Indications: Macitentan is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Macitentan also reduced hospitalization for PAH.
Mechanism: Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of harmful effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells.
Dosing: Macitentan is dosed at 10 mg once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.
Efficacy: The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term, placebo-controlled study in 742 patients with symptomatic [WHO functional class (FC) II-IV] PAH who were randomized to placebo(n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily. The primary study endpoint was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC) prostanoids, or “other worsening of PAH” during double-blind treatment plus 7 days. A critical secondary endpoint was time to PAH death or PAH hospitalization.
The mean patient age was 46 years (14% were age 65 or above). Most patients were white (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively. Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%) and HIV (1%)].
Study results are described for the placebo and OPSUMIT 10 mg groups. Treatment with OPSUMIT 10 mg resulted in a 45% reduction (HR 0.55, 97.5% CI 0.39-0.76; p<0.0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 1 and Figure 1). The beneficial effect of OPSUMIT 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment).
*No patients experienced an event of lung transplantation or atrial septostomy in the placebo or Opsumit 10 mg treatment groups.
PAH-related death or hospitalization for PAH was assessed as a secondary endpoint. The risk of PAH-related death or hospitalization for PAH was reduced by 50% in patients receiving OPSUMIT 10 mg compared to placebo (HR 0.50, 97.5% CI 0.34-0.75; p<0.0001) (Table 2 and Figure 2).
Treatment with OPSUMIT 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97.5% CI 3-41; p=0.0078), with significant improvement in 6MWD by Month 3; 6MWD increased more in patients with worse baseline WHO Functional Class. Treatment with OPSUMIT 10 mg led to an improvement of at least one WHO Functional Class at Month 6.
Adverse Events: Most common adverse reactions (more frequent than placebo by ≥3%) are anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection.
Warnings:
- EMBRYO-FETAL TOXICITY–Do not administer macitentan to a pregnant female because it may cause fetal harm. Females of reproductive potential: exclude pregnancy before start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after treatment by using acceptable methods of contraception. For all female patients, macitentan is available only through a restricted program called the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS).
- Hepatotoxicity–Other ERAs cause hepatotoxicity and liver failure. Obtain baseline liver enzymes and monitor as clinically indicated.
- Decreases in hemoglobin
- Pulmonary edema–in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment.
- Decreases in sperm count have been observed in patients taking ERAs
Contraindications: Pregnancy
Metabolism/Drug interactions: Macitentan is metabolized primarily by CYP3A4 with a minor contribution of CYP2C19.
- Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with macitentan
- Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with macitentan
Access Program: Due to the risk of serious birth defects, Opsumit is only available through a network of certified pharmacies. For information on Opsumit certified pharmacies or wholesale distributors, please call Actelion Pathways™ at 1.866.228.3546.
Female patients must be registered with the Opsumit REMS (Risk Evaluation and Mitigation Strategy Program, a program required by the Food and Drug Administration (FDA) to manage serious risks associated with a drug product. Information on the Opsumit REMS program may be found at http://www.opsumitrems.com/. The Opsumit REMS Program is for females only. Male patients are not required to enroll in the Opsumit REMS Program.
The goals of the Opsumit REMS are:
- To inform prescribers, patients, and pharmacists about the risk of serious birth defects and safe-us conditions for Opsumit
- To minimize the risk of fetal exposure and adverse fetal outcomes in females of reproductive potential prescribed Opsumit:
- a.Females who are pregnant must not be prescribed Opsumit
- b.Females taking Opsumit must not become pregnant
Patient Enrollment form: http://www.opsumitrems.com/pdf/Opsumit-Patient-Enrollment-and-Consent-Form.pdf
Full US Prescribing Information can be found here: http://opsumit.com/splash/pdf/OPSUMIT-Full-Prescribing-Information.pdf
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