Hepatotoxicity

• Causes 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 WARNINGS: Potential Liver Injury and DOSAGE AND ADMINISTRATION). In the post-marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with TRACLEER® in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of TRACLEER® 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 nonspecific symptoms, all of which resolved slowly over time after discontinuation of TRACLEER®. 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® 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® 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 should be stopped. There is no experience with the re-introduction of TRACLEER® in these circumstances.

Teratogenecity:  Contraindicated in Pregnancy

• Use is contraindicated in pregnancy
• TRACLEER® (bosentan) is very likely to produce major birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals (see CONTRAINDICATIONS). Therefore, pregnancy must be excluded before the start of treatment with TRACLEER® and prevented thereafter by the use of a reliable method of contraception. 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 Precautions: Drug Interactions). Therefore, effective contraception through additional forms of contraception must be practiced. Monthly pregnancy tests should be obtained.

Tracleer Access Program

• Because of potential liver injury and in an effort to make the chance of fetal exposure to TRACLEER® (bosentan) as small as possible, TRACLEER® may be prescribed only through the TRACLEER® Access Program by calling 1 866 228 3546. Adverse events can also be reported directly via this number.
• Limited Distribution/Access Program

MONITORING RECOMMENDATIONS RELATED TO BLACK BOX DATA

• Avoid use in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring liver injury may be more difficult.

  Dosage Adjusment and Monitoring in Patients Developing Aminotransferase Abnormalities:
  ALT/AST Levels Treatment and Monitoring Recommendations

• > 3 and equal to or less than 5 x ULN: Confirm by another aminotransferase test; if confirmed, reduce the daily dose or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pre-treatment values, continue or re-introduce the treatment as appropriate (see below).
• > 5 and equal to or less than 8 x ULN: Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pre-treatment values, consider re-introduction of the treatment (see below).
• > 8 x ULN: Treatment should be stopped and re-introduction of TRACLEER@ should not be considered. There is no experience with re-introduction ofTRACLEER@ in these circumstances.

Pregnancy

• Exclude pregnancy prior to initiation of therapy. Negative urine/serum pregnancy test performed during first 5 days of normal menstrual period and > 11 days after the last unprotected act of sexual intercourse. Follow-up serum pregnancy tests should be obtained monthly in women of child bearing potential.
• Hormonal contraception may not be reliable due to a drug interaction and should not be used as sole contraceptive

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Tracleer (bosentan) Tablets (PDF - 1000KB)

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Tracleer

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Patient Medication Guide

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Bosentan