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Novel Postmarketing Surveillance System Confirms Bosentan's Safety


 

STOCKHOLM — An Internet-based postmarketing surveillance program has provided reassurance regarding the long-term safety of bosentan (Tracleer) in routine clinical practice for treating various subgroups of pulmonary arterial hypertension.

The experience with this novel Internet-based data collection system has been so favorable that the system deserves broader consideration as a possible new model for widespread postmarketing surveillance—and not just for orphan drugs such as bosentan, the nonselective dual endothelin receptor antagonist that is the only approved oral treatment for pulmonary arterial hypertension (PAH), Dr. Jørn Carlsen said at the annual congress of the European Society of Cardiology.

The program, known as the Tracleer Excellence Post Marketing Surveillance (TRAX PMS), was set up by Actelion Pharmaceuticals in cooperation with the European Agency for the Evaluation of Medicinal Products.

Liver abnormalities were a particular focus of attention in the surveillance program. That's because in the clinical trials that led to bosentan's marketing approval, 12.7% of treated patients developed elevated liver enzyme levels.

Although regulators approved bosentan on the grounds that its demonstrated clinical benefits trumped the safety concerns as they were understood at the time, they also sought additional data about the drug's long-term liver effects.

In less than 2.5 years, the TRAX PMS program enrolled nearly 5,000 patients treated with bosentan in 18 European countries. Mean exposure time was 39 weeks, for a total of more than 3,400 patient-years of follow-up on bosentan. To put the resultant accrued wealth of safety data in context, Dr. Carlson, of the Rigshospitalet, Copenhagen, noted the pivotal trial that led to bosentan's marketing approval featured just 59 patient-years of follow-up. The interactive surveillance program provided prescribing physicians with treatment and safety-monitoring algorithms. The program also collected what Dr. Carlsen termed “safety signals”—data on adverse events, hospitalizations, deaths, and reasons for drug discontinuation.

In the total group of nearly 5,000 treated patients, 7.7% developed liver enzyme levels in excess of three times the upper limit of normal. In the overall PAH population, the risk was greatest during the first 3 months of therapy and declined with time. Half of the affected patients required permanent discontinuation of treatment. Roughly 30 continued to have elevated enzymes after discontinuation; however, there were no cases of fatal or permanent clinical hepatic injury.

Dr. Carlsen presented additional data on liver enzyme elevation rates in three subgroups of patients in TRAX PMS: 5.5% in the 470 patients with chronic thromboembolic pulmonary hypertension (CTEPH); 2.8% in 579 patients with PAH associated with congenital heart disease; and 8.4% in 1,583 with idiopathic PAH.

The mean time on bosentan before liver enzyme abnormalities occurred was 127 days in the CTEPH group. That was longer than in patients with idiopathic or congenital heart disease-associated PAH.

The Internet-based system has been so effective it should be considered for widespread use. DR. CARLSEN

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