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)] .

2.1 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)].

5.1 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.

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%.

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

7.1 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.

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 estimated glomerular filtration rate >15 mL/min/1.73 m2.

There is no clinical experience with selexipag in patients undergoing dialysis or in patients with glomerular filtration rates < 15 mL/min/1.73 m2[see Clinical Pharmacology (12.3)].

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 (EP1 to 4, DP, FP, and TP).

12.2 Pharmacodynamics

Cardiac Electrophysiology:

At the maximum tolerated dose of 1,600 mcg selexipag tablets 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 tablets in healthy subjects from 400 mcg up to 1,800 mcg twice daily.

Pulmonary Hemodynamics:

A Phase 2 clinical study assessed hemodynamic variables after 17 weeks of oral treatment in patients with PAH WHO Functional Class II–III and concomitantly receiving another PAH therapy and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating selexipag tablets 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 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 tablets (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 oral administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1,800 mcg twice daily.

In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state following oral administration 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.

The corresponding selexipag tablets and selexipag for injection doses provide similar exposure to the active metabolite in PAH patients at steady-state, whereas the exposure to selexipag is approximately twice as high after intravenous administration compared to oral administration.

Both in healthy subjects and PAH patients, after oral administration, exposure at steady-state to the active metabolite is approximately 3-to 4-fold that of selexipag.

Absorption

The absolute bioavailability of orally administered selexipag is approximately 49%. Upon oral administration, maximum observed plasma concentrations of selexipag and its active metabolite are reached within about 1 to 3 hours and 3 to 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

The volume of distribution of selexipag at steady-state is 11.7 L.

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 is hydrolyzed to its active metabolite, (free carboxylic acid) in the liver and intestine by carboxylesterases. Oxidative metabolism, catalyzed mainly by CYP2C8 and to a smaller extent by CYP3A4, 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.

Elimination

Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8 to 2.5 hours. The terminal half-life of the active metabolite is 6.2 to 13.5 hours. Selexipag does not accumulate following twice daily repeat administration. There is minimal accumulation of the active metabolite upon twice daily repeat administration suggesting that the effective half-life is in the range of 3 to 4 hours. The total body clearance of selexipag is 17.9 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 to 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 m2and <30 mL/min/1.73 m2) [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Drug interaction studies have been performed in adult subjects using selexipag tablets.

In Vitro Studies

Selexipag is hydrolyzed to its active metabolite by carboxylesterases. Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by 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, 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 cytochrome P450 enzymes and transport proteins at clinically relevant concentrations.

The results of in vivo drug interaction studies are presented in Figure 1 and 2.

Figure 1 Effect of Other Drugs on Selexipag and its Active Metabolite

*PDE-5 inhibitor data from GRIPHON.

Figure 2 Effect of Selexipag on Other Drugs

13.1 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 which resulted in the exposures to the active metabolite more than 25 times the human exposure at the maximum recommended human oral dose of 1,600 mcg twice daily on an AUC basis.

Mutagenesis: Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted genotoxicity studies.

Fertility: In rats administered with selexipag orally, the no effect dose for effects on fertility was 60 mg/kg/day which resulted in the exposure to the active metabolite approximately 175 times the human exposure at the maximum recommended human oral dose of 1,600 mcg twice daily on an AUC basis.

14.1 Efficacy of Selexipag Tablets in Patients with Pulmonary Arterial Hypertension

The effect of selexipag tablets on progression of PAH was demonstrated in a multi-center, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON) in 1,156 patients with symptomatic (WHO Functional Class I [0.8%], II [46%], III [53%], and IV [1%]) PAH. Patients were randomized to either placebo (N = 582), or selexipag tablets (N = 574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1,600 mcg twice a day.

The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15% decrease from baseline in 6MWD plus worsening of Functional Class or need for additional PAH-specific therapy.

The mean age was 48 years, the majority of patients were white (65%) and female (80%). Nearly all patients were in WHO Functional Class II and III at baseline.

Idiopathic or heritable PAH was the most common etiology in the study population (58%) followed by PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%).

At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of another PAH therapy (15%), PDE-5 inhibitor (32%), or both (33%).

Patients on selexipag tablets achieved doses within the following groups: 200 to 400 mcg (23%), 600 to 1,000 mcg (31%) and 1,200 to 1,600 mcg (43%).

Treatment with selexipag tablets resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank p-value < 0.0001) of the occurrence of primary endpoint events compared to placebo (Table 2; Figure 3). The beneficial effect of selexipag was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events (Table 2). The observed benefit of selexipag was similar regardless of the dose achieved when patients were titrated to their highest tolerated dose [see Dosage and Administration (2.1)].

Figure 3 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in GRIPHON

Table 2 Primary Endpoints and Related Components in GRIPHON

It is not known if the excess number of deaths in the selexipag group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON.

Figures 4A, B, and C show time to first event analyses for primary endpoint components of hospitalization for PAH (A), other disease progression (B), and death (C) all censored 7 days after any primary end point event (because many patients on placebo transitioned to open-label selexipag at this point).

Figure 4A Hospitalization for PAH as the First Endpoint in GRIPHON

Figure 4B Disease Progression as the First Endpoint in GRIPHON

Figure 4C Death as the First Endpoint in GRIPHON

The treatment effect of selexipag on time to first primary event was consistent irrespective of background PAH therapy (i.e. in combination with another PAH therapy, PDE-5i, both, or without background therapy) (Figure 5).

Figure 5 Subgroup Analyses of the Primary Endpoint in GRIPHON

Note: Race group "Other" is not displayed in analysis, as the population is less than 30. EU = Number of selexipag patients with events, NU = Number of patients randomized to selexipag, EP = Number of Placebo patients with events, NP = Number of patients randomized to Placebo, HR = Hazard Ratio, CI = Confidence Interval, the size of the squares represent the number of patients in the subgroup.

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all were pre-specified. The 99% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

6-Minute Walk Distance (6MWD)

Exercise capacity was evaluated as a secondary endpoint. Median absolute change from baseline to week 26 in 6MWD measured at trough (i.e., at approximately 12 hours post-dose) was +4 meters with selexipag and -9 meters in the placebo group. This resulted in a placebo-corrected median treatment effect of 12 meters (99% CI: 1, 24 meters; two-sided p = 0.005).

Long-Term Treatment of PAH

In long-term follow-up of patients who were treated with selexipag in the pivotal study and the open-label extension (N=574), Kaplan-Meier estimates of survival of these patients across the GRIPHON study and the long-term extension study at 1, 2, 5 and 7 years were 92%, 85%, 71%, and 63%, respectively. The median exposure to selexipag was 3 years. These uncontrolled observations do not allow comparison with a control group not given selexipag and cannot be used to determine the long-term effect of selexipag on mortality.