Selexipag is a first-in-class oral treatment option to reduce progression and hospitalization for pulmonary arterial hypertension.
Limited treatment options exist for pulmonary arterial hypertension (PAH), a chronic progressive disease that causes the walls of the arteries to stiffen leading to increased blood pressure in the lungs. In many cases, PAH can lead to heart failure, the need for a lung transplant, and death.
FDA approved selexipag (Uptravi, Actelion) on December 21, 2015 as a first-in-class oral treatment option to reduce progression and hospitalization for PAH. It is a prostacyclin receptor agonist, which causes relaxation of the lung arteries resulting in lower blood pressure.
Selexipag’s efficacy was demonstrated in a multicenter, double-blind, placebo-controlled, parallel group, event-driven study known as the GRIPHON trial (PGI2 Receptor agonist In Pulmonary arterial HypertensiON).
At baseline, the majority of 1,156 patients with PAH (80%) were being treated with a stable dose of an endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%). Patients were randomized to either selexipag (N=574) or placebo (N=582).
The dose was increased weekly by increments of 200 mcg twice daily to the highest tolerated dose up to 1,600 mcg twice daily. Patients achieved doses within the following groups: 200-400 mcg (23%), 600-1,000 mcg (31%), and 1,200-1,600 mcg (43%).
Treatment with selexipag resulted in a 40% reduction of the occurrence of primary endpoint events compared to placebo.
Primary endpoints included: hospitalization for PAH, other disease progression (decrease in 6-minute walking distance plus worsening functional class or need for other therapy), death, parenteral prostanoid or chronic oxygen therapy, and worsening of PAH, resulting in the need for lung transplantation or balloon atrial septostomy.
The beneficial effect was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease-progression events. The observed benefit of selexipag was similar irrespective of the dose achieved, when patients were appropriately titrated to their highest tolerated dose.
There was no significant difference in mortality between the two study groups. Participants received selexipag for a median duration of 1.4 years.
Adverse effects associated with selexipag were more common than with placebo and included headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, arthralgia, anemia, decreased appetite, and rash, all of which occurred more frequently during the titration phase. Hyperthyroidism was observed in 1% of patients on selexipag. A decrease in hemoglobin concentration below
10 g/dL was reported in 8.6% of treated patients.
Selexipag has not been studied in pregnant women. Selexipag did not cause adverse developmental effects to the fetus in rat and rabbit reproduction studies. It is not known whether selexipag is present in human breast milk, though its metabolites were present in the milk of rats.
Safety and effectiveness in pediatric patients has not been established. No overall differences were observed between younger subjects and subjects over 65 years of age.
The recommended starting dose of selexipag is 200 mcg given twice daily. Tolerability may be improved when taken with food. Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.
Tablets should not be split, crushed, or chewed.
No adjustment to the dosing regimen is needed in patients with anestimated glomerular filtration rate >15 mL/min. There is no clinical experience with selexipag in patients undergoing dialysis or in patients with glomerular filtration rates <15 mL/min.
No adjustment to the dosing regimen is needed in patients with mild hepatic impairment.
A once-daily regimen is recommended in patients with moderate hepatic impairment, because of the increased exposure to selexipag and its active metabolite.
Selexipag use should be avoided in cases of severe hepatic impairment.
Lauren J. VanHook is a PGY-1 pharmacy resident at John Dempsey Hospital/UConn Health, Farmington, Conn. Kevin W. Chamberlin is an associate clinical professor and assistant department head, pharmacy practice, UConn School of Pharmacy, Storrs, Conn.