General Information

Uptravi (selexipag) is a prostacyclin receptor agonist, which exerts vasodilating effects.

Uptravi is specifically indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) to delay disease progression and reduce the risk of hospitalization for PAH. 

Mechanism of Action

Uptravi (selexipag) is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective for the IP receptor versus other prostanoid receptors (EP1-4, DP, FP and TP).

Side Effects

Adverse effects associated with the use of Uptravi may include, but are not limited to, the following:

• headache
• diarrhea
• jaw pain
• nausea
• myalgia
• vomiting
• pain in extremity
• flushing

Dosing/Administration

Uptravi is supplied as tablets for oral administration. The recommended starting dose of Uptravi is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food. The dose should be increased 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. Do not split, crush, or chew tablets.

Clinical Trial Results

The FDA approval of Uptravi was based on a multicenter, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON). The study enrolled 1,156 patients with symptomatic (WHO Functional Class 1 [0.8 percent], 2 [46 percent], 3 [53 percent], and 4 [1 percent]) PAH. Patients were randomized to either placebo (N = 582), or Uptravi (N = 574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1600 mcg twice a day. The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15 percent decrease from baseline in 6MWD plus worsening of Functional Class or need for additional PAH-specific therapy. Treatment with Uptravi resulted in a 40 percent reduction (p-value < 0.0001) of the occurrence of primary endpoint events compared to placebo. The beneficial effect of Uptravi was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events. The observed benefit of Uptravi was similar regardless of the dose achieved when patients are titrated to their highest tolerated dose.