Selexipag

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 )] .

5 WARNINGS AND PRECAUTIONS Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment. ( 5.1 ) 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 selexipag.

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 )

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 )] .

8.1 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.

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