ROCKVILLE, MD. — The postmarketing safety program in place for the pulmonary arterial hypertension drug bosentan resulted in a label change that describes rare cases of cirrhosis in closely monitored patients after prolonged treatment with the drug and reemphasizes the importance of monthly liver function testing in patients.
The changes in the label were announced in a “Dear Healthcare Professional” letter dated March 1, from bosentan manufacturer Actelion Pharmaceuticals US Inc., which describes a case of a female patient who was treated with the recommended dose of bosentan for 21 months. During the second year of treatment, the patient developed worsening liver function tests and eventually, developed liver failure but improved months after stopping the drug.
Bosentan was approved in 2001 for PAH (World Health Organization group I) patients, with WHO Class I or IV symptoms. A required postmarketing surveillance program was in place to monitor patients for liver damage and pregnancies as long as they are on the drug, which can cause liver damage and is teratogenic. Bosentan, an endothelin receptor antagonist marketed as Tracleer by Actelion, was approved in 2001, based on two placebo-controlled studies of 245 patients with PAH, representing 59 patient-years of treatment. The studies found that treatment resulted in improvements in exercise tolerance and delayed clinical worsening. The drug was associated with increased liver aminotransferase levels in 11% of treated subjects, which was reversible when the drug was discontinued.
Speaking at a meeting sponsored by the International Society for Pharmacoepidemiology, Dr. Eleanor Segal, vice president and head, global drug safety for Actelion Pharmaceuticals, South San Francisco, Calif., said that the hepatic risks of the drug were known, because a higher dose of the drug had been developed as an antihypertensive treatment, but was dropped because of the hepatic risks. The drug's benefits were considered higher than its risks for people with PAH, a life-threatening orphan disease, she said. (Bosentan was the first oral treatment approved for treating PAH; other treatments have since been approved.)
The postmarketing risk management program for bosentan in the United States, the Tracleer Access Program (TAP), tracks and reports to the Food and Drug Administration all adverse events related to liver injury in treated patients and the outcomes; prescribing physicians are required to enroll patients in the program, which relies on controlled distribution and patient contact to ensure monthly tests for liver enzyme changes are done.
Specifically, the distributors contact every patient on the drug before shipping their monthly supply, asking them if they have had their monthly liver function tests (LFTs), and, for female patients who are of childbearing potential, if they have had their monthly pregnancy test. If they have not, or can't remember if they were tested, the patients don't get the drug and the distributor contacts the prescribing physician.
The company is also required by the FDA to initiate a safety report for any pregnancy, any elevation in liver enzymes greater than eight times the upper limit of normal, any elevation of liver enzyme that occurred with bilirubin elevation at least two times the ULN, and any clinical liver injury associated with hospitalization, liver transplant, or death. A black box warning about the risk of liver damage and pregnancy is included in the label.
As of April, 31,000 patients had been exposed to the drug, with 21,000 patient-years of experience, Dr. Segal said.
The letter issued by Actelion describes the report of the patient whose LFTs remained near baseline during the first year of treatment on the recommended dosage of bosentan. At about 1 year, her (alanine aminotransferase (ALT) level gradually increased to 2–4 times her baseline level, which remained within normal limits, but 9 months later, she had marked elevations in aminotransferase and bilirubin levels and the drug was stopped. Aspartate aminotransferase (AST) and ALT levels remained high and bilirubin continued to increase. She developed liver failure and biopsy-confirmed cirrhosis, according to the letter, which said that the contribution of bosentan to the development of liver failure “could not be ruled out.”
Eventually, the letter said, the liver failure abated, and LFTs recovered about 7 months after stopping the drug. The patient had had PAH since she was a child, had many comorbidities, and was on various drug treatments when she started bosentan.
“This case underscores the need to continue monthly monitoring for the duration of Tracleer treatment,” the letter says.