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WARNING

RISKS OF LIVER INJURY and TERATOGENICITY

Because of the risk of liver injury and birth defects, Tracleer (bosentan) is available only through a special restricted distribution program called the Tracleer (bosentan) Access Program (T.A.P.), by calling 1 866 228 3546. Only prescribers and pharmacies registered with T.A.P. may prescribe and distribute Tracleer (bosentan) . In addition, Tracleer (bosentan) may be dispensed only to patients who are enrolled in and meet all conditions of T.A.P. [see WARNINGS AND PRECAUTIONS].

Liver Injury

In clinical studies, Tracleer (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 liver injury, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged ( > 12 months) therapy with Tracleer (bosentan) in patients with multiple co-morbidities and drug therapies. There have also been reports of liver failure. The contribution of Tracleer (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 Tracleer (bosentan) . 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 Tracleer (bosentan) with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see DOSAGE AND ADMINISTRATION].

Elevations in aminotransferases require close attention [see DOSAGE AND ADMINISTRATION]. Tracleer (bosentan) should generally be avoided in patients with elevated aminotransferases ( > 3 x ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment with Tracleer (bosentan) should be stopped. There is no experience with the re-introduction of Tracleer (bosentan) in these circumstances.

Teratogenicity

Tracleer (bosentan) is likely to cause major birth defects if used by pregnant females based on animal data [see CONTRAINDICATIONS]. Therefore, pregnancy must be excluded before the start of treatment with Tracleer (bosentan) . Throughout treatment and for one month after stopping Tracleer (bosentan) , females of childbearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving Tracleer [see DRUG INTERACTIONS]. Monthly pregnancy tests should be obtained.