Opsumit by Actelion Pharmaceuticals US, Inc

Opsumit (macitentan) was approved to reduce the risk of hospitalization and delay disease progression in patients with WHO group I pulmonary arterial hypertension.

The FDA approved Opsumit (macitentan) on October 18, 2013, to reduce the risk of hospitalization and delay disease progression in patients with WHO group I pulmonary arterial hypertension (PAH).¹ Opsumit carries a black box warning for embryofetal toxicity. As a pregnancy category X medication, Opsumit use is contraindicated in pregnant women.²

Pharmacology and Pharmacokinetics

Opsumit is an endothelin (ET)-receptor agonist that works on ET-1, ET_A, and ET_B. The endothelin system is involved in the pathogenesis of PAH, mediating vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation.²

After oral administration, maximum plasma concentrations occur within approximately 8 hours. The elimination half-life of Opsumit is 16 hours, and the half-life of its active metabolite is 48 hours. As a result, the active metabolite accounts for 40% of the activity of Opsumit, despite the fact that the metabolite has one-fifth the activity of the parent drug.²

In patients with renal impairment, levels of Opsumit were 30% to 60% higher than levels in healthy adults. Patients with mild, moderate, or severe hepatic impairment experienced a 6% to 34% reduction in exposure to the parent drug and a 20% to 25% reduction in exposure to the active metabolite. The manufacturer does not consider the changes in exposure to Opsumit in patients with renal impairment or hepatic impairment to be clinically relevant. No dosage adjustment is recommended.²

Dosage and Administration

Each 10-mg tablet of Opsumit should be taken at approximately the same time daily and should not be chewed or crushed. Exposure to Opsumit was unchanged by coadministration with a high-fat breakfast meal. As a result, Opsumit may be taken with or without food.²

Clinical Trials

In the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hyper- tension to Improve Clinical Outcome (SERAPHIN), over a median time of about 2 years, 742 patients with WHO group II, III, or IV PAH received Opsumit. Of the 742 patients, 542 received treatment for 1 year, 429 continued treatment for 2 years, and 98 continued treatment for 3 years or more. Discontinuations due to adverse events occurred in 11% of trial participants.²

Patients received daily doses of 3-mg Opsumit tablets, 10-mg Opsumit tablets, or placebo in an approximately 1:1:1 ratio. Investigators measured the time to first occurrence of death or a significant morbidity event, including atrial septostomy, lung transplantation, initiation of intravenous or subcutaneous prostanoids, or an investigator-defined unspecified worsening of PAH. In addition to the primary end point, investigators measured increases in the 6-minute walk distance, changes in WHO functional class, and need for additional treatment for PAH.²

Compared with placebo use, use of Opsumit 10 mg daily reduced the risk of progression to the primary end point by 45% (P <.0001). Most of the improvement with Opsumit was due to the reduction in the percentage of patients experiencing clinical worsening, from 37.2% in patients receiving placebo to 24.4% in patients receiving Opsumit. Although the risk of PAH-related death or hospitalization for PAH was 50% lower than in the placebo group (P <.0001), unfortunately, the risk of death over the course of the trial remained virtually unchanged at 6.8% with placebo and 6.6% with Opsumit 10 mg.²

Warnings and Precautions

The metabolism of Opsumit depends on CYP3A4 and, to a smaller degree, CYP2C19. Strong inhibitors of CYP3A4, such as ritonavir or ketoconazole, may increase exposure to Opsumit. To manage this drug interaction, the manufacturer recommends avoiding concomitant use of Opsumit with strong CYP3A4 inhibitors. Although the interaction is clinically insignificant, sildenafil 20 mg taken 3 times daily may increase steady-state levels of Opsumit by approximately 15%.²

Patients taking Opsumit should be aware of the signs of hepatotoxicity (ie, unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) due to the potential for hepatotoxicity among endothelin agonists. In addition, regular monitoring of liver function may be necessary.²

Scientists observed reductions in hemoglobin to levels <10 g/dL in 8.7% of patients receiving Opsumit 10 mg daily compared with 3.4% of patients receiving placebo. In addition, pulmonary edema may occur in patients with primary veno-occlusive disease and Opsumit may reduce sperm counts.²

Common adverse events with Opsumit in SERAPHIN included anemia (13%), nasopharyngitis/pharyngitis (20%), bronchitis (12%), headache (14%), influenza (6%), and urinary tract infection (9%). For a complete discussion of potential drug interactions and adverse events, please consult the product package insert.² SPT

References

• FDA approves Opsumit to treat pulmonary arterial hypertension [press release]. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm371362.htm. Accessed April 2014.
• OPSUMIT (macitentan) tablets [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2013.

About the Author Michael R. Page, PharmD, RPh, earned his PharmD from the Ernest Mario School of Pharmacy at Rutgers University. He has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at Pharmacy Times.