`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`OPSUMIT safely and effectively. See full prescribing information
`for OPSUMIT.
`OPSUMIT (macitentan) tablets, for oral use
`
`
`Initial U.S. Approval: 2013
`
`WARNING: EMBRYO-FETAL TOXICITY
`See full prescribing information for complete boxed warning
`• Do not administer OPSUMIT to a pregnant female because it
`may cause fetal harm (4.1, 5.1, 8.1).
`• Females of reproductive potential: exclude pregnancy before
`
`start of treatment, monthly during treatment, and 1 month
`treatment. Prevent pregnancy during
`after
`stopping
`
`treatment and for one month after treatment by using
`
`acceptable methods of contraception (2.2, 8.6).
`
`• For all female patients, OPSUMIT is available only through
`
`a restricted program called the OPSUMIT Risk Evaluation
`and Mitigation Strategy (REMS) (5.2).
`
`
`
`----------------------RECENT MAJOR CHANGES----------------------
` Warnings and Precautions (5.4)
` 03/2017
`
`
`
`
`
`
`-----------------------INDICATIONS AND USAGE----------------------
`OPSUMIT is an endothelin receptor antagonist (ERA) indicated for
`
`the treatment of pulmonary arterial hypertension (PAH, WHO Group
`
`I) to delay disease progression. Disease progression included: death,
`
`initiation of intravenous (IV) or subcutaneous prostanoids, or clinical
`worsening of PAH (decreased 6-minute walk distance, worsened
`
`PAH symptoms and need for additional PAH treatment). OPSUMIT
`also reduced hospitalization for PAH (1.1).
`------------------DOSAGE AND ADMINISTRATION-----------------
`10 mg once daily. Doses higher than 10 mg once daily have not
`
`
`
`
`been studied in patients with PAH and are not recommended
`(2.1).
`
`
`
`----------------DOSAGE FORMS AND STRENGTHS-----------------
`Tablet: 10 mg (3)
`
`
`
`-------------------------CONTRAINDICATIONS-------------------------
`Pregnancy (4.1)
`
`
`
`
`-------------------WARNINGS AND PRECAUTIONS----------------
`ERAs cause hepatotoxicity and liver failure. Obtain baseline
`
`
`
`liver enzymes and monitor as clinically indicated (5.3).
`
`Fluid retention may require intervention (5.4).
`
`
`
` Decreases in hemoglobin (5.5).
`
`Pulmonary edema in patients with pulmonary veno-occlusive
`
`
`
`disease. If confirmed, discontinue treatment (5.6).
`
` Decreases in sperm count have been observed in patients taking
`
`
`ERAs (5.7).
`-------------------------ADVERSE REACTIONS--------------------------
`Most common adverse reactions (more frequent than placebo by
`
`≥3%) are anemia, nasopharyngitis/pharyngitis, bronchitis, headache,
`influenza, and urinary tract infection (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 CYP3A4 inducers (rifampin) reduce exposure to macitentan:
`avoid co-administration with OPSUMIT (7.1, 12.3).
`Strong CYP3A4
`inhibitors
`(ketoconazole,
`ritonavir)
`increase
`exposure to macitentan: avoid co-administration with OPSUMIT
`
`(7.2, 12.3).
`--------------------USE IN SPECIFIC POPULATIONS-----------------
`Nursing mothers: discontinue OPSUMIT or breastfeeding (8.3).
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`
`Revised: 03/2017
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: EMBRYO-FETAL TOXICITY
`INDICATIONS AND USAGE
`1
`
`1.1 Pulmonary Arterial Hypertension
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Pregnancy Testing in Females of Reproductive
`
`Potential
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`
`4.1 Pregnancy
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Embryo-fetal Toxicity
`5.2 OPSUMIT REMS Program
`
`5.3 Hepatotoxicity
`
`
`5.4 Fluid Retention
`
`5.5 Hemoglobin Decrease
`5.6 Pulmonary Edema with Pulmonary Veno-occlusive
`
`Disease (PVOD)
`5.7 Decreased Sperm Counts
`
` ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`
`
`6.2 Postmarketing Experience
` DRUG INTERACTIONS
`
`7.1 Strong CYP3A4 Inducers
`
`
`
`6
`
`7
`
`
`
`7.2 Strong CYP3A4 Inhibitors
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Females and Males of Reproductive Potential
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
` NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology
`
` 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.
`
`13
`
`14
`
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`FULL PRESCRIBING INFORMATION
`
`WARNING: EMBRYO-FETAL TOXICITY
`
` Do not administer OPSUMIT to a pregnant female because it may cause fetal harm
`
`
`[see Contraindications (4.1), Warnings and Precautions (5.1), Use in Specific
`
`Populations (8.1)].
`
` Females of reproductive potential: Exclude pregnancy before the start of treatment,
`
`monthly during treatment, and 1 month after stopping treatment. Prevent
`pregnancy during treatment and for one month after stopping treatment by using
`acceptable methods of contraception [see Use in Specific Populations (8.6)].
`
` For all female patients, OPSUMIT is available only through a restricted program
`
`called the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) [see
`
`Warnings and Precautions (5.2)].
`
`1
`
`INDICATIONS AND USAGE
`
`Pulmonary Arterial Hypertension
`1.1
`OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary
`arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression
`included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening
`of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional
`PAH treatment). OPSUMIT also reduced hospitalization for PAH.
`Effectiveness was established in a long-term study in PAH patients with predominantly
`
`WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated
`with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled
`prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue
`
`disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%) [see
`Clinical Studies (14.1)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosage
`2.1
`The recommended dosage of OPSUMIT is 10 mg once daily for oral administration. Doses
`higher than 10 mg once daily have not been studied in patients with PAH and are not
`recommended.
`
`Pregnancy Testing in Females of Reproductive Potential
`2.2
`Initiate treatment with OPSUMIT in females of reproductive potential only after a negative
`pregnancy test. Obtain monthly pregnancy test during treatment [see Use in Specific Populations
`
`(8.6)].
`
`
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`DOSAGE FORMS AND STRENGTHS
`3
`Tablets: 10 mg, bi-convex film-coated, round, white, and debossed with “10” on one side.
`
`4
`
`
`
` CONTRAINDICATIONS
`
`Pregnancy
`4.1
` OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is
`
`contraindicated in females who are pregnant. OPSUMIT was consistently shown to have
`teratogenic effects when administered to animals. If OPSUMIT is used during pregnancy,
`apprise the patient of the potential hazard to a fetus [see Warnings and Precautions (5.1) and
`
` Use in Specific Populations (8.1)].
`
`5
`
`
`
` WARNINGS AND PRECAUTIONS
`
`Embryo-fetal Toxicity
`5.1
` OPSUMIT may cause fetal harm when administered during pregnancy and is contraindicated for
`
`use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to
`initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly
`
`pregnancy tests [see Dosage and Administration (2.2) and Use in Specific Populations (8.1,
`8.6)].
`OPSUMIT is available for females through the OPSUMIT REMS Program, a restricted
`distribution program [see Warnings and Precautions (5.2)].
`
`
`OPSUMIT REMS Program
`5.2
`For all females, OPSUMIT is available only through a restricted program called the OPSUMIT
`REMS Program, because of the risk of embryo-fetal toxicity [see Contraindications (4.1),
`Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].
`Notable requirements of the OPSUMIT REMS Program include the following:
` Prescribers must be certified with the program by enrolling and completing training.
`
` All females, regardless of reproductive potential, must enroll in the OPSUMIT REMS
`
`Program prior to initiating OPSUMIT. Male patients are not enrolled in the REMS.
` Females of reproductive potential must comply with the pregnancy testing and
`
`contraception requirements [see Use in Specific Populations (8.6)].
` Pharmacies must be certified with the program and must only dispense to patients who
`
`are authorized to receive OPSUMIT.
`
`Further information is available at www.OPSUMITREMS.com or 1-866-228-3546. Information
`on OPSUMIT certified pharmacies or wholesale distributors is available through Actelion
`Pathways at 1-866-228-3546.
`
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`Hepatotoxicity
`5.3
`ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The
`incidence of elevated aminotransferases in the study of OPSUMIT in PAH is shown in Table 1.
`Table 1
` Incidence of Elevated Aminotransferases in the SERAPHIN Study
`OPSUMIT 10 mg
`Placebo
`(N=242)
`(N=249)
`
`
`
`
`
`4.5%
`3.4%
`>3 x ULN
`
`
`
`0.4%
`2.1%
`>8 x ULN
` In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were
`
` 3.3% in the OPSUMIT 10 mg group vs. 1.6% for placebo.
`Obtain liver enzyme tests prior to initiation of OPSUMIT and repeat during treatment as
`clinically indicated [see Adverse Reactions (6.2)].
`Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper
`quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant
`
`aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin
`>2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT. Consider re­
`initiation of OPSUMIT when hepatic enzyme levels normalize in patients who have not
`
`experienced clinical symptoms of hepatotoxicity.
`
`Fluid Retention
`5.4
`Peripheral edema and fluid retention are known clinical consequences of PAH and known effects
`
`of ERAs. In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema was
`21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group.
`Patients with underlying left ventricular dysfunction may be at particular risk for developing
`significant fluid retention after initiation of ERA treatment. In a small study of OPSUMIT in
`patients with pulmonary hypertension because of left ventricular dysfunction, more patients in
`the OPSUMIT group developed significant fluid retention and had more hospitalizations because
`
`of worsening heart failure compared to those randomized to placebo. Postmarketing cases of
`edema and fluid retention occurring within weeks of starting OPSUMIT, some requiring
`intervention with a diuretic or hospitalization for decompensated heart failure, have been
`reported [see Adverse Reactions (6.2)].
`Monitor for signs of fluid retention after OPSUMIT initiation. If clinically significant fluid
`retention develops, evaluate the patient to determine the cause, such as OPSUMIT or underlying
`heart failure, and the possible need to discontinue OPSUMIT.
`
`Hemoglobin Decrease
`5.5
`Decreases in hemoglobin concentration and hematocrit have occurred following administration
`of other ERAs and were observed in clinical studies with OPSUMIT. These decreases occurred
`early and stabilized thereafter. In the placebo-controlled study of OPSUMIT in PAH,
`OPSUMIT 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of
`about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below
`10.0 g/dL was reported in 8.7% of the OPSUMIT 10 mg group and in 3.4% of the placebo group.
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`
` is not
`transfusion. Initiation of OPSUMIT
`in hemoglobin seldom require
`Decreases
`
`recommended in patients with severe anemia. Measure hemoglobin prior to initiation of
`treatment and repeat during treatment as clinically indicated [see Adverse Reactions (6.1)].
`
`Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
`5.6
`
`Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If
`confirmed, discontinue OPSUMIT.
`
`Decreased Sperm Counts
`5.7
`Other ERAs have caused adverse effects on spermatogenesis. Counsel men about potential
`effects on fertility [see Use in Specific Populations (8.6) and Nonclinical Toxicology (13.1)].
`
` ADVERSE REACTIONS
`6
`
`Clinically significant adverse reactions that appear in other sections of the labeling include:
` Embryo-fetal Toxicity [see Warnings and Precautions (5.1)]
`
`
` Hepatotoxicity [see Warnings and Precautions (5.3)]
`
`
` Fluid Retention [see Warnings and Precautions (5.4)]
`
`
` Decrease in Hemoglobin [see Warnings and Precautions (5.5)]
`
`
`
`Clinical Trial Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in 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 clinical practice.
`
`Safety data for OPSUMIT were obtained primarily from one placebo-controlled clinical study in
`742 patients with PAH (SERAPHIN study) [see Clinical Studies (14)]. The exposure to
`OPSUMIT in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1
`
`year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment
`discontinuations because of adverse events was similar across OPSUMIT 10 mg and placebo
`treatment groups (approximately 11%).
`Table 2 presents adverse reactions more frequent on OPSUMIT than on placebo by ≥3%.
`Table 2
`Adverse Reactions
`
`Adverse Reaction
`Anemia
`Nasopharyngitis/pharyngitis
`Bronchitis
`Headache
`Influenza
`Urinary tract infection
`
`OPSUMIT 10 mg
`(N=242)
`
`(%)
`
`13
`
`20
`
`12
`14
`
`6
`9
`
`Placebo
`
`(N=249)
`
`(%)
`
`3
`
`13
`6
`9
`
`2
`6
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`Postmarketing Experience
`6.2
`The following adverse reactions have been identified during postapproval use of OPSUMIT.
`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.
`Immune system disorders: hypersensitivity reactions (angioedema, pruritus and rash)
`Respiratory, thoracic and mediastinal disorders: nasal congestion
`Gastrointestinal disorders: Elevations of liver aminotransferases (ALT, AST) and liver injury
`have been reported with Opsumit use; in most cases alternative causes could be identified (heart
`failure, hepatic congestion, autoimmune hepatitis). Endothelin receptor antagonists have been
`
`
`associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see
`Warnings and Precautions (5.3)].
`General disorders and administration site conditions: edema/fluid retention. Cases of edema and
`fluid retention occurred within weeks of starting Opsumit, some requiring intervention with a
`diuretic, fluid management or hospitalization for decompensated heart failure [see Warnings and
`Precautions (5.4)].
`Cardiac disorders: symptomatic hypotension
`
`7
`
`
`
` DRUG INTERACTIONS
`
` Strong CYP3A4 Inducers
`7.1
`
`Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure.
`
` Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided [see Clinical
`Pharmacology (12.3)].
`
`Strong CYP3A4 Inhibitors
`7.2
`Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double
`macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid
`
` concomitant use of OPSUMIT with strong CYP3A4 inhibitors [see Clinical Pharmacology
`(12.3)]. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of
`HIV treatment [see Clinical Pharmacology (12.3)].
`
`8
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category X.
`Risk Summary
`OPSUMIT may cause fetal harm when administered to a pregnant woman and is contraindicated
`during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect
`dose was not established in either species. If this drug is used during pregnancy, or if the patient
`becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see
`Contraindications (4.1)].
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`Animal Data
`In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities.
`
`Administration of macitentan to female rats from late pregnancy through lactation caused
`reduced pup survival and impairment of the male fertility of the offspring at all dose levels
`tested.
`
`Nursing Mothers
`8.3
`
`It is not known whether OPSUMIT is present in human milk. Macitentan and its metabolites
`were present in the milk of lactating rats. Because many drugs are present in human milk and
`because of the potential for serious adverse reactions from macitentan in nursing infants, nursing
`mothers should discontinue nursing or discontinue OPSUMIT.
`
`Pediatric Use
`8.4
`The safety and efficacy of OPSUMIT in children have not been established.
`
`Geriatric Use
`8.5
`Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and
`over. No overall differences in safety or effectiveness were observed between these subjects and
`younger subjects.
`
`Females and Males of Reproductive Potential
`
`8.6
`Females
`Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy
`test prior to starting treatment with OPSUMIT and monthly pregnancy tests during treatment
`with OPSUMIT. Advise patients to contact their health care provider if they become pregnant or
`suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason.
`
`For positive pregnancy tests, counsel patients on the potential risk to the fetus [see Boxed
`Warning and Dosage and Administration (2.2)].
`Contraception: Female patients of reproductive potential must use acceptable methods of
`contraception during treatment with OPSUMIT and for 1 month after treatment with OPSUMIT.
`
`Patients may choose one highly effective form of contraception (intrauterine devices (IUD),
`contraceptive implants or tubal sterilization) or a combination of methods (hormone method with
`
`a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of
`
`contraception, a hormone or barrier method must be used along with this method. Counsel
`patients on pregnancy planning and prevention, including emergency contraception, or designate
`counseling by another healthcare provider trained in contraceptive counseling [see Boxed
`Warning].
`Males
`Testicular effects: Like other endothelin receptor antagonists, OPSUMIT may have an adverse
`effect on spermatogenesis [see Warnings and Precautions (5.7) and Nonclinical Toxicology
`(13.1)].
`
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`OVERDOSAGE
`10
`OPSUMIT has been administered as a single dose of up to and including 600 mg to healthy
`subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting
`were observed. In the event of an overdose, standard supportive measures should be taken, as
`required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.
`
`DESCRIPTION
`11
`OPSUMIT (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan
`is
`N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'­
`propylsulfamide. It has a molecular formula of C19H20Br2N6O4S and a molecular weight of
`588.27. Macitentan is achiral and has the following structural formula:
`
`
`
`
`
`Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very
`stable, is not hygroscopic, and is not light sensitive.
`OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration. The
`tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate,
`microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The
`tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc,
`titanium dioxide, and xanthan gum.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such
`as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions
`
`such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in
`organ damage.
`Macitentan is an endothelin receptor antagonist that prevents the binding of ET-1 to both ETA
`
`and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET
`
`
`receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan
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` is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent
`as the parent drug in vitro.
`
` Pharmacodynamics
`12.2
`
`Pulmonary Hemodynamics: The clinical efficacy study in patients with pulmonary arterial
`
` hypertension assessed hemodynamic parameters in a subset of patients after 6 months of
`treatment. Patients treated with OPSUMIT 10 mg (N=57) achieved a median reduction of 37%
`(95% CI 22-49) in pulmonary vascular resistance and an increase of 0.6 L/min/m2 (95% CI
`0.3-0.9) in cardiac index compared to placebo (N=67).
`Cardiac Electrophysiology: In a randomized, placebo-controlled four-way crossover study with a
`positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the
`
`recommended dosage) had no significant effect on the QTc interval.
`
`Pharmacokinetics
`12.3
`The pharmacokinetics of macitentan and its active metabolite have been studied primarily in
`healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1
`mg to 30 mg after once daily administration.
`A cross study comparison shows that the exposures to macitentan and its active metabolite in
`patients with PAH are similar to those observed in healthy subjects.
`Absorption and Distribution
`The maximum plasma concentration of macitentan is achieved about 8 hours after oral
`administration. The absolute bioavailability after oral administration is not known. In a study in
`
`
`healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a
`high fat breakfast. Macitentan may therefore be taken with or without food.
`
`Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to
`albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution
`(Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy
`subjects.
`
`Metabolism and Elimination
`Following oral administration, the apparent elimination half-lives of macitentan and its active
`metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized
`primarily by oxidative depropylation of the sulfamide to form the pharmacologically active
`metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4
`with a minor contribution of CYP2C19. At steady state in PAH patients, the systemic exposure
`to the active metabolite is 3-times the exposure to macitentan and is expected to contribute
`approximately 40% of the total pharmacologic activity. In a study in healthy subjects with
`radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine
`but none was in the form of unchanged drug or the active metabolite. About 24% of the
`radioactive drug material was recovered from feces.
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` Special Populations
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`There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan
`
`and its active metabolite.
`Renal impairment: Exposure to macitentan and its active metabolite in patients with severe renal
`impairment (CrCl 15-29 mL/min) compared to healthy subjects was increased by 30% and 60%,
`respectively. This increase is not considered clinically relevant.
`Hepatic impairment: Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure
`to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate,
`
`or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not
`
`considered clinically relevant.
`
`Drug Interactions
`In vitro studies
`At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory
`
`or inducing effects on CYP enzymes, and is neither a substrate nor an inhibitor of the multi-drug
`
`resistance protein (P-gp, MDR-1). Macitentan and its active metabolite are neither substrates nor
`inhibitors of the organic anion transporting polypeptides (OATP1B1 and OATP1B3) and do not
`significantly interact with proteins involved in hepatic bile salt transport, i.e., the bile salt export
`pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).
`In vivo studies
`Effect of other drugs on macitentan: The effect of other drugs on macitentan and its active
`metabolite are studied in healthy subjects and are shown in Figure 1 below.
`
` Figure 1
`
`
`Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but
`are likely to result in an increase in macitentan exposure at steady state similar to that seen with
`ketoconazole [see Drug Interactions (7.2)].
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`Effect of macitentan on other drugs
`Warfarin: Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their
`effect on international normalized ratio (INR).
`Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during
`concomitant administration of macitentan 10 mg once daily. This change is not considered
`clinically relevant.
`
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`Carcinogenesis: Carcinogenicity studies of 2 years’ duration did not reveal any carcinogenic
`potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and
`female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively.
`Mutagenesis: Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays
`
`
`that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma
`cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in
`
`rats.
`Impairment of Fertility: Treatment of juvenile rats from postnatal Day 4 to Day 114 led to
`reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure.
`Fertility was not affected.
`Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures
`greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years
`of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not
`affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure,
`respectively, and had no effect on sperm count, motility, and morphology in male rats. No
`
`testicular findings were noted in mice after treatment up to 2 years.
`
`Animal Toxicology
`13.2
`In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human
`exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure
`after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin,
`this finding is considered not relevant for humans.
`There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at
`
`exposures of 12- to 116-fold the human exposure.
`
`14
`
`CLINICAL STUDIES
`
`Pulmonary Arterial Hypertension
`14.1
`The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term
`(average duration of exposure approximately 2 years), placebo-controlled study in 742 patients
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`with symptomatic [WHO functional class (FC) II-IV] PAH who were randomized to placebo
`(n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily.
`The primary study endpoint was time to the first occurrence of death, a significant morbidity
`event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC)
`prostanoids, or “other worsening of PAH” during double-blind treatment plus 7 days. Other
`
` worsening was defined as all of the following: 1) a sustained ≥15% decrease from baseline in 6
` minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and
`
`3) need for additional treatment for PAH. All of these other worsening events were confirmed by
`an independent adjudication committee, blinded to treatment allocation. A critical secondary
`endpoint was time to PAH death or PAH hospitalization.
`The mean patient age was 46 years (14% were age 65 or above). Most patients were white (55%)
`or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO
`
` FC II, III, and IV, respectively.
`Idiopathic or heritable PAH was the most common etiology in the study population (57%)
`followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart
`disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%)
`and HIV (1%)].
`
`
`At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of
`
`specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral
`prostanoids (6%).
`Study results are described for the placebo and OPSUMIT 10 mg groups. The median treatment
`
`durations were 101 and 118 weeks in the placebo and OPSUMIT 10 mg groups, respectively, up
`to a maximum of 188 weeks.
`Treatment with OPSUMIT 10 mg resulted in a 45% reduction (HR 0.55, 97.5% CI 0.39-0.76;
`
`logrank p<0.0001) in the occurrence of the primary endpoint up to end of double-blind treatment
`compared to placebo (Table 3 and Figure 2). The beneficial effect of OPSUMIT 10 mg was
`primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and
`worsening of PAH symptoms and need for additional PAH treatment).
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`Figure 2
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`
`Kaplan-Meier Estimates of the Occurrence of the Primary Endpoint Event in
`the SERAPHIN Study
`
`
`
`
`
`Table 3
`
`
`Summary of Primary Endpoint Events
`OPSUMIT 10 mg
`Placebo
`
`N=242
`N=250
`n (%)
`n (%)
`76 (31.4)
`116 (46.4)
`Patients with a primary endpoint event*
`Component as first event
`
`
`59 (24.4)
`93 (37.2)
` Worsening PAH
`16 (6.6)
`17 (6.8)
`Death
`1 (0.4)
`6 (2.4)
`IV/SC prostanoid
`
` *No patients experienced an event of lung transplantation or atria