nimals was observed after treatment with macitentan (see section 5.3). The relevance of this finding to humans is unknown, but a deterioration of spermatogenesis cannot be excluded.
4.7 Effects on ability to drive and use machines
Macitentan may have a minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of macitentan (such as headache, hypotension) should be kept in mind when considering the patient's ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile.
The most commonly reported adverse drug reactions are nasopharyngitis (14.0%), headache (13.6%) and anaemia (13.2%, see section 4.4). The majority of adverse reactions are mild to moderate in intensity.
Tabulated list of adverse reactions
The safety of macitentan has been eva luated in a long-term placebo-controlled trial of 742 patients with symptomatic PAH. The mean treatment duration was 103.9 weeks in the macitentan 10 mg group, and 85.3 weeks in the placebo group. Adverse reactions associated with macitentan obtained from this clinical study are tabulated below.
Frequencies are defined as: 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).
Data derived from pooled placebo-controlled studies.
Description of selected adverse reactions
Hypotension has been associated with the use of ERAs. In a long-term double-blind study in patients with PAH, hypotension was reported for 7.0% and 4.4% of patients on macitentan 10mg and placebo, respectively. This corresponded to 3.5 events/100 patient-years on macitentan 10 mg compared to 2.7 events/100 patient-years on placebo.
*** Oedema/fluid retention has been associated with the use of ERAs. In a long-term double-blind study in patients with PAH, the incidence of oedema AEs in the macitentan 10 mg and placebo treatment groups was 21.9% and 20.5%, respectively. In a double-blind study in patients with idiopathic pulmonary fibrosis, the incidence of peripheral oedema AEs in the macitentan and placebo treatment groups was 11.8% and 6.8%, respectively. In two double-blind clinical studies in patients with digital ulcers associated with systemic sclerosis, the incidences of peripheral oedema AEs ranged from 13.4% to 16.1% in the macitentan 10 mg groups and from 6.2% to 4.5% in the placebo groups.
Laboratory abnormalities
Liver aminotransferases
The incidence of aminotransferase elevations (ALT/AST) > 3 × ULN was 3.4% on macitentan 10 mg and 4.5% on placebo in a double-blind study in patients with PAH. Elevations > 5 × ULN occurred in 2.5% of patients on macitentan 10 mg versus 2% of patients on placebo.
Haemoglobin
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a mean decrease in haemoglobin versus placebo of 1 g/dL. A decrease from baseline in haemoglobin concentration to below 10 g/dL was reported in 8.7% of patients treated with macitentan 10 mg and 3.4% of placebo-treated patients.
White blood cells
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a decrease in mean leucocyte count from baseline of 0.7 × 109/L versus no change in placebo-treated patients.
Platelets
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a decrease in mean platelet count of 17 × 109/L, versus a mean decrease of 11 &time |
