The FDA ( U.S. Food and Drug Administration ) has changed labelling for Tracleer ( Bosentan ). The notification underscored the need to continue monthly liver function monitoring ( LFT ) for the duration of Tracleer treatment and the need to adhere to the recommended dosage adjustment and monitoring guidelines described in the product labeling.

The labeling changes are based on rare cases of hepatotoxicity.

In one case, a female patient, treated for pulmonary arterial hupertension since childhood, with multiple co-morbidities and on multiple drug therapies was treated with Tracleer for 21 months at the recommended dosage.
After her first year of treatment, her LFTs ( aminotransferases, alkaline phosphatase, and total bilirubin ) remained near her baseline values, but about one year after starting Tracleer her ALT gradually rose from baseline ( 2-4 x baseline ) but stayed within normal limits.
After another nine months of treatment, marked elevations in aminotransferase and bilirubin levels were noted and Tracleer was discontinued.
After discontinuation of Tracleer, AST and ALT remained elevated and bilirubin continued to rise. In this period, she was hospitalized for an i.v. catheter line infection.
The patient developed liver failure and biopsy-confirmed cirrhosis.
A contribution of Tracleer to the development of liver failure could not be ruled out. Eventually, her liver failure abated and her LFTs recovered about seven months after discontinuation of Tracleer.

This case underscores the need to continue monthly monitoring for the duration of Tracleer treatment.
It also emphasizes the need to adhere to the recommended dosage adjustment and monitoring guidelines.


Dosage adjustment and monitoring in patients developing aminotransferase abnormalities

ALT/AST levels: > 3 and < / = 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.

ALT/AST levels: > 5 and < / = 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.

ALT/AST levels: > 8 x ULN

Treatment should be stopped and re-introduction of Tracleer should not be considered.
There is no experience with re-introduction of Tracleer in these circumstances.


Tracleer received FDA approval on November 20, 2001. Tracleer is the first of a new class of orally active, dual endothelin-receptor antagonists available for the treatment of Pulmonary Arterial Hypertension ( PAH ). Tracleer is indicated for the treatment of PAH patients in the World Health Organization ( WHO ) functional Class III or IV, a life-threatening condition that can severely impair the function of the heart and the lungs.

Tracleer inhibits the activity of endothelin-1 ( ET-1 ) by competitively binding to both ETA and ETB receptors. ET-1 plays an important role in the pathophysiology of PAH by inducing vasoconstriction of the pulmonary arteries and promoting proliferation of the vascular smooth muscle and profibrotic effects of the endothelium. Inhibition of the ET-1 leads to therapeutic effects of decreased pulmonary fibrosis and inflammation, decreased pulmonary vascular hypertrophy and right ventricular hypertrophy, and decreased pulmonary artery pressure.

Source: FDA, 2006


XagenaMedicine2006