44/15 PRODUCT DETAILS 

Drug Name-                UPTRAVI

Active Ingredient-      Selexipag

 Approved date         12/21/2015                                                                                      

FDA approved use-  To treat pulmonary arterial hypertension                                                                                                              

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use UPTRAVI® safely and effectively. See full prescribing information for UPTRAVI® . UPTRAVI® (selexipag) tablets, for oral use Initial U.S. Approval: 2015 -----------------------INDICATIONS AND USAGE---------------------- UPTRAVI® is a prostacyclin receptor agonist indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. (1.1) ------------------DOSAGE AND ADMINISTRATION----------------- ? Starting dose: 200 mcg twice daily. (2.1) ? Increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily. (2.1) ? Maintenance dose is determined by tolerability. (2.1) ? Moderate hepatic impairment: Starting dose 200 mcg once daily, increase the dose by 200 mcg once daily at weekly intervals to the highest tolerated dose up to 1600 mcg. (2.3) ----------------DOSAGE FORMS AND STRENGTHS----------------- Tablets: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1000 mcg, 1200 mcg, 1400 mcg, 1600 mcg. (3)

--CONTRAINDICATIONS------------------------- None (4) -------------------WARNINGS AND PRECAUTIONS------------------ Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment. (5.1) -------------------------ADVERSE REACTIONS-------------------------- Adverse reactions occurring more frequently (>5%) on UPTRAVI compared to placebo are headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-866-228-3546 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------DRUG INTERACTIONS-------------------------- Strong CYP2C8 inhibitors: increased exposure to selexipag and its active metabolite. Avoid concomitant use. (7.1, 12.3) --------------------USE IN SPECIFIC POPULATIONS----------------- ? Nursing mothers: discontinue UPTRAVI or breastfeeding. (8.2) ? Severe hepatic impairment: Avoid use.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Package Insert). Inform patients: ? what to do if they miss a dose ? not to split, crush, or chew tablets.

Manufactured for: Actelion Pharmaceuticals US, Inc. 5000 Shoreline Court, Ste. 200 South San Francisco, CA 94080, USA ACT20151221 ? 2015 Actelion Pharmaceuticals US, Inc. All rights reserved.

CLINICAL PHARMACOLOGY Mechanism of Action 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). 12.2 Pharmacodynamics Cardiac electrophysiology: At the maximum tolerated dose of 1600 mcg twice daily, selexipag does not prolong the QT interval to any clinically relevant extent. Platelet aggregation: Both selexipag and its active metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with an IC50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters as seen following multiple-dose administrations of selexipag in healthy subjects from 400 mcg up to 1800 mcg twice daily. Pulmonary hemodynamics: A Phase 2 clinical study assessed hemodynamic variables after 17 weeks of treatment in patients with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating selexipag to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI] -44.7%, -12.2%) and an increase in cardiac Reference ID: 3864143 index (median treatment effect) of 0.41 L/min/m2 (95% CI 0.10, 0.71) compared to placebo (N=10). Drug interaction: In a study in healthy subjects, selexipag (400 mcg twice a day) did not influence the pharmacodynamic effect of warfarin on the international normalized ratio. 12.3 Pharmacokinetics The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of selexipag and the active metabolite, after both single and multiple-dose administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1800 mcg twice daily. No accumulation in plasma, either of parent compound or active metabolite, occurred after multiple-dose administration. In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively. Exposures to selexipag and the active metabolite at steady-state in PAH patients and healthy subjects were similar. The pharmacokinetics of selexipag and the active metabolite in PAH patients were not influenced by the severity of the disease and did not change with time. Both in healthy subjects and PAH patients, exposure at steady-state to the active metabolite is approximately 3- to 4-fold that of selexipag. Absorption Upon oral administration, maximum observed plasma concentrations of selexipag and its active metabolite after oral administration are reached within about 1–3 hours and 3–4 hours, respectively. In the presence of food, the absorption of selexipag was prolonged resulting in a delayed time to peak concentration (Tmax) and ~30% lower peak plasma concentration (Cmax). The exposure to selexipag and the active metabolite (AUC) did not significantly change in the presence of food. Distribution Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total and to the same extent to albumin and alpha1-acid glycoprotein). Metabolism Selexipag undergoes enzymatic hydrolysis of the acylsulfonamide by hepatic carboxylesterase 1, to yield the active metabolite. Oxidative metabolism catalyzed by CYP3A4 and CYP2C8 leads to the formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Except for the active metabolite, none of the circulating metabolites in human plasma exceeds 3% of the total drug-related material. Reference ID: 3864143 Elimination Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8-2.5 hours. The active metabolite has a terminal half-life of 6.2-13.5 hours. The apparent oral clearance of selexipag is on average 35 L/hour. Excretion In a study in healthy subjects with radiolabeled selexipag, approximately 93% of radioactive drug material was eliminated in feces and only 12% in urine. Neither selexipag nor its active metabolite were found in urine. Specific Populations: No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag and its active metabolite have been observed in healthy subjects or PAH patients. Age: The pharmacokinetic variables (Cmax and AUC) were similar in adult and elderly subjects up to 75 years of age. There was no effect of age on the pharmacokinetics of selexipag and the active metabolite in PAH patients. Hepatic Impairment: In subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure to selexipag was 2- and 4-fold that seen in healthy subjects. Exposure to the active metabolite of selexipag remained almost unchanged in subjects with mild hepatic impairment and was doubled in subjects with moderate hepatic impairment. [see Use in Specific Populations (8.6)]. Based on pharmacokinetic modeling of data from a study in subjects with hepatic impairment, the exposure to the active metabolite at steady state in subjects with moderate hepatic impairment (Child-Pugh class B) after a once daily regimen is expected to be similar to that in healthy subjects receiving a twice daily regimen. The exposure to selexipag at steady state in these patients during a once daily regimen is predicted to be approximately 2-fold that seen in healthy subjects receiving a twice-daily regimen. Renal Impairment: A 40-70% increase in exposure (maximum plasma concentration and area under the plasma concentration-time curve) to selexipag and its active metabolite was observed in subjects with severe renal impairment (estimated glomerular filtration rate > 15 mL/min/1.73 m2 and < 30 mL/min/1.73 m2) [see Use in Specific Populations (8.7)]. Drug Interaction Studies: In vitro studies Selexipag is hydrolyzed to its active metabolite by hepatic carboxylesterase 1. Selexipag and its active metabolite both undergo oxidative metabolism by CYP2C8 and CYP3A4. The glucuronidation of the active metabolite is catalyzed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a substrate of P-gp, Reference ID: 3864143 and the active metabolite is a substrate of the transporter of breast cancer resistance protein (BCRP). Selexipag and its active metabolite do not inhibit or induce hepatic cytochrome P450 enzymes at clinically relevant concentrations. Selexipag and its active metabolite do not inhibit hepatic or renal transport proteins. The effect of strong inhibitors of CYP2C8 (such as gemfibrozil) on the exposure to selexipag or its active metabolite has not been studied. Concomitant administration with strong inhibitors of CYP2C8 may result in a significant increase in exposure to selexipag and its active metabolite [see Drug Interactions (7.1)]. The results on in vivo drug interaction studies are presented in Figure 1. Figure 1 Effect of Other Drugs on UPTRAVI and its Active Metabolite (A) and Effect of UPTRAVI on Warfarin (B) *ERA and PDE-5 inhibitor data from GRIPHON.

13 13.1 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: In the 2-year carcinogenicity studies, chronic oral administration of selexipag revealed no evidence of carcinogenic potential in rats at 100 mg/kg/day and mice at 500 mg/kg/day. The exposures were more than 25-fold human exposure. Reference ID: 3864143 Mutagenesis: Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted geno

DRUG INTERACTIONS 7.1 Strong CYP2C8 Inhibitors Concomitant administration with strong inhibitors of CYP2C8 may result in a significant increase in exposure to selexipag and its active metabolite. Avoid concomitant administration of UPTRAVI with strong inhibitors of CYP2C8 (e.g., gemfibrozil) [see Clinical Pharmacology (12.3)]. 8 8.1 USE IN SPECIFIC POPULATIONS 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 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 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. 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 at the maximum recommended human dose of 1600 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 dose of 1600 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. 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 Reference ID: 3864143 potential for serious adverse reactions in nursing infants, discontinue nursing or discontinue UPTRAVI. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 1368 subjects in clinical studies of UPTRAVI 248 subjects were 65 years of age and older, while 19 were 75 and older. No overall differences were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity cannot be ruled out. 8.6 Patients with Hepatic Impairment No adjustment to the dosing regimen is needed in patients with mild hepatic impairment (Child Pugh class A). A once-daily regimen is recommended in patients with moderate hepatic impairment (Child Pugh class B) due to the increased exposure to selexipag and its active metabolite. There is no experience with UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C). Avoid use of UPTRAVI in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment No adjustment to the dosing regimen is needed in patients with estimated glomerular filtration rate > 15 mL/min/1.73 m2 . There is no clinical experience with UPTRAVI in patients undergoing dialysis or in patients with glomerular filtration rates < 15 mL/min/1.73 m2 [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Isolated cases of overdose up to 3200 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. 11 DESCRIPTION