Selexipag TITRATION PACK Dailymed
Generic: selexipag
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Recent Major Changes
Contraindications ( 4 )Â Â Â Â Â Â Â Â Â Â Â Â Â Â 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 )
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-OcclusiveDisease
Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease. If confirmed, discontinue selexipag.
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.
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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 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)].
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.
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 C26H32N4O4S 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.
12 Clinical Pharmacology
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 Nonclinical Toxicology
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 Clinical Studies
14.1 Efficacy of Selexipag Tablets in Patients withPulmonary 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
Selexipag N=574 Placebo N=582 Hazard Ratio (99% CI) p-value n % n % Primary endpoint events up to the end of treatment All primary endpoint events As first event: 155 27.0 242 41.6 0.60 [0.46,0.78] <0.0001 • Hospitalization for PAH • Other disease progression (Decrease in 6MWD plus worsening functional class or need for other therapy) • Death 78 38 13.6 6.6 109 100 18.7 17.2 28 4.9 18 3.1 • Parenteral prostanoid or chronic oxygen therapy • PAH worsening resulting in need for lung transplantation or balloon atrial septostomy 10 1 1.7 0.2 13 2 2.2 0.3 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.
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 70771-1793-6 in bottles of 60 tablets with child-resistant closure
NDC 70771-1793-8 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 70771-1794-6 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 70771-1795-6 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 70771-1796-6 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 70771-1797-6 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 70771-1798-6 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 70771-1799-6 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 70771-1800-6 in bottles of 60 tablets with child-resistant closure
Selexipag tablets are also supplied in a Titration Pack [NDC 70771-1801-7] 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.
17 Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform Patients:
- To take a missed dose as soon as possible, unless the next dose is within the next 6 hours.
- Not to split, crush, or chew tablets.
Manufactured by:
Zydus Lifesciences Ltd.
Ahmedabad, India
Rev.: 09/22
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Spl Patient Package Insert Section
PATIENT INFORMATION Selexipag (se lex' i pag) tablets What is selexipag tablets? It is not known if selexipag tablets are safe and effective in children.
- Selexipag tablets are a prescription medicine used to treat pulmonary arterial hypertension (PAH) which is high blood pressure in the arteries of your lungs.
- Selexipag tablets can help slow down the progression of your disease and lower your risk of being hospitalized for PAH.
Do not take selexipag tablets if you
- take gemfibrozil because this medicine may affect how selexipag tablets work and cause side effects.
- are allergic to selexipag or any of the other ingredients of this medicine (uled under Inactive ingredients).
Before you take selexipag tablets, tell your healthcare provider about all of your medical conditions, including if you: Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Selexipag tablets and other medicines may affect each other causing side effects. Do not start any new medicine until you check with your healthcare provider.
- have liver problems.
- have narrowing of the pulmonary veins, a condition called pulmonary veno-occlusive disease.
- are pregnant or plan to become pregnant. It is not known if selexipag tablets will harm your unborn baby.
- are breastfeeding or plan to breastfeed. It is not known if selexipag passes into your breast milk. You and your healthcare provider should decide if you will take selexipag tablets or breastfeed. You should not do both.
How should I take selexipag tablets?
- Take selexipag tablets exactly as your healthcare provider tells you to take it. Do not stop taking selexipag tablets unless your healthcare provider tells you to stop.
- Your healthcare provider will slowly increase your dose to find the dose of selexipag tablets that is right for you.
- If you have side effects, your healthcare provider may tell you to change your dose of selexipag tablets.
- Selexipag tablets can be taken with or without food. Taking selexipag tablets with food may help you tolerate selexipag tablets better.
- Selexipag tablets are usually taken 2 times each day.
- Swallow selexipag tablets whole. Do not split, crush or chew selexipag tablets.
- If you miss a dose of selexipag tablets, take it as soon as you remember. If your next scheduled dose is due within 6 hours, skip the missed dose. Take the next dose at your regular time.
- If you miss 3 or more days of selexipag tablets, call your healthcare provider to see if your dose needs to be changed.
- If you take too much selexipag tablets, call your healthcare provider or go to the nearest hospital emergency room right away.
What are the possible side effects of selexipag tablets? The most common side effects of selexipag tablets include:
- headache
- jaw pain
- muscle pain
- pain in arms or legs
- pain in joints
- decreased appetite
- diarrhea
- nausea
- vomiting
- flushing
- low red blood cell count
- rash
These are not all of the possible side effects of selexipag tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store selexipag tablets? Keep selexipag tablets and all medicines out of the reach of children.
- Store selexipag tablets at room temperature between 68°F and 77°F (20°C and 25°C).
General information about the safe and effective use of selexipag tablets Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use selexipag tablets for a condition for which it was not prescribed. Do not give selexipag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about selexipag tablets that is written for health professionals. What are the ingredients in selexipag tablets? Active ingredient: selexipag 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. Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India For more information, call 1-877-993-8779. The Patient Information has been approved by the U.S. Food and Drug Administration.         Revised: 09/2022
Package Label.principal Display Panel
NDC 70771-1793-6
Selexipag Tablets
200 mcg
60 Tablets
Rx only
NDC 70771-1794-6
Selexipag Tablets
400 mcg
60 Tablets
Rx only
NDC 70771-1795-6
Selexipag Tablets
600 mcg
60 Tablets
Rx only
NDC 70771-1796-6
Selexipag Tablets
800 mcg
60 Tablets
Rx only
NDC 70771-1797-6
Selexipag Tablets
1,000 mcg
60 Tablets
Rx only
NDC 70771-1798-6
Selexipag Tablets
1,200 mcg
60 Tablets
Rx only
NDC 70771-1799-6
Selexipag Tablets
1,400 mcg
60 Tablets
Rx only
NDC 70771-1800-6
Selexipag Tablets
1,600 mcg
60 Tablets
Rx only
NDC 70771-1801-7
TITRATION PACK
Selexipag Tablets
200 mcg
140 Tablets
Rx only
Selexipag Tablets
800 mcg
60 Tablets
Rx only
DISCLAIMER:
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
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