Selexipag

RECENT MAJOR CHANGES Contraindications ( 4 ) 10/2021

1 INDICATIONS AND USAGE Selexipag tablets are 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 ) 1.1 Pulmonary Arterial Hypertension Selexipag tablets are indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness of selexipag tablets was established in a long-term study in 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 )] .

2 DOSAGE AND ADMINISTRATION Selexipag tablets 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 1,600 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 1,600 mcg. ( 2.5 ) 2.1 Recommended Dosage The recommended starting dosage of selexipag tablets is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food [see Clinical Pharmacology ( 12.3 )] . Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1,600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose. Do not split, crush, or chew tablets. 2.4 Interruptions and Discontinuations If a dose of selexipag tablets 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 selexipag tablets at a lower dose and then retitrate. 2.5 Dosage Adjustment in Patients with Hepatic Impairment No dose adjustment of selexipag is necessary for patients with mild hepatic impairment (Child-Pugh class A). For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of selexipag tablets is 200 mcg once daily . Increase in increments of 200 mcg once daily at weekly intervals, as tolerated [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . Avoid use of selexipag in patients with severe hepatic impairment (Child-Pugh class C). 2.6 Dosage Adjustment with Co-administration of Moderate CYP2C8 Inhibitors When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), reduce the dosing of selexipag to once daily [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] .

3 DOSAGE FORMS AND STRENGTHS Selexipag tablets are available in the following strengths: 200 mcg [Beige colored, round, film coated tablet, debossed with "S2" on one side and plain on other side] 400 mcg [Pink colored, round, film coated tablet, debossed with "S4" on one side and plain on other side.] 600 mcg [Grey colored, round, film coated tablet, debossed with "S6" on one side and plain on other side.] 800 mcg [Green colored, round, film coated tablet, debossed with "S8" on one side and plain on other side.] 1,000 mcg [Yellow colored, round, film coated tablet, debossed with "S10" on one side and plain on other side.] 1,200 mcg [Dark grey colored, round, film coated tablet, debossed with "S12" on one side and plain on other side.] 1,400 mcg [Dark yellow colored, round, film coated tablet, debossed with "S14" on one side and plain on other side.] 1,600 mcg [Brown colored, round, film coated tablet, debossed with "S16" on one side and plain on other side.] Tablets: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,000 mcg, 1,200 mcg, 1,400 mcg, 1,600 mcg.

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 occurring more frequently (≥5%) on selexipag compared to placebo are headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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. The safety of selexipag tablets has been evaluated in a long-term, placebo-controlled study enrolling 1,156 patients with symptomatic PAH (GRIPHON study) [see Clinical Studies ( 14 )] . The exposure to selexipag in this trial was up to 4.2 years with median duration of exposure of 1.4 years. Table 1 presents adverse reactions more frequent on selexipag tablets than on placebo by ≥3%. Table 1 Adverse Reactions Adverse Reaction Selexipag tablets N=575 Placebo 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 selexipag tablets and in none of the patients on placebo. Laboratory Test Abnormalities Hemoglobin In a Phase 3 placebo-controlled study in 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 selexipag 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 selexipag tablets and 5 % of placebo-treated patients. Thyroid Function Tests In a Phase 3 placebo-controlled study in 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 the selexipag group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of selexipag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Vascular disorders: Symptomatic hypotension

7 DRUG INTERACTIONS Moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide) increase exposure to the active metabolite of selexipag. Reduce the dosing of selexipag to once daily ( 2.6 , 7.1 , 12.3 ). CYP2C8 inducers (e.g., rifampin) decrease exposure to the active metabolite. Increase up to twice the dose of selexipag ( 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 selexipag with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 )] . Concomitant administration of selexipag 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 selexipag to once daily in patients on a moderate CYP2C8 inhibitor [see Dosage and Administration ( 2.6 )] . 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 dose up to twice of selexipag when co-administered with rifampin. Reduce selexipag when rifampin is stopped [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Discontinue selexipag 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 selexipag 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 to 4% and 15 to 20%, respectively. Data Animal Data Pregnant rats were treated with selexipag using oral doses of 2 mg/kg/day, 6 mg/kg/day, 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 mg/kg, 10 mg/kg, 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 selexipag 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 selexipag. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 1,368 subjects in clinical studies of selexipag tablets, 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 selexipag in patients with severe hepatic impairment (Child-Pugh class C). Avoid use of selexipag in patients with severe hepatic impairment [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Patients with Renal Impairment No adjustment to the dosing regimen is needed in patients with estima …

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 to 4 , DP, FP, and TP).

11 DESCRIPTION Selexipag tablets 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 an off white to 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. Depending on the dose strength, each round film-coated tablet for oral administration contains 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,000 mcg, 1,200 mcg, 1,400 mcg, or 1,600 mcg of selexipag. The tablets include the following inactive ingredients: corn starch, colloidal silicon dioxide, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate. The tablets are film coated with a coating material containing hypromellose, propylene glycol, carnauba wax, titanium dioxide, along with mixtures of ferrosoferric oxide, iron oxide red or iron oxide yellow. Image

10 OVERDOSAGE Isolated cases of overdose with selexipag 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 Selexipag tablets, 200 mcg are beige colored, round, film coated tablet, debossed with "S2" on one side and plain on other side and are supplied as follows: NDC 70710-1551-6 in bottles of 60 tablets with child-resistant closure NDC 70710-1551-8 in bottles of 140 tablets with child-resistant closure Selexipag tablets, 400 mcg are pink colored, round, film coated tablet, debossed with "S4" on one side and plain on other side and are supplied as follows: NDC 70710-1552-6 in bottles of 60 tablets with child-resistant closure Selexipag tablets, 600 mcg are grey colored, round, film coated tablet, debossed with "S6" on one side and plain on other side and are supplied as follows: NDC 70710-1553-6 in bottles of 60 tablets with child-resistant closure Selexipag tablets, 800 mcg are green colored, round, film coated tablet, debossed with "S8" on one side and plain on other side and are supplied as follows: NDC 70710-1554-6 in bottles of 60 tablets with child-resistant closure Selexipag tablets, 1,000 mcg are yellow colored, round, film coated tablet, debossed with "S10" on one side and plain on other side and are supplied as follows: NDC 70710-1555-6 in bottles of 60 tablets with child-resistant closure Selexipag tablets, 1,200 mcg are dark grey colored, round, film coated tablet, debossed with "S12" on one side and plain on other side and are supplied as follows: NDC 70710-1556-6 in bottles of 60 tablets with child-resistant closure Selexipag tablets, 1,400 mcg are dark yellow colored, round, film coated tablet, debossed with "S14" on one side and plain on other side and are supplied as follows: NDC 70710-1557-6 in bottles of 60 tablets with child-resistant closure Selexipag tablets, 1,600 mcg are brown colored, round, film coated tablet, debossed with "S16" on one side and plain on other side and are supplied as follows: NDC 70710-1558-6 in bottles of 60 tablets with child-resistant closure Selexipag tablets are also supplied in a Titration Pack [NDC 70710-1653-7] that includes a 140-count bottle of 200-mcg tablets and a 60-count bottle of 800-mcg tablets. Store at 20oC to 25oC (68oF to 77oF) [see USP Controlled Room Temperature]. Keep this and all drugs out of the reach of children.