Risks of Hepatotoxicity and Embryo-Fetal Toxicity
- Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted program called the Tracleer REMS Program. The Tracleer REMS Program is a component of the Tracleer Risk Evaluation and Mitigation Strategy (REMS). Under the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program.
- In clinical studies, Tracleer 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. 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 in patients with multiple comorbidities and drug therapies. There have also been 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 non-specific 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.
- Elevations in aminotransferases require close attention. Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) 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 ? 2 × ULN, treatment with Tracleer should be stopped. There is no experience with the reintroduction of Tracleer in these circumstances.
- Tracleer is likely to cause major birth defects if used by pregnant females based on animal data. Therefore, pregnancy must be excluded before the start of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, 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. Obtain monthly pregnancy tests.
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.
- 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
Approved Risk Evaluation and Mitigation Strategies (REMS)
Patient Counseling Information