selexipag (Rx)

>10%

Headache (65%)

Diarrhea (42%)

Jaw pain (26%)

Nausea (33%)

Vomiting (18%)

Pain in extremity (17%)

Myalgia (16%)

Flushing (12%)

Arthralgia (11%)

Rash (11%)

1-10%

Hemoglobin decreased below 10 g/dL (8.6%)

Anemia (8%)

Decreased appetite (6%)

Frequency Not Defined

TSH reduced (up to −0.3 MU/L from a baseline of 2.5 MU/L)

Symptomatic hypotension

Contraindications

Concomitant use of strong CYP2C8 inhibitors (eg, gemfibrozil)

Cautions

If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease (PVOD); if PVOD is confirmed, discontinue selexipag

Drug interaction overview

• Contraindicated with strong CYP2C8 inhibitors; coadministration with strong CYP2C8 inhibitors may result in significant increased exposure to selexipag and its active metabolite
• Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to active metabolite; increase dose up to twice of the normal dose when coadministered with rifampin; reduce therapy dose when rifampin is stopped
• An increased selexipag dose (up to 2-fold) may be necessary if coadministered with strong CYP2C8 inducers

Pregnancy

No adequate and well-controlled studies with selexipag exist in pregnant women

Animal studies

• Reproduction studies performed with selexipag showed no clinically relevant effects on embryofetal development and survival
• A slight reduction in maternal as well as in fetal body weight was observed when pregnant rats were administered selexipag during organogenesis at a dose producing an exposure ~47 times that in humans at the maximum recommended human dose

Lactation

Unknown if distributed in human breast milk

Selexipag or its metabolites were present in the milk of rats

Because many drugs are present in the human milk and because of the potential for serious adverse reactions in nursing infants, discontinue nursing or discontinue selexipag

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Selectively activates the prostacyclin receptor (ie, IP-receptor), one of 5 types of prostanoid receptors

Unlike prostacyclin analogs, selexipag is selective for the IP receptor over other prostanoid receptors (ie, EP1-4, DP, FP, TP)

Activating the IP receptor induces vasodilation and inhibits proliferation of vascular smooth muscle cells

Absorption

Peak plasma time: 1-3 hr; 3-4 hr (active metabolite)

Distribution

Protein bound: ~99% (albumin and alpha1-acid glycoprotein)

Metabolism

Undergoes enzymatic hydrolysis of the acylsulfonamide by hepatic carboxylesterase 1, to yield the active metabolite, which is ~37-fold as potent as selexipag

Elimination

Half-life: 0.8-2.5 hr; 6.2-13.5 hr (active metabolite)

Oral clearance: 35 L/hr

Excretion: 93% in feces; neither selexipag nor its metabolite were found in urine

Oral Administration

Swallow tablet whole; do not split, crush, or chew

Tolerability may be improved when taken with food

Dose interruptions and discontinuations

• If a dose is missed, patients should take a missed dose as soon as possible unless the next dose is within the next 6 hr
• If treatment is missed for ≥3 days, restart selexipag at a lower dose and then titrate to desired effect and tolerance

Storage

Store at 20-25ºC (68-77ºF)

Excursions permitted between 15-30°C (59-86°F)