Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile.
The most commonly reported adverse reactions are nasopharyngitis (14 %), 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 evaluated in a long-term placebo-controlled trial of 742 patients with symptomatic PAH (SERAPHIN study). 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.
Post-marketing adverse reactions are also included.

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); not known (cannot be estimated from the available data).

System organ class                   Frequency                Adverse reaction Infections and infestations          Very common                Nasopharyngitis Very common                Bronchitis
Common                     Pharyngitis
Common                     Influenza
Common                     Urinary tract infection
Blood and lymphatic system           Very common              Anaemia; haemoglobin disorders                                                     decrease5 P 


Common                   Leukopenia6   P



Opsumit_PI_EUPI update_January-2023
Common                        Thrombocytopenia7        P


Immune system disorders              Uncommon                      Hypersensitivity reactions (e.g., angioedema, pruritus,
rash) 1
P



Nervous system disorders             Very common                   Headache Vascular disorders                   Common                        Hypotension2, flushing P



Respiratory, thoracic and            Common                        Nasal congestion1P   P 

 mediastinal disorders
Hepatobiliary disorders              Common                        Aminotransferase elevations4
General disorders and                Very common                   Oedema, fluid retention3     P 

 administration site conditions
1
P   P           Data derived from pooled placebo-controlled studies.

Description of selected adverse reactions
2 Hypotension
P           P     has been associated with the use of ERAs including Macitentan. In a long-term double-blind study in patients with PAH, hypotension was reported for 7.0% and 4.4% of patients on macitentan 10 mg 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.
3Oedema/fluid
P       P           retention has been associated with the use of ERAs including Macitentan.
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
4Liver
P       P            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.
5Haemoglobin
P       P



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.
6White
P       P             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- P   P


 treated patients.



Opsumit_PI_EUPI update_January-2023
7Platelets
P   P


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 × 109/L in P   P                               P   P


 placebo-treated patients.

Long-term safety
Of the 742 patients who participated in the pivotal SERAPHIN double-blind study, 550 patients entered a long-term open-label (OL) extension study. (The OL cohort included 182 patients who continued on macitentan 10 mg and 368 patients who received placebo or macitentan 3 mg and crossed over to macitentan 10 mg.)

Long-term follow-up of these 550 patients for a median exposure of 3.3 years and a maximum exposure of 10.9 years showed a safety profile that was consistent as described above during the SERAPHIN double-blind phase.

Paediatric population

The safety of macitentan in children and adolescents below 18 years has not yet been S


 established.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form at the following link: https://sideeffects.health.gov.il