In 20 placebo-controlled studies conducted in various indications, 2486 patients were treated with bosentan at doses ranging from 100 mg to 2000 mg and 1,838 patients were treated with placebo. Treatment fluoxymesterone duration was 45 weeks on average.
The most frequently (at 1% or more receiving bosentan and 0.5% placebo) reported headache (11.5% vs. 9.8%), edema of lower limbs and / or fluid retention (13.2% vs. 10 9%), increased activity of “liver” transaminases aspartate aminotransferase and / or alanine aminotransferase (10.9%) versus 4.6%) and anemia / hemoglobin decrease (9.9% vs. 4.9%).
The use of bosentan is associated with a dose-dependent increase in the activity of “liver” transaminases and decreased hemoglobin.
Adverse reaction reports have been received in the postmarketing phase of the drug are included with the frequency of occurrence of specified during the 20 placebo-controlled studies, and are marked in italics.
Frequency categories do not account for factors such as the duration of the use of bosentan, the data history, initial clinical data. In each group, the side reactions listed in decreasing order of severity.Clinically significant differences in adverse reactions listed in a common database and separately registered indications were observed.
Frequency can not be estimated from the available data. fluoxymesterone reactions were reported in 9.9% of patients who received bosentan, and 9.1% -. Placebo 3 Headache noted 11.5% of patients who received bosentan and 9.8% – placebo. 4 These reactions may be due to the underlying disease. 5 The appearance of peripheral edema and fluid retention observed 13.2% of patients who received bosentan and 10.9% – placebo.
In post-marketing period there have been reports of rare cases of liver cirrhosis of unknown etiology with long-term use in patients with serious underlying medical conditions while applying multiple medications. Also noted rare cases of liver failure function. These cases raise the importance of strict adherence to the monthly monitoring of liver function during the entire treatment period .
The safety profile of the use of bosentan in children (BREATH-3: n = 19, bosentan 2 mg / kg, 2 times / day .; for 12 weeks) did not differ from the corresponding safety profile in adult patients with PAH in the supporting studies. The most frequently observed in children “tides” of blood to the skin of the face (21%), headache, and increased activity of “liver” transaminases (16% for each adverse reaction).
Changes in laboratory parameters
Changes in the activity of “liver” transaminases
In the clinical program, dose-dependent increase in “liver” transaminases were observed for 26 weeks of treatment, developed gradually, usually asymptomatic. In post-marketing period have been reports of rare cases of patients with liver cirrhosis and liver failure function.
The mechanism of occurrence fluoxymesterone of adverse reactions mentioned above is unclear. The activity of “liver” transaminases may spontaneously decrease with continued treatment without modifying or after the reduction, however, discontinuation of treatment or brief interruption in therapy may still be required.
In 20 conducted studies noted increased activity of “liver” transaminases 3 times or more in 11.2% of patients receiving bosentan and 2.4% -platsebo. Increase in 8 or more times the upper limit of normal (ULN) were observed in 3.6% of patients on bosentan and 0.4% – placebo. It is noted that the increase in “liver” transaminases are associated with increased bilirubin plasma levels (of 2 or more times higher than the ULN) patients in the absence of biliary obstruction in 0.2% of cases (5 cases), and receiving bosentan 0 3% of patients (6 patients) – placebo.