Macitentan
Fuentes regulatorias consultadas
Indicaciones aprobadas
- Tratamiento a largo plazo de la hipertensión arterial pulmonar en adultos en clase funcional II a III de la OMS, como monoterapia o en combinación.
Contraindicaciones
Absolutas
- Embarazo o mujeres con potencial reproductivo sin anticoncepción eficaz.
- Hipersensibilidad a macitentán o a sus excipientes.
- Lactancia, insuficiencia hepática grave, aminotransferasas basales superiores a 3 veces el límite superior normal o alergia a la soja.
Advertencias clínicas
- Advertencia destacada (boxed warning) · Puede causar daño embriofetal; excluir embarazo antes de iniciar y utilizar anticoncepción eficaz durante el tratamiento y un mes después. — DailyMed label; AEMPS CIMA registro 113893002
- Advertencia mayor · Vigilar anemia o disminución de hemoglobina, edema o retención de líquidos y signos de hepatotoxicidad. — AEMPS CIMA registro 113893002
- Advertencia mayor · Los vasodilatadores pulmonares pueden causar edema pulmonar en enfermedad venooclusiva pulmonar; si aparece, considerar este diagnóstico y suspender macitentán. — AEMPS CIMA registro 113893002
Interacciones medicamentosas
- ModeradaInhibidores potentes de CYP3A4
Mecanismo: Pueden aumentar la exposición a macitentán.
Recomendación: Usar con precaución y vigilar estrechamente el perfil de seguridad.
https://cima.aemps.es/cima/dochtml/ft/113893002/FT_113893002.html
- SeveraInductores potentes de CYP3A4
Mecanismo: Reducen la exposición y pueden disminuir la eficacia de macitentán.
Recomendación: Evitar el uso concomitante.
https://cima.aemps.es/cima/dochtml/ft/113893002/FT_113893002.html
Eventos adversos
Comunes (≥1%)
Anemia · Nasofaringitis · Cefalea · Edema
Raros pero graves
Hepatotoxicidad · Anemia grave
Embarazo y lactancia
Categoría FDA: Contraindicado en el embarazo
Puede causar daño fetal. Usar anticoncepción eficaz; en España la lactancia está contraindicada durante el tratamiento.
Bibliografía reciente (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.