UPTRAVI

Indications and Usage ( 1 ) 5/2026 Dosage and Administration ( 2.1 , 2.6 , 2.7 ) 5/2026

1 INDICATIONS AND USAGE UPTRAVI is a prostacyclin receptor agonist indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I): In adults to delay disease progression and reduce the risk of hospitalization for PAH. ( 1.1 ) In pediatric patients aged 2 years and older. UPTRAVI reduces NT-proBNP and is expected to delay disease progression and reduce the risk of hospitalization for PAH. ( 1.1 ) 1.1 Pulmonary Arterial Hypertension Adult Patients UPTRAVI is indicated for the treatment of pulmonary arterial hypertension in adults (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness of UPTRAVI tablets was established in a long-term study in adult PAH patients with WHO Functional Class II–III symptoms. Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%) [see Clinical Studies (14.1) ] . Pediatric Patients UPTRAVI is indicated for the treatment of PAH (WHO Group I) in pediatric patients aged two years and older. UPTRAVI reduces NT-proBNP and is expected to delay disease progression and reduce the risk of hospitalization for PAH.

2 DOSAGE AND ADMINISTRATION Adult patients: UPTRAVI tablets starting dose: 200 mcg orally twice daily. Increase the dose by 200 mcg orally twice daily at weekly intervals to the highest tolerated dose up to 1,600 mcg orally twice daily. ( 2.1 ) Pediatric patients: See Full Prescribing Information for recommended starting dose, titration increments, and maximum allowed dose based on body weight category. ( 2.1 ) Maintenance dose is determined by tolerability. ( 2.1 ) Moderate hepatic impairment: Starting dose once daily, increase in increments of the starting dose once daily at weekly intervals to the maximum allowed or highest tolerated dose. ( 2.6 ) Adult patients: UPTRAVI for injection dose is determined by the patient's current dose of UPTRAVI tablets. Administer UPTRAVI for injection by intravenous infusion, twice daily. ( 2.2 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.3 , 2.4 ) 2.1 Recommended Dosage and Administration for UPTRAVI Film-coated Tablets Adult Patients The recommended starting dosage of UPTRAVI tablets is 200 mcg given orally twice daily. Tolerability may be improved when taken with food [see Clinical Pharmacology (12.3) ] . Increase the dose in increments of 200 mcg orally twice daily, usually at weekly intervals, to the highest tolerated dose up to 1,600 mcg orally twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose. Swallow the UPTRAVI tablets whole. Do not split or crush the tablets. Pediatric Patients Two Years and Older The recommended starting dose of UPTRAVI is determined based on the patient's body weight and is given orally twice daily. The recommended UPTRAVI starting doses, titration increments, and maximum allowed doses based on body weight categories in pediatric patients are shown in Table 1. Table 1: Pediatric Dosing Regimen Body weight (kg) Recommended starting dose Recommended titration increments Maximum dose allowed 9 kg to less than 25 kg 100 mcg orally twice daily 100 mcg orally twice daily 800 mcg orally twice daily 25 kg to less than 40 kg 150 mcg orally twice daily 150 mcg orally twice daily 1,200 mcg orally twice daily 40 kg to less than 50 kg 150 mcg orally twice daily 150 mcg orally twice daily 1,600 mcg orally twice daily For pediatric patients with a body weight ≥40 kg to <50 kg multiple tablet dose strengths may be needed to reach the doses up to 1,600 mcg twice daily. 50 kg and greater 200 mcg orally twice daily 200 mcg orally twice daily 1,600 mcg orally twice daily Increase the dose in increments equivalent to the starting dose (i.e., 100 mcg, 150 mcg or 200 mcg given orally twice daily), at weekly intervals, to the highest tolerated dose up to the maximum dose allowed for the patient's body weight (see Table 1 ). If a patient reaches a dose that cannot be tolerated or medically managed, the dose should be reduced to the previous tolerated dose. Re-evaluate further dose titration based on changes in body weight category over time. Tolerability may be improved when taken with food [see Clinical Pharmacology (12.3) ] . Swallow the UPTRAVI tablets whole. Do not split or crush the tablets. Alternate Methods of Administration of 100 mcg and 150 mcg UPTRAVI Film-coated Tablets For patients who cannot swallow the tablets whole, 100 mcg or 150 mcg UPTRAVI tablets can be dispersed and administered in apple or orange juice. Do not disperse the tablet(s) in water or milk. Do not crush or split the tablet(s). At least 1 mL of juice per tablet is recommended. Add the juice to the required number of tablet(s) per dosing schedule (see Table 1 ). Wait for 5 min and then stir until the tablets are dispersed. Administer the mixture immediately after dispersion. Do not store tablets that are mixed with juice for later use. Alternatively, 100 mcg and 150 mcg UPTRAVI tablets can also be administered with soft foods such as yogurt, applesauce, or mashed banana. Cover the require …

3 DOSAGE FORMS AND STRENGTHS UPTRAVI is available in the following presentations: Film-Coated Tablets 100 mcg selexipag [Light yellow tablet debossed with 1, 3 mm diameter] 150 mcg selexipag [Red tablet with no debossing, 3 mm diameter] 200 mcg selexipag [Light yellow tablet debossed with 2, 7 mm diameter] 400 mcg selexipag [Red tablet debossed with 4, 7 mm diameter] 600 mcg selexipag [Light violet tablet debossed with 6, 7 mm diameter] 800 mcg selexipag [Green tablet debossed with 8, 7 mm diameter] 1,000 mcg selexipag [Orange tablet debossed with 10, 7 mm diameter] 1,200 mcg selexipag [Dark violet tablet debossed with 12, 7 mm diameter] 1,400 mcg selexipag [Dark yellow tablet debossed with 14, 7 mm diameter] 1,600 mcg selexipag [Brown tablet debossed with 16, 7 mm diameter] UPTRAVI for Injection 1,800 mcg selexipag [Lyophilized powder white to almost white broken cake or powdered material, supplied in a 10 mL single-dose glass vial] Tablets: 100 mcg, 150 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,000 mcg, 1,200 mcg, 1,400 mcg, 1,600 mcg. ( 3 ) For Injection: 1,800 mcg of selexipag as a lyophilized powder in a single-dose vial for reconstitution and dilution. ( 3 )

4 CONTRAINDICATIONS Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Concomitant use with strong CYP2C8 inhibitors. ( 4 , 7.1 , 12.3 ) Hypersensitivity to the active substance or to any of the excipients. ( 4 )

6 ADVERSE REACTIONS Adverse reactions in adult and pediatric patients occurring more frequently (≥5%) on UPTRAVI compared to placebo are headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing. Additional adverse reaction occurring in pediatric patients more frequently (≥5%) on UPTRAVI compared to placebo is abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. UPTRAVI Tablets Adult Patients The safety of UPTRAVI tablets has been evaluated in a long-term, placebo-controlled study enrolling 1,156 adult patients with symptomatic PAH (GRIPHON study) [see Clinical Studies (14.1) ] . The exposure to UPTRAVI in this trial was up to 4.2 years with median duration of exposure of 1.4 years. Table 3 presents adverse reactions more frequent on UPTRAVI tablets than on placebo by ≥3%. Table 3: Adverse Reactions UPTRAVI Placebo Adverse Reaction N=575 N=577 Headache 65% 32% Diarrhea 42% 18% Jaw pain 26% 6% Nausea 33% 18% Myalgia 16% 6% Vomiting 18% 9% Pain in extremity 17% 8% Flushing 12% 5% Arthralgia 11% 8% Anemia 8% 5% Decreased appetite 6% 3% Rash 11% 8% These adverse reactions are more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI tablets and in none of the patients on placebo. Pediatric Patients Two Years and Older The safety of UPTRAVI tablets has been evaluated in a long-term, Phase 3, double-blind, placebo-controlled study (SALTO), where a total of 138 pediatric patients with symptomatic PAH ≥2 to <18 years of age were randomized 1:1 to receive either UPTRAVI or placebo [see Clinical Studies (14.2) ] . The exposure to UPTRAVI in this study was up to 4.1 years with a median duration of exposure of 1.5 years. The safety profile in pediatric patients was consistent with that observed in adults with PAH. Compared to adults, a higher frequency of vomiting was observed (39% on UPTRAVI versus 19% on placebo). In addition, abdominal pain was observed in 15% of pediatric patients on UPTRAVI and in 6% on placebo. UPTRAVI-treated pediatric patients experienced a smaller mean increase in body weight and height compared to the placebo group. The mean change in weight Z-score from baseline at 48 weeks in UPTRAVI-treated pediatric patients (n=54) was –0.31 compared to –0.09 in the placebo group (n=61); and at 96 weeks in UPTRAVI-treated pediatric patients (n=32) was –0.46 compared to –0.12 in the placebo group (n=35). The mean change in height Z-score from baseline at 48 weeks in UPTRAVI-treated pediatric patients (n=54) was –0.16 compared to –0.04 in the placebo group (n=61); and at 96 weeks in the UPTRAVI-treated pediatric patients (n=32) was –0.30 compared to –0.05 in the placebo group (n=35). When treating pediatric patients with UPTRAVI, monitor growth. UPTRAVI for Injection Infusion-site reactions (infusion site erythema/redness, pain and swelling) were reported with UPTRAVI for Injection in adult patients. Laboratory Test Abnormalities Hemoglobin In a Phase 3 placebo-controlled study in adult patients with PAH, mean absolute changes in hemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the UPTRAVI group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with UPTRAVI tablets and 5.0% of placebo-treated patients. Thyroid Function Tests In a Phase 3 placebo-controlled study in adult patients with PAH, a reduction (up to −0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone (TSH) was observed at most visits in th …

7 DRUG INTERACTIONS Moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide) increase exposure to the active metabolite of UPTRAVI. Reduce the dosing of UPTRAVI to once daily. ( 2.7 , 7.1 , 12.3 ) CYP2C8 inducers (e.g., rifampin) decrease exposure to the active metabolite. Increase up to twice the dose of UPTRAVI. ( 7.2 , 12.3 ) 7.1 CYP2C8 Inhibitors Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled the exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant administration of UPTRAVI with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3) ] . Concomitant administration of UPTRAVI tablets with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold [see Clinical Pharmacology (12.3) ] . Reduce the dosing of UPTRAVI to once daily in adult and pediatric patients on a moderate CYP2C8 inhibitor [see Dosage and Administration (2.7) ] . 7.2 CYP2C8 Inducers Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI up to twice the dose when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Discontinue UPTRAVI or breastfeeding. ( 8.2 ) Severe hepatic impairment: Avoid use. ( 8.6 ) 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with UPTRAVI in pregnant women. Animal 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 to the active metabolite approximately 47 times that in humans at the maximum recommended human dose. No adverse developmental outcomes were observed with oral administration of selexipag to pregnant rabbits during organogenesis at exposures to the active metabolite up to 50 times the human exposure at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including heart failure, stroke, spontaneous abortion, intrauterine growth restriction, premature labor, and preterm birth. Data Animal Data Pregnant rats were treated with selexipag using oral doses of 2, 6, and 20 mg/kg/day (up to 47 times the exposure to the active metabolite at the maximum recommended human oral dose of 1,600 mcg twice daily on an area under the curve [AUC] basis) during the period of organogenesis (gestation days 7 to 17). Selexipag did not cause adverse developmental effects to the fetus in this study. A slight reduction in fetal body weight was observed in parallel with a slight reduction in maternal body weight at the high dose. Pregnant rabbits were treated with selexipag using oral doses of 3, 10, and 30 mg/kg (up to 50 times the exposure to the active metabolite at the maximum recommended human oral dose of 1,600 mcg twice daily on an AUC basis) during the period of organogenesis (gestation days 6 to 18). Selexipag did not cause adverse developmental effects to the fetus in this study. In a pre- and post-natal development study, pregnant rats were treated with selexipag from gestation day 7 through lactation day 20 at oral doses of 2, 6, and 20 mg/kg/day (up to 35 times the exposure to the active metabolite at the maximum recommended human dose of 1,600 mcg twice daily on an AUC basis). Treatment with selexipag did not cause adverse developmental effects in this study at any dose. 8.2 Lactation It is not known if UPTRAVI is present in human 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 UPTRAVI. 8.4 Pediatric Use Safety and effectiveness of UPTRAVI have been established for the treatment of PAH in pediatric patients aged 2 years and older. Use of UPTRAVI for this indication is supported by evidence from an adequate and well-controlled study in adults with additional pharmacokinetic, pharmacodynamic, and safety data in pediatric patients aged 2 years and older (N=132) [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ]. The safety profile observed in pediatric patients was consistent with that of adults. A higher frequency of vomiting and abdominal pain was observed in UPTRAVI-treated pediatric patients compared to UPTRAVI-treated adults. UPTRAVI-treated pediatric patients experienced a smaller mean increase in body weight and height compared to placebo. When treating pediatric patients with UPTRAVI, monitor g …

12.1 Mechanism of Action Selexipag is a 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 (EP 1–4 , DP, FP, and TP).

11 DESCRIPTION UPTRAVI contains selexipag, a prostacyclin receptor agonist. The chemical name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N -(methylsulfonyl) acetamide. It has a molecular formula of C 26 H 32 N 4 O 4 S and a molecular weight of 496.62. Selexipag has the following structural formula: Selexipag is a pale yellow crystalline powder that is practically insoluble in water. In the solid state selexipag is very stable, is not hygroscopic, and is not light sensitive. UPTRAVI ® (selexipag) tablets: depending on the dose strength, each round film-coated tablet for oral administration contains 100, 150, 200, 400, 600, 800, 1,000, 1,200, 1,400, or 1,600 mcg of selexipag. The tablets include the following inactive ingredients: corn starch, D-mannitol, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, and magnesium stearate. The tablets are film coated with a coating material containing carnauba wax, hypromellose, propylene glycol, titanium dioxide, along with mixtures of iron oxide black, iron oxide red and/or iron oxide yellow. The coating material of the 100 mcg and 150 mcg tablets also contains talc. UPTRAVI ® (selexipag) for injection: contains 1,800 mcg of selexipag per vial. UPTRAVI for injection includes the following inactive ingredients: glycine (180 mg), phosphoric acid (3.53 mg), polysorbate 20 (10.8 mg) and sodium hydroxide (for pH adjustment). UPTRAVI for injection is provided in 10 mL Type I clear glass vials closed by a stopper and tear-off aluminum seal. Chemical Structure

10 OVERDOSAGE Isolated cases of overdose in adults with UPTRAVI tablets up to 3,200 mcg were reported. Mild, transient nausea was the only reported consequence. In the event of overdose, supportive measures must be taken as required. Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein-bound.

16 HOW SUPPLIED/STORAGE AND HANDLING UPTRAVI ® (selexipag) film-coated, round tablets are supplied in the following configurations: Strength (mcg) Color Debossing NDC-XXX Bottle of 60 NDC-XXX Bottle of 140 100 Light yellow 1 Not Available 66215-910-14 150 Red No debossing is present on the 150 mcg tablets. Not Available 66215-915-14 200 Light yellow 2 66215-602-06 66215-602-14 400 Red 4 66215-604-06 Not Available 600 Light violet 6 66215-606-06 Not Available 800 Green 8 66215-608-06 Not Available 1,000 Orange 10 66215-610-06 Not Available 1,200 Dark violet 12 66215-612-06 Not Available 1,400 Dark yellow 14 66215-614-06 Not Available 1,600 Brown 16 66215-616-06 Not Available UPTRAVI ® (selexipag) tablets are also supplied in a Titration Pack [NDC 66215-628-20] that includes a 140-count bottle of 200-mcg tablets and a 60-count bottle of 800-mcg tablets. Store at 20 °C to 25 °C (68 °F to 77 °F). Excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F) [see USP Controlled Room Temperature]. Recommended storage for UPTRAVI 100 mcg and 150 mcg tablets: Store and dispense in the original package to protect from moisture. Keep out of reach of children. UPTRAVI ® (selexipag) for injection, for intravenous use, is supplied in a 10 mL Type I glass vial closed by a stopper and sealed with an aluminum flip-off button, containing 1,800 mcg of selexipag [NDC 66215-718-01]. UPTRAVI ® (selexipag) for injection is available in cartons containing 1 single-dose vial. Storage conditions for UPTRAVI for injection: Store the original carton containing glass vial in a refrigerator at 2 °C to 8 °C (36 oF to 46 oF) until use in order to protect from light.