentan caused at least 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) ] . In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy with bosentan in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan in these cases could not be excluded. In at least one case, the initial presentation (after >20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of bosentan tablets. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping bosentan with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.4) ] . Elevations in aminotransferases require close attention [see Dosage and Administration (2.4) ] . Bosentan should generally be avoided in patients with elevated aminotransferases (>3xULN) at baseline because monitoring for hepatotoxicity may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥2xULN, treatment with bosentan should be stopped. There is no experience with the reintroduction of bosentan in these circumstances. Embryo-Fetal Toxicity Bosentan is contraindicated for use during pregnancy because it may cause fetal harm if used by pregnant females based on animal data. Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with bosentan tablets. Advise use of effective contraception before initiation, during treatment and for one month after stopping bosentan. When pregnancy is detected, discontinue bosentan as soon as possible [see Dosage and Administration (2.1) , Contraindications (4.1) , Warnings and Precautions (5.3) , Drug Interactions (7.2) , Use in Specific Populations (8.1 , 8.3 )] . WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Bosentan tablets are available only through a restricted distribution program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS) because of the risk of hepatotoxicity ( 5.2 ): Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with bosentan ( 5.1 ). Measure liver aminotransferases prior to initiation of treatment and then monthly ( 2.1 , 5.1 ). Discontinue bosentan if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2xULN ( 2.4 , 5.1 ). Based on animal data, bosentan may cause fetal harm if used during pregnancy ( 4.1 , 5.3 , 8.1) . Females of reproductive potential: Exclude pregnancy before initiating treatment. Use effective contraception prior to initiation of treatment, during treatment and for one month after stopping bosentan ( 2.1 , 4.1 , 5.3 , 8.1 , 8.3 ). When pregnancy is detected, discontinue bosentan as soon as possible ( 5.3 ).

5 WARNINGS AND PRECAUTIONS Fluid retention: May require intervention ( 5.4 ). Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing bosentan ( 5.5 ). Decreased sperm counts ( 5.6 ). Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter ( 5.7 ). 5.1 Hepatotoxicity ALT or AST >3xULN were observed in 11% of bosentan-treated patients (n=658) compared to 2% of placebo-treated patients (n=280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥3xULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. In a pooled analysis of four pediatric studies conducted in PAH (n=100), elevations in liver aminotransferases ≥3×ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3xULN) and increases in total bilirubin (≥2xULN) is a marker for potential serious hepatotoxicity. Elevations of AST or ALT associated with bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with bosentan. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see Dosage and Administration (2.1 , 2.4) ] . Discontinue bosentan if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥2xULN. Avoid initiation of bosentan in patients with elevated aminotransferases (>3xULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning , D osage and Administration (2.6) , Use in Specific Populations (8.6) ] . In WHO Functional Class II patients, consider whether the benefits of bosentan are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses. Bosentan is only available through a restricted program under REMS [see Warnings and Precautions (5.2) ]. 5.2 Bosentan REMS Because of the risks of hepatotoxicity, bosentan tablets are available only through a restricted program called the Bosentan REMS. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning , Warnings and Precautions (5.1) ] . Required components of the Bosentan REMS are: Healthcare professionals who prescribe bosentan tablets must review the prescriber educational materials, enroll in the Bosentan REMS and comply with its requirements. Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly. To receive bosentan tablets, all patients must understand the risks and benefits, and complete a patient enrollment form with their prescriber. Pharmacies that dispense bosentan tablets must enroll in the program and agree to comply with the Bosentan REMS requirements. Further information about bosentan tablets and the Bosentan REMS is available at www.BosentanREMSProgram.com or 1-866-359-2612. 5.3 Embryo-Fetal Toxicity Based on data from animal reproduction studies, bosentan may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of bosentan tablets. Advise females of reproductive potential about the potential risk to a fetus. Exclude pregnancy prior to bosentan treatment. Advise females of reproductive potential to use effective contraception prior to initiation of treatment with bosentan tablets, during treatment, and for at least one month after the last dose. When pregnancy is detected, discontinue bosentan as soon as possible [see Dosage and Administration (2.1) , Contraindications (4.1) , Drug Interactions (7.2) , Use in Specific Populations (8.1 , 8.3) ] . 5.4 Fluid Retention Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of bosentan and other endothelin receptor antagonists. In PAH clinical trials with bosentan, combined adverse events of fluid retention or edema were reported in 1.7% (placebo-corrected) of patients. In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting bosentan. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure. If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as bosentan or underlying heart failure, and the possible need for treatment or discontinuation of bosentan [see Adverse Reactions (6.1) , Clinical Studies (14.2) ] . 5.5 Pulmonary Veno-Occlusive Disease If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether bosentan should be discontinued. 5.6 Decreased Sperm Counts Decreased sperm counts have been observed in patients receiving bosentan. Preclinical data also suggest that bosentan, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions (6.1) , Nonclinical Toxicology (13.1) ] . 5.7 Decreases in Hemoglobin and Hematocrit Treatment with bosentan can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment [see Adverse Reactions (6.1) ] .

4 CONTRAINDICATIONS Pregnancy ( 4.1 ). Use with Cyclosporine A ( 4.2 ). Use with Glyburide ( 4.3 ). Hypersensitivity ( 4.4 ). 4.1 Pregnancy Use of TRACLEER is contraindicated in females who are pregnant [see Boxed Warning , Dosage and Administration (2.1) , Warnings and Precautions (5.3) , Use in Specific Populations (8.1) ] . 4.2 Use with Cyclosporine A Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER and cyclosporine A is contraindicated [see Drug Interactions (7.1) ] . 4.3 Use with Glyburide An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and TRACLEER is contraindicated [see Drug Interactions (7.1) ] . 4.4 Hypersensitivity TRACLEER is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema [see Adverse Reactions (6.2) , Description (11) ] .

10 OVERDOSAGE Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. In the postmarketing period, there was one reported overdose of 10,000 mg of TRACLEER taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support. Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.