Macitentan
Regulatory sources consulted
Approved indications
- Long-term treatment of pulmonary arterial hypertension in adults in WHO functional class II to III, as monotherapy or in combination.
Contraindications
Absolute
- Pregnancy or females of reproductive potential without effective contraception.
- Hypersensitivity to macitentan or its excipients.
- Breastfeeding, severe hepatic impairment, baseline aminotransferases above 3 times the upper limit of normal, or soy allergy.
Clinical warnings
- Boxed warning · May cause embryo-fetal harm; exclude pregnancy before starting and use effective contraception during treatment and for one month after. — DailyMed label; AEMPS CIMA registro 113893002
- Major warning · Monitor for anemia or decreased hemoglobin, edema or fluid retention, and signs of hepatotoxicity. — AEMPS CIMA registro 113893002
- Major warning · Pulmonary vasodilators may cause pulmonary edema in pulmonary veno-occlusive disease; if it occurs, consider this diagnosis and discontinue macitentan. — AEMPS CIMA registro 113893002
Drug interactions
- ModerateStrong CYP3A4 inhibitors
Mechanism: They may increase macitentan exposure.
Recommendation: Use cautiously and monitor the safety profile closely.
https://cima.aemps.es/cima/dochtml/ft/113893002/FT_113893002.html
- HighStrong CYP3A4 inducers
Mechanism: They reduce exposure and may decrease macitentan efficacy.
Recommendation: Avoid concomitant use.
https://cima.aemps.es/cima/dochtml/ft/113893002/FT_113893002.html
Adverse events
Common (≥1%)
Anemia · Nasopharyngitis · Headache · Edema
Rare but serious
Hepatotoxicity · Severe anemia
Pregnancy and lactation
FDA category: Contraindicado en el embarazo
May cause fetal harm. Use effective contraception; in Spain breastfeeding is contraindicated during treatment.
Recent literature (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.