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 2000 mg and 1,838 patients were treated with placebo. The mean treatment duration was 45 weeks.
5% more than on placebo. 9%). 4). 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. 4) Hepatobiliary disorders Rare Liver cirrhosis, liver failure1 Skin and subcutaneous disorders Common Erythema General disorders and administration site conditions Very common Oedema, fluid retention5 1 Data derived from post-marketing experience, frequencies based on statistical modelling of placebo-controlled clinical trial data.
1% of patients on placebo. 8% of patients on placebo. 4 These types of reactions can also be related to the underlying disease. 9% of patients on placebo. In the post-marketing period rare cases of unexplained hepatic cirrhosis were reported after prolonged therapy with bosentan in patients with multiple co-morbidities and therapies with medicinal products.
There have also been rare reports of liver failure. 4).
Paediatric population Uncontrolled clinical studies in paediatric patients:
The safety profile in the first paediatric uncontrolled study performed with the film- coated tablet (BREATHE-3: n = 19, median age 10 years [range 3–15 years], open- label bosentan 2 mg/kg twice daily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in adult patients with PAH.
In BREATHE-3, the most frequent adverse reactions were flushing (21%), headache, and abnormal liver function test (each 16%). A pooled analysis of uncontrolled paediatric studies conducted in PAH with the bosentan 32 mg dispersible tablet formulation (FUTURE 1/2, FUTURE 3/Extension) included a total of 100 children treated with bosentan 2 mg/kg twice daily (n = 33), 2 mg/kg three times daily (n = 31), or 4 mg/kg twice daily (n = 36).
At enrolment, six patients were between 3 months and 1 year old, 15 children were between 1 and less than 2 years old, and 79 were between 2 and 12 years old. 4–258 weeks). 4 weeks). The most frequent adverse events were upper respiratory tract infections (25%), pulmonary (arterial) hypertension (20%), nasopharyngitis (17%), pyrexia (15%), vomiting (13%), bronchitis (10%), abdominal pain (10%), and diarrhoea (10%).
There was no relevant difference in adverse event frequencies between patients above and below the age of 2 years, however this is based on only 21 children less than 2 years, including 6 patients between 3 months to 1 year of age.
Adverse events of liver abnormalities and anaemia/haemoglobin decrease occurred in 9% and 5% of patients, respectively. In a randomised placebo-controlled study, conducted in PPHN patients (FUTURE-4), a total of 13 neonates were treated with the bosentan dispersible tablet formulation at a dose of 2 mg/kg twice daily (8 patients were on placebo).
5 days). The most frequent adverse events in the bosentan- and placebo-treated patients […]