Tracleer Adverse Reactions

In 20 placebo-controlled studies, conducted in a variety of therapeutic indications, a total of 2 486 patients were treated with bosentan at daily doses ranging from 100 mg to 2 000 mg and 1 838 patients were treated with placebo. The mean treatment duration was 45 weeks. Adverse reactions were defined as events occurring in at least 1% of patients on bosentan and at a frequency at least 0.5% more than on placebo. The most frequent adverse reactions are headache (11.5%), oedema/fluid retention (13.2%), abnormal liver function test (10.9%) and anaemia/haemoglobin decrease (9.9%).
Treatment with bosentan has been associated with dose-dependent elevations in liver aminotransferases and decreases in haemoglobin concentration (see Precautions).
Adverse reactions observed in 20 placebo-controlled studies and post-marketing experience with bosentan are ranked according to frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. No clinically relevant differences in adverse reactions were observed between the overall dataset and the approved indications. (See Table 3.)

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In the post-marketing period, rare cases of unexplained hepatic cirrhosis were reported after prolonged therapy with Tracleer in patients with multiple co-morbidities and therapies with medicinal products. There have also been rare reports of liver failure. These cases reinforce the importance of strict adherence to the monthly schedule for monitoring of liver function for the duration of treatment with Tracleer (see Precautions).
Laboratory abnormalities: Liver test abnormalitiesIn the clinical programme, dose-dependent elevations in liver aminotransferases generally occurred within the first 26 weeks of treatment, usually developed gradually, and were mainly asymptomatic. In the post-marketing period rare cases of liver cirrhosis and liver failure have been reported.
The mechanism of this adverse effect is unclear. These elevations in aminotransferases may reverse spontaneously while continuing treatment with the maintenance dose of Tracleer or after dose reduction, but interruption or cessation may be necessary (see Precautions).
In the 20 integrated placebo-controlled studies, elevations in liver aminotransferases ≥ 3 x ULN were observed in 11.2% of the bosentan-treated patients as compared to 2.4% of the placebo-treated patients. Elevations to ≥ 8 x ULN were seen in 3.6% of the bosentan-treated patients and 0.4% of the placebo-treated patients. Elevations in aminotransferases were associated with elevated bilirubin (≥ 2 x ULN) without evidence of biliary obstruction in 0.2% (5 patients) on bosentan and 0.3% (6 patients) on placebo.
Haemoglobin: In the adult placebo-controlled studies, a decrease in haemoglobin concentration to below 10 g/dL from baseline was reported in 8.0% of bosentan-treated patients and 3.9% of placebo-treated patients (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the National Centre for Adverse Drug Reactions Monitoring.