Other (see comment). Use Caution/Monitor. Omaveloxolone may reduce systemic exposure of sensitive CYP2C8 substrates. Check prescribing information of substrate if dosage modification is needed. osimertinibMonitor Closely (1)osimertinib will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.oteseconazoleMonitor Closely (1)oteseconazole will increase the level or effect of selexipag by Other (see comment). Modify Therapy/Monitor Closely. Otesezonale, a BCRP inhibitor, may increase the effects and risk of toxicities of BCRP substrates. Use lowest starting dose of BCRP substrate, or consider reducing BCRP substrate dose.pantoprazoleMonitor Closely (1)pantoprazole will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.phenobarbitalMonitor Closely (1)phenobarbital will decrease the level or effect of selexipag by increasing metabolism. Modify Therapy/Monitor Closely. Increase selexipag dose (up to 2-fold) if coadministered with strong CYP2C8 inducers.phenytoinMonitor Closely (1)phenytoin will decrease the level or effect of selexipag by increasing metabolism. Modify Therapy/Monitor Closely. Increase selexipag dose (up to 2-fold) if coadministered with strong CYP2C8 inducers.pioglitazoneMonitor Closely (1)pioglitazone will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.ponatinibMonitor Closely (1)ponatinib will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.primidoneMonitor Closely (1)primidone will decrease the level or effect of selexipag by increasing metabolism. Modify Therapy/Monitor Closely. Increase selexipag dose (up to 2-fold) if coadministered with strong CYP2C8 inducers.quinineMonitor Closely (1)quinine will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.rabeprazoleMonitor Closely (1)rabeprazole will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.regorafenibMonitor Closely (1)regorafenib will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.rifampinMonitor Closely (1)rifampin will decrease the level or effect of selexipag by increasing metabolism. Modify Therapy/Monitor Closely. Coadministration of selexipag with rifampin, an inducer of CYP2C8, UGT1A3, and 2B7 enzymes, decreased exposure to selexipag's active metabolite by 50%. Increase selexipag dose up to twice of the typical dose if coadministered with rifampin.rifapentineMonitor Closely (1)rifapentine will decrease the level or effect of selexipag by increasing metabolism. Modify Therapy/Monitor Closely. Increase selexipag dose (up to 2-fold) if coadministered with strong CYP2C8 inducers.ritonavirMinor (1)ritonavir will increase the level or effect of selexipag by decreasing metabolism. Minor/Significance Unknown. Coadministration of selexipag with ritonavir may result in an increase in exposure to selexipag. Despite this pharmacokinetic change, this interaction is likely of little clinical significancerolapitantMonitor Closely (1)rolapitant will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.rosiglitazoneMonitor Closely (1)rosiglitazone will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.safinamideMonitor Closely (1)safinamide will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.secobarbitalMonitor Closely (1)secobarbital will decrease the level or effect of selexipag by increasing metabolism. Modify Therapy/Monitor Closely. Increase selexipag dose (up to 2-fold) if coadministered with strong CYP2C8 inducers.sofosbuvir/velpatasvirMonitor Closely (1)sofosbuvir/velpatasvir will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.stiripentolMonitor Closely (1)stiripentol will increase the level or effect of selexipag by Other (see comment). Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors. Stiripentol is also a BCRP transport inhibitor.sunitinibMonitor Closely (1)sunitinib will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.tafamidisMonitor Closely (1)tafamidis will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.tafamidis meglumineMonitor Closely (1)tafamidis meglumine will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.tamoxifenMonitor Closely (1)tamoxifen will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.teriflunomideMonitor Closely (1)teriflunomide will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.trimethoprimMonitor Closely (1)trimethoprim will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.vandetanibMonitor Closely (1)vandetanib will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.vemurafenibMonitor Closely (1)vemurafenib will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.voxilaprevirMonitor Closely (1)voxilaprevir will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors. >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) Vascular disorders: Symptomatic hypotension Contraindications Hypersensitivity to the active substance or to any of the excipients 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 selexipagPregnancy 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 IV Preparation Reconstitution Remove vials from refrigerator and for ~30-60 min to reach room temperature (20-25ºC [68-77ºF]) Protect vials from light at all times; ensure protective wrap around the label is covering vial Peel back light protective wrap on vial to inspect vial and then immediately close light protective wrap on the vial; contents should appear white-to-almost white broken cake or powder material Reconstitute vial contents using a polypropylene syringe with 8.6 mL of 0.9% NaCl; slowly inject stream directed toward the inside wall of vial to obtain concentration of 225 mcg/mL Gently invert vial and repeat until powder is completely dissolved; do NOT shake Inspect vial for discoloration by peeling back light protect wrap; solution is clear, colorless, and free from foreign material; discard if solution is discolored, cloudy, or contains visible particles Dilution Must be diluted in glass containers only Withdraw 100 mL of 0.9% NaCl and transfer into an empty sterile glass container Calculate and withdraw required volume of reconstituted solution from vial using a single, appropriately sized polypropylene syringe; dilute into glass container containing 100 mL 0.9% NaCl to obtain desired final dose Mix diluted infusion solution by gentle inversion of the glass container 5 times; do NOT shake Always protect the diluted solution from light Assign a 4-hr expiration from the time of first vial puncture and wrap the glass container completely with light protective cover Visually inspect solution for particulate matter and discoloration prior to administration; diluted solution is clear and colorless; discard if particulate matter observed IV Administration Infuse over 80 minutes using an infusion set made of DEHP-free polyvinyl chloride, natural latex rubber-free, microbore tubing protected from light Do not use a filter for administration Once glass container is empty, continue infusion at the same rate with 0.9% NaCl to ensure that the entire dose has been administered Oral Administration Swallow tablet whole; do not split, crush, or chew Tolerability may be improved when taken with food Dose interruptions and discontinuations Missed dose: Take missed dose as soon as possible unless the next dose is within the next 6 hr Missed treatment for ≥3 days: Restart selexipag at a lower dose and then titrate to desired effect and tolerance Storage Tablet Store at 20-25ºC (68-77ºF); excursions permitted to 15-30°C (59-86°F) Keep out of reach of children Unopened vials Refrigerate in the original carton at 2-8ºC (36-46ºF) until use to protect from light Diluted solutions Store at room temperature (20-25ºC [68-77ºF]); must complete infusion within 4 hr from the first puncture of the vial stopper BRAND FORM. UNIT PRICE PILL IMAGE Uptravi oral- 1,200 mcg tabletUptravi oral- 600 mcg tabletUptravi oral- 200 mcg tabletUptravi oral- 200 mcg (140)- 800 mcg (60) tabletUptravi oral- 1,400 mcg tabletUptravi oral- 1,000 mcg tabletUptravi oral- 800 mcg tabletUptravi oral- 400 mcg tabletUptravi oral- 1,600 mcg tabletCopyright © 2010 First DataBank, Inc.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can