Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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. 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 section 4.4).

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.

System organ class                 Frequency                       Adverse reaction Blood and lymphatic system         Common                          Anaemia, haemoglobin disorders                                                          decrease, (see section 4.4) Not known                       Anaemia or haemoglobin decreases requiring red blood cell transfusion1
Uncommon                        Thrombocytopenia1
Uncommon                        Neutropenia, leukopenia1
Immune system disorders            Common                          Hypersensitivity reactions (including dermatitis, pruritus and rash)2
Rare                            Anaphylaxis and/or angioedema1
Nervous system disorders           Very common                     Headache3 
Common                          Syncope1,4
Eye disorders                      Not known                       Blurred vision1 Cardiac disorders                  Common                          Palpitations1,4 Vascular disorders                 Common                          Flushing Common                          Hypotension1,4
Respiratory, thoracic and          Common                          Nasal congestion1 mediastinal disorders
Gastrointestinal disorders         Common                          Gastrooesophageal reflux disease
Diarrhoea
Hepatobiliary disorders            Very common                     Abnormal liver function test, (see section 4.4)
Uncommon                        Aminotransferase elevations associated with hepatitis
(including possible exacerbation of underlying hepatitis) and/or jaundice1
(see section 4.4)
Rare                            Liver cirrhosis, liver failure1
Skin and subcutaneous              Common                          Erythema disorders
General disorders and              Very common                     Oedema, Fluid retention5 administration site conditions
1 Data derived from post-marketing experience, frequencies based on statistical modelling of placebo- controlled clinical trial data.
2 Hypersensitivity reactions were reported in 9.9% of patients on bosentan and 9.1% of patients on
 placebo.
3 Headache was reported in 11.5% of patients on bosentan and 9.8% of patients on placebo.
4 These types of reactions can also be related to the underlying disease.

5Oedema or fluid retention was reported in 13.2% of patients on bosentan and 10.9% of patients on placebo.

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 section 4.4).


Laboratory abnormalities

Liver test abnormalities

In 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 section 4.4).

In the 20 integrated placebo-controlled studies, elevations in liver aminotransferases ≥ 3 x the upper limit of normal (ULN) were observed in 11.2% of the bosentan-treated patients as compared to 2.4% of the placebo-treated patients. Elevations to ≥ 8 × 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 × 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 section 4.4).


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. Side effects can be reported to the Ministry of Health by clicking on the link “Report Side Effects of Drug Treatment” found on the Ministry of Health homepage (www.health.gov.il ) that directs you to the online form for reporting side effects, or by entering the link: https://sideeffects.health.gov.il/