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

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. 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

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%) . 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.

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. For Injection: 1,800 mcg of selexipag as a lyophilized powder in a single-dose vial for reconstitution and dilution.

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. Pediatric patients: See Full Prescribing Information for recommended starting dose, titration increments, and maximum allowed dose based on body weight category. Maintenance dose is determined by tolerability. 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. 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. See Full Prescribing Information for instructions on preparation and administration

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 . 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 . 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 . 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 . 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 required number of tablets with soft food. Administer the mixture immediately. To ensure no tablet residue is left, add more soft food and administer the contents immediately. Do not store tablets that are mixed with soft food for later use

Recommended Dosage for UPTRAVI for Injection in Adults Use UPTRAVI for injection in adult patients who are temporarily unable to take oral therapy. Administer UPTRAVI for injection twice daily by intravenous infusion at a dose that corresponds to the patient's current dose of UPTRAVI tablets . Administer UPTRAVI for injection as an 80-minute intravenous infusion

Preparation Instructions for UPTRAVI for Injection Reconstitute and further dilute UPTRAVI for injection prior to intravenous infusion following aseptic procedures. Determine the dose and total volume of reconstituted UPTRAVI solution required . Reconstitution Remove the carton of UPTRAVI for injection from the refrigerator and allow to stand for approximately 30 to 60 minutes to reach room temperature (20 °C to 25 °C [68 °F to 77 °F]). The vial needs to be protected from light at all times. Ensure the protective wrap around label is covering the entire vial. Peel back light protective wrap on vial to inspect the contents in the vial. It should appear white to almost white broken cake or powdered material. Immediately close the light protective wrap on the vial. Reconstitute UPTRAVI for injection using a polypropylene syringe with 8.6 mL of 0.9% Sodium Chloride Injection, USP and slowly inject into the UPTRAVI vial with the stream directed toward the inside wall of the vial to obtain a concentration of 225 mcg/mL of selexipag. Document date and time of first puncture. Complete infusion within 4 hours of first puncture. Gently invert the vial and repeat until powder is completely dissolved. Do not shake. Inspect the vial by peeling back the light protective wrap around label for discoloration. The reconstituted solution should appear clear, colorless and free from foreign material. Do not use if the reconstituted solution is discolored, cloudy, or contains visible particles. Image Image Dilution UPTRAVI for injection must be diluted in glass containers only . Withdraw 100 mL of 0.9% Sodium Chloride Injection, USP and transfer into an empty sterile glass container. Withdraw the required volume of reconstituted solution from the UPTRAVI vial using a single, appropriately sized polypropylene syringe and dilute into the glass container containing 100 mL 0.9% Sodium Chloride Injection, USP to obtain the desired final dose. Mix the diluted UPTRAVI infusion solution by gentle inversion of the glass container 5 times. Do not shake. Protect diluted UPTRAVI infusion solution from light at all times. Assign a 4-hour expiry from the time of first vial puncture and wrap the glass container completely with light protective cover. The UPTRAVI infusion solution should be kept at room temperature (20 °C to 25 °C [68 °F to 77 °F]) and must be infused within 4 hours from the first puncture of the vial stopper (including infusion time). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. The diluted UPTRAVI infusion solution should be clear and colorless. Discard if particulate matter is observed. UPTRAVI for injection vials are single-dose, for single administration. All remaining reconstituted product must be discarded. Table 2: Dosing Table for UPTRAVI Intravenous Based on Current UPTRAVI Tablets Dose UPTRAVI tablets dose (mcg) for twice daily dosing Corresponding intravenous UPTRAVI dose (mcg) for twice daily dosing Reconstituted transfer volume (mL) for dilution 200 225 1 400 450 2 600 675 3 800 900 4 1,000 1,125 5 1,200 1,350 6 1,400 1,575 7 1,600 1,800 8 2.4 Administration Instructions for UPTRAVI for Injection Administer by intravenous infusion over 80 minutes using an infusion set made of DEHP-free polyvinyl chloride (PVC), natural latex rubber-free microbore tubing protected from light. Do not use a filter for administration. Once the solution for infusion glass container is empty, continue the infusion at the same rate with 0.9% Sodium Chloride Injection to empty the remaining solution for infusion in the intravenous line, to ensure that the entire solution for infusion has been administered

Interruptions and Discontinuations If a dose of UPTRAVI is missed, patients should take a missed dose as soon as possible unless the next dose is within the next 6 hours. If treatment is missed for 3 days or more, restart UPTRAVI at a lower dose and then re-titrate

Dosage Adjustment in Patients with Hepatic Impairment No dose adjustment of UPTRAVI is necessary for patients with mild hepatic impairment (Child-Pugh class A). For adult and pediatric patients with moderate hepatic impairment (Child-Pugh class B), reduce the starting dose of UPTRAVI tablets (200 mcg for adults and as determined by body weight category for pediatric patients) to once daily . Increase in increments equal to the starting dose once daily at weekly intervals, as tolerated . Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C)

Dosage Adjustment with Co-administration of Moderate CYP2C8 Inhibitors When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide) in adult and pediatric patients, reduce the dosing of UPTRAVI to once daily .

Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment. 5.1 Pulmonary Edema with Pulmonary Veno-Occlusive Disease Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease. If confirmed, discontinue UPTRAVI.

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 . 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 . Reduce the dosing of UPTRAVI to once daily in adult and pediatric patients on a moderate CYP2C8 inhibitor

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 .