-------------------------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. (8.6)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`Revised: 12/2015
`
`
`8.5 Geriatric Use
`
`8.6
`Patients with Hepatic Impairment
`8.7 Renal Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`14.1 Pulmonary Arterial Hypertension
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`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)
`
`
`
`
`2
`
`6
`
`7
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`
`Pulmonary Arterial Hypertension
`1.1
`
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`
`2.2
`Interruptions and Discontinuations
`2.3 Dosage Modifications in Patients with Hepatic Impairment
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Pulmonary Veno-Occlusive Disease (PVOD)
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`DRUG INTERACTIONS
`
`Strong CYP2C8 Inhibitors
`7.1
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Lactation
`8.4
`Pediatric Use
`
`8
`
`
`
`
`
`
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`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`Pulmonary Arterial Hypertension
`1.1
`UPTRAVI is 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 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
`
`Recommended Dosage
`
`2.1
`
`The recommended starting dose of UPTRAVI 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 1600 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.
`
`Interruptions and Discontinuations
`2.2
`If a dose of medication 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 UPTRAVI at a lower dose and then retitrate.
`
`Dosage Adjustment in Patients with Hepatic Impairment
`2.3
`No dose adjustment of UPTRAVI 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
`UPTRAVI 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 UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C).
`
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`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`UPTRAVI is available in the following strengths:
`– 200 mcg [Light yellow tablet debossed with 2]
`– 400 mcg [Red tablet debossed with 4]
`– 600 mcg [Light violet tablet debossed with 6]
`– 800 mcg [Green tablet debossed with 8]
`– 1000 mcg [Orange tablet debossed with 10]
`– 1200 mcg [Dark violet tablet debossed with 12]
`– 1400 mcg [Dark yellow tablet debossed with 14]
`– 1600 mcg [Brown tablet debossed with 16]
`
`
`
` CONTRAINDICATIONS
`
`4
`None.
`
`5
`
`
`WARNINGS AND PRECAUTIONS
`
`Pulmonary Veno-Occlusive Disease (PVOD)
`5.1
` Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If
`
` confirmed, discontinue UPTRAVI.
`
`
`
`6
`
`
`
` ADVERSE REACTIONS
`
`Clinical Trial Experience
`6.1
`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 UPTRAVI has been evaluated in a long-term, placebo-controlled study enrolling
`
` 1156 patients with symptomatic PAH (GRIPHON study) [see Clinical Studies (14)]. The
`exposure to UPTRAVI in this trial was up to 4.2 years with median duration of exposure of 1.4
`years.
`
`
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`Table 1 presents adverse reactions more frequent on UPTRAVI than on placebo by >3%.
`Table 1
`Adverse Reactions
`
`Adverse Reaction
`
`
`Headache
`
`
`Diarrhea
`
`
`Jaw pain
`
`
`Nausea
`
`Myalgia
`
`Vomiting
`
`Pain in Extremity
`
`
`
`
`Flushing
`
`Arthralgia
`
`
`Anemia
`
`
`
`Decreased appetite
`
`UPTRAVI
`
`N=575
`
`65%
`
`42%
`
`26%
`
`33%
`
`16%
`
`18%
`
`
`17%
`
`12%
`
`11%
`
`8%
`
`
`6%
`
`Placebo
`
`N=577
`
`32%
`
`18%
`
`6%
`
`18%
`
`6%
`
`9%
`
`
`8%
`
`5%
`
`
`8%
`
`5%
`
`
`3%
`
`8%
`
`11%
`
`
`Rash
`
`These adverse reactions are more frequent during the dose titration phase.
`
`Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI 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 and 5.0%
`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.
`
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`7
`
`
`
` DRUG INTERACTIONS
`
`Strong CYP2C8 Inhibitors
`7.1
`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
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`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.
`
`Lactation
`8.2
`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
`
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`potential for serious adverse reactions in nursing infants, discontinue nursing or discontinue
`UPTRAVI.
`
`Pediatric Use
`8.4
`Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`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.
`
`Patients with Hepatic Impairment
`8.6
`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)].
`
`Patients with Renal Impairment
`8.7
`
`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)].
`
`
`OVERDOSAGE
`10
`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.
`
`DESCRIPTION
`11
`UPTRAVI (selexipag) is a selective non-prostanoid IP 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:
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`
`
`N
`
`N
`
`N
`
`O
`
`O
`
`O
`
`O
`
`S
`
`NH
`
`
`
`
`
`
` Selexipag is a 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, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The tablets include the
`following inactive ingredients: D-mannitol, corn starch, low substituted hydroxypropylcellulose,
`hydroxypropylcellulose, and magnesium stearate. The tablets are film coated with a coating
`material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with
`mixtures of iron oxide red, iron oxide yellow or iron oxide black.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 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
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`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.
`
`Pharmacokinetics
`12.3
`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.
`
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`
`
`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,
`
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`
`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.
`
`Effect of Other Drugs on UPTRAVI and its Active Metabolite (A) and
` Figure 1
`Effect of UPTRAVI on Warfarin (B)
`
`
`
`
`
`*ERA and PDE-5 inhibitor data from GRIPHON.
`
`
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`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.
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`Mutagenesis: Selexipag and the active metabolite are not genotoxic on the basis of the overall
`evidence of conducted genotoxicity studies.
` Fertility: The no effect dose for effects on fertility was 60 mg/kg/day in a study in which rats
`
`
`were administered selexipag orally. This dose corresponded to an exposure of 175-times (active
`
` metabolite) the human therapeutic exposure.
`
`14
`
`CLINICAL STUDIES
`
`Pulmonary Arterial Hypertension
`14.1
`The effect of selexipag on progression of PAH was demonstrated in a multi-center, double-blind,
`
`placebo-controlled, parallel group, event-driven study (GRIPHON) in 1156 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 UPTRAVI (N = 574). The dose was increased
`in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to
`1600 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 an
`
`endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%).
`Patients on selexipag achieved doses within the following groups: 200 - 400 mcg (23%), 600 ­
`1000 mcg (31%) and 1200 - 1600 mcg (43%).
`Treatment with UPTRAVI 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 2). The beneficial effect of UPTRAVI was primarily attributable to a reduction in
`hospitalization for PAH and a reduction in other disease progression events (Table 2). The
`observed benefit of UPTRAVI was similar regardless of the dose achieved when patients are
`titrated to their highest tolerated dose [see Dosage and Administration (2.1)].
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`Figure 2
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`
`
`Kaplan-Meier Estimates of the First Morbidity-Mortality Event
`GRIPHON
`
`
`in
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`
`
`242
`
`109
`100
`
`
`
`18
`13
`
`2
`
`78
`38
`
`
`
`28
`10
`
`1
`
`
`
`13.6
`6.6
`
`
`
`4.9
`1.7
`
`0.2
`
`Table 2 Primary Endpoints and Related Components in GRIPHON
`UPTRAVI
`Placebo
`Hazard Ratio
`N=574
`N=582
`(99% CI)
`n
`%
`n
`%
`Primary endpoint events up to the end of treatment
`155
`27.0
`All primary endpoint events
`
`As first event:
` Hospitalization for PAH
` Other disease Progression
`(Decrease in 6MWD plus
`worsening functional class or
`need for other therapy)
` Death
` Parenteral prostanoid or
`chronic oxygen therapy
` PAH worsening resulting in
`need for lung transplantation
`
`or balloon atrial septostomy
`
`
`
`p-value
`
`
`
`
`
`41.6
`
`0.60 [0.46,0.78] <0.0001
`
`18.7
`17.2
`
`
`
`3.1
`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 3A, 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
`
`UPTRAVI at this point).
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`Figure 3 A
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`Hospitalization for PAH as the First Endpoint in GRIPHON
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`Figure 3B
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`Disease Progression as the First Endpoint in GRIPHON
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`Figure 3 C
`
`Death as the First Endpoint in GRIPHON
`
`
`The treatment effect of UPTRAVI on time to first primary event was consistent irrespective of
`
`(i.e., in combination with ERA, PDE5i, or both, or without
`background PAH therapy
`background therapy) (Figure 4).
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`Figure 4
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`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 UPTRAVI
`
`
`
`
` patients with events, NU = Number of patients randomized to UPTRAVI, 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.
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`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 UPTRAVI 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).
`
`HOW SUPPLIED/STORAGE AND HANDLING
` 16
`
`UPTRAVI (selexipag) film-coated, round tablets are supplied in the following configurations:
`
`Strength
`(mcg)
`
`
`Color
`
`
`
` Debossing
`
`200
`
`400
`
`
`600
`
`800
`
`1000
`
`1200
`
`1400
`
`1600
`
`
`Light yellow
`
`Red
`
`
`Light violet
`
`Green
`
`
`Orange
`
`
`Dark violet
`
`
`Dark yellow
`
`Brown
`
`2
`
`4
`
`
`6
`
`8
`
`
`10
`
`
`12
`
`
`14
`
`
`16
`
`
` NDC-XXX
`
` Bottle of 60
`
`
` NDC-XXX
`
` Bottle of 140
`
`
`66215-602-06
`
`66215-602-14
`
`66215-604-06
`
`Not Applicable
`
`
`66215-606-06
`
`
`Not Applicable
`
`66215-608-06
`
`Not Applicable
`
`66215-610-06
`
`Not Applicable
`
`66215-612-06
`
`Not Applicable
`
`66215-614-06
`
`Not Applicable
`
`66215-616-06
`
`Not Applicable
`
`
` Store at 20ºC to 25ºC (68ºF to 77ºF). Excursions are permitted between 15°C and 30°C (59°F
`and 86°F). [See USP Controlled Room Temperature].
`
`
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`PATIENT COUNSELING INFORMATION
`17
`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.
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` Patient Information
`
`UPTRAVI (up-TRA-vee)
`
`(selexipag) tablets
`Read this Patient Information before you start taking UPTRAVI and each time you get a refill. There may
`be new information. This information does not take the place of talking to your healthcare provider about
`
`your medical condition or your treatment.
`What is UPTRAVI?
`
` UPTRAVI is a prescription medicine used to treat pulmonary arterial hypertension (PAH) which is high
`
`blood pressure in the arteries of your lungs.
`
`
` UPTRAVI can help slow down the progression of your disease and lower your risk of being hospitalized
`for PAH.
`
`It is not known if UPTRAVI is safe and effective in children.
`What should I tell my healthcare provider before taking UPTRAVI?
`
`Before you take UPTRAVI, tell your healthcare provider if you:
`
` 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 UPTRAVI will harm your unborn baby.
`
` are breastfeeding or plan to breastfeed. It is not known if UPTRAVI passes into your breast milk. You
`and your healthcare provider should decide if you will take UPTRAVI or breastfeed. You should not do
`both.
`
` have any other medical conditions
`Tell your healthcare provider about all the medicines you take, including prescription and over-the­
`counter medicines, vitamins, and herbal supplements. UPTRAVI and other medicines may affect each
`other causing side effects. Do not start any new medicine until you check with your healthcare provider.
`
`How should I take UPTRAVI?
`
` Take UPTRAVI exactly as your healthcare provider tells you to take it. Do not stop taking UPTRAVI
`unless your healthcare provider tells you to stop.
`
` Your healthcare provider will slowly increase your dose to find the dose of UPT