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Newly Approved: Macitentan (Opsumit®)

By: Rebecca Gilene, PharmD Candidate c/o 2014, St. Louis College of Pharmacy

The FDA approved macitentan (Opsumit®) on October 18, 2013 for the treatment of pulmonary arterial hypertension.1 Pulmonary arterial hypertension, often referred to as PAH, is a disease characterized by high blood pressure in the arteries between the heart and lungs. An increase in peripheral vascular resistance of these arteries places a strain on the right side of the heart, requiring it to pump with greater contractile force. Typically, PAH is idiopathic, meaning there is no known cause. However, genetic factors, heart disease, human immunodeficiency virus (HIV), and illicit substance abuse may contribute to this disorder. PAH currently affects over 50,000 patients in the US, with a mortality rate around 15% after one year.2

Typical symptoms of PAH include fatigue, shortness of breath, exercise intolerance, and chest pain. Patients are evaluated based on a six-minute walking distance as well as their World Health Organization (WHO) functional class to determine their risk and prognosis. The six-minute walking distance measures the distance a patient can walk in six minutes- better prognosis is associated with lengths greater than 400 meters. WHO functional classes are based on the extent to which PAH limits a patient’s physical activity. A patient’s ability to perform daily activities are ranked from I-IV, with class IV exhibiting poor prognosis.2 Because PAH is a chronic disease, symptoms may worsen over time if untreated. PAH may progress and necessitate lung transplantation, or even lead to death.2 Although there is no cure, the goal of therapy is to normalize blood pressure. The mainstays of PAH treatment include endothelin-receptor antagonists (ERA), calcium channel blockers (CCB), and phosphodiesterase-5 inhibitors (PDEI).

CCBs are typically used as first-line treatment; usual agents include non-dihydropyridine diltiazem (Cartia®) as well as dihydropyridines amlodipine (Norvasc®) and nifedipine (Procardia®).  However, some patients may not respond to this therapy. Patients in most WHO functional classes who are unresponsive to CCBs are started on an ERA or PDEI. Examples of PDEIs are sildenafil (Revatio®) or tadalafil (Adcirca®). Third line treatment for patients with progressing disease on these agents is prostanoids, such as epoprostenol (Flolan®, Veletri®), treprostinil (Remodulin®, Tyvaso®), or iloprost (Ventavis®).

Macitentan belongs to the ERA class along with ambrisentan (Letairis®) and bosentan (Tracleer®). These agents work to decrease constriction of the pulmonary arteries by blocking endothelin receptor A, located on smooth muscle cells, and endothelin receptor B, located on vascular endothelium. Ambrisentan selectively works on the endothelin A receptor, whereas bosentan and macitentan work on both A and B receptors.3 Bosentan has more supporting data compared to macitentan, has been approved for pediatric use, and has been studied in combination with a PDEI. However, macitentan, a derivative of bosentan, is being studied for use in both ischemic digital ulcers as well as glioblastoma.4

The results of a multicenter, double-blind, randomized, placebo-controlled, event-driven study evaluating safety and efficacy showed favorability of macitentan. In this study, 741 adult patients, primarily in WHO classes II and III, were randomly assigned to one of three groups: 3mg of macitentan, 10mg of macitentan, or placebo. Macitentan had a statistically significant decrease in occurrence of worsening disease compared to the placebo group. Worsening disease was defined as death, lung transplantation, necessity of treatment with intravenous or subcutaneous prostanoids, and/or worsening of PAH symptoms. The incidence of worsening disease occurred in 46.4% of patients in the placebo group compared to only 38% of patients in the 3mg group and 31.4% of patients in the 10mg group (hazard ratio for 3mg vs. placebo 0.70, p = 0.01; hazard ratio for 10mg vs. placebo 0.55, p < 0.1). Both macitentan groups also showed a reduction in death and hospitalizations.5

Secondary endpoints of six minute walking distance and WHO functional class after six months of treatment showed a slowing of progression with macitentan. Some adverse events experienced by both of the macitentan groups included headache, nasopharyngitis, and anemia.  Compared to the patients receiving 3mg of mactitentan, the patients in the 10mg group did not have more frequent side effects. Overall, these adverse events caused 12.4% of patients in the placebo group, 13.6% of patients in the 3mg group, and 10.7% of patients in the 10mg group to discontinue therapy.3,5

Similar to other ERAs, macitentan is classified as pregnancy category X, due to its teratogenic effects. Therefore, the Risk Evaluation and Mitigation Strategy (REMS) Program must be employed for all women taking this drug. Additionally, pharmacies must be authorized to dispense macitentan in compliance with this program. Other potential side effects with this medication include spermatogenesis impairment, sore throat, liver dysfunction, and increased risk for infections such as bronchitis, influenza, and urinary tract infections.1,4

The study that led to the approval of macitentan was evaluated over a period of two years, so lengthier studies are needed to assess potential long-term effects. Additionally, Actelion Pharmaceuticals, the same company that markets both macitentan and bosentan, funded the study. There may be a major conflict of interest, considering that bosentan loses its patent protection in a couple years.6 Therefore, despite the approval of macitentan, it is yet to be determined where this drug fits in the PAH algorithm.  Further studies comparing this new drug to current standards of care, utilizing it in combination therapy, and evaluating its uses in other patient populations are warranted to truly identify the role of macitentan in treatment of pulmonary arterial hypertension.


  1. FDA approves Opsumit to treat pulmonary arterial hypertension.  US Food and Drug Administration  Published October 18th, 2013.  Accessed October 25, 2013.
  2. Moote R, Attridge RL, Levine DJ. Chapter 35. Pulmonary Arterial Hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey M, eds. Pharmacotherapy: A Pathophysiological Approach. 8th ed. China: McGraw-Hill Companies, Inc; 2011. AccessPharmacy Web site. Available at:
  3. SERAPHIN: Novel PAH drug reduced morbidity, mortality rates.  Cardiology Today  Published August 28th, 2013.  Accessed October 25, 2013.
  4. Actelion’s Clinical Development. Acteloin Pharmaceuticals Ltd.  Published October 2013.  Accessed November 7, 2013.
  5. Pulido T, Adzerikho I, Channick RN, et al.  Macitentan and morbidity and mortality in pulmonary arterial hypertension.  N Engl J Med.  2013; 369: 809-818.
  6. US FDA approves actelion’s lung disease drug opsumit.  Reuters Published October 18th, 2013.  Accessed October 25, 2013.
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