Tracleer Linked to Rare Cases of Hepatoxicity

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Yael Waknine

March 2, 2006 — The US Food and Drug Administration (FDA) and Actelion, Inc, reminded healthcare professionals of the continued need for monthly liver function testing in patients receiving bosentan (Tracleer), according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program.

The reminder was based on rare postmarketing reports of hepatotoxicity in bosentan-treated patients. One of these cases occurred in a woman who had been treated for pulmonary arterial hypertension since childhood and was receiving multiple drug therapies for multiple comorbidities.

After approximately 1 year of bosentan therapy at the recommended dose, the patient's alanine aminotransferase (ALT) values gradually doubled and quadrupled from baseline levels but remained within normal limits.

After an additional 9 months of treatment, marked elevations of aminotransferase and bilirubin levels were noted and bosentan was discontinued. However, the patient's ALT and aspartate aminotransferase (AST) levels remained elevated and her bilirubin levels continued to rise.

Upon hospitalization for an intravenous catheter line infection, the patient developed liver failure and biopsy-confirmed cirrhosis that eventually resolved approximately 7 months after discontinuation of bosentan therapy.

The FDA notes that a potential role for the drug in the development liver failure could not be ruled out, underscoring the need to continue monthly liver function testing and make recommended dose adjustments during therapy.

A reduction in dose or interruption of treatment is indicated in patients with confirmed elevation of ALT/AST levels greater than 3 but less than or equal to 5 times the upper limit of normal (ULN). Treatment should be discontinued in patients with ALT/AST levels greater than 5 but less than or equal to 8 times the ULN.

In these patients, ALT/AST levels should be monitored at least every 2 weeks and therapy may be continued or reintroduced upon their return to baseline values.

Permanent discontinuation of therapy is advised in patients with ALT/AST levels 8 times the ULN or greater. The FDA notes that there is no experience with reintroduction of treatment in these circumstances.

Bosentan is indicated for the treatment of pulmonary arterial hypertension in patients with World Health Organization class 3 or 4 symptoms to improve exercise ability and decrease the rate of clinical worsening.

The drug is only available through a risk-management program (Tracleer Access Program), which requires monthly assessments of liver function in all patients and negative pregnancy test results in women of childbearing age.

Healthcare professionals are encouraged to report bosentan-related adverse events to Actelion by calling 1-888-835-5445. Alternatively, this information may be reported to the FDA's MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

Reviewed by Gary D. Vogin, MD


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