Macitentan
Sources réglementaires consultées
Indications approuvées
- Traitement au long cours de l hypertension arterielle pulmonaire chez l adulte en classe fonctionnelle OMS II a III, en monotherapie ou en association.
Contre-indications
Absolues
- Grossesse ou femmes en age de procreer sans contraception efficace.
- Hypersensibilite au macitentan ou a ses excipients.
- Allaitement, insuffisance hepatique severe, aminotransferases initiales superieures a 3 fois la limite superieure de la normale ou allergie au soja.
Mises en garde cliniques
- Mise en garde encadrée · Peut causer des dommages embryo-foetaux; exclure une grossesse avant le debut et utiliser une contraception efficace pendant le traitement et un mois apres. — DailyMed label; AEMPS CIMA registro 113893002
- Mise en garde majeure · Surveiller l anemie ou la baisse de l hemoglobine, l oedeme ou la retention hydrique et les signes d hepatotoxicite. — AEMPS CIMA registro 113893002
- Mise en garde majeure · Les vasodilatateurs pulmonaires peuvent provoquer un oedeme pulmonaire en cas de maladie veino-occlusive pulmonaire; s il apparait, envisager ce diagnostic et arreter le macitentan. — AEMPS CIMA registro 113893002
Interactions médicamenteuses
- ModéréeInhibiteurs puissants du CYP3A4
Mécanisme: Ils peuvent augmenter l exposition au macitentan.
Recommandation: Utiliser avec prudence et surveiller etroitement le profil de securite.
https://cima.aemps.es/cima/dochtml/ft/113893002/FT_113893002.html
- SévèreInducteurs puissants du CYP3A4
Mécanisme: Ils reduisent l exposition et peuvent diminuer l efficacite du macitentan.
Recommandation: Eviter l utilisation concomitante.
https://cima.aemps.es/cima/dochtml/ft/113893002/FT_113893002.html
Effets indésirables
Communs (≥1%)
Anemie · Rhinopharyngite · Cefalee · Oedeme
Rares mais graves
Hepatotoxicite · Anemie severe
Grossesse et allaitement
Catégorie FDA: Contraindicado en el embarazo
Peut causer des dommages foetaux. Utiliser une contraception efficace; en Espagne l allaitement est contre-indique pendant le traitement.
Bibliographie récente (PubMed)
Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).
According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities. Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups. Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups.