`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
`LETAIRIS® safely and effectively. See full prescribing information
`
`
`
`
`for LETAIRIS.
`
`
`
`Letairis (ambrisentan) tablets, for oral use
`
`
`
`Initial U.S. Approval: 2007
`
`
`
`•
`
`
`
`•
`
`
`
`•
`
`
`
`
`WARNING: EMBRYO-FETAL TOXICITY
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`Do not administer Letairis to a pregnant female because it
`
`
`may cause fetal harm (4.1, 5.1, 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 (2.2, 8.6).
`
`
`For all female patients, Letairis is available only through a
`
`
`
`restricted program called the Letairis Risk Evaluation and
`
`
`
`Mitigation Strategy (REMS) (5.2).
`
`
`
`-----------------------RECENT MAJOR CHANGES-----------------------------­
`
`Indications and Usage (1)
`10/2015
`•
`
`
`
`
`
`
`
`Dosage and Administration (2.1)
`10/2015
`•
`
`
`
`
`
`
`
`• Warnings and Precautions (5.3)
`10/2015
`
`
`
`
`
`
`-------------------------INDICATIONS AND USAGE------------------------------
`
`
`Letairis is an endothelin receptor antagonist indicated for the treatment
`
`
`
`of pulmonary arterial hypertension (PAH) (WHO Group 1):
`
`
`
`To improve exercise ability and delay clinical worsening.
`•
`
`
`
`
`In combination with tadalafil to reduce the risks of disease
`•
`
`
`
`
`
`
`
`
`progression and hospitalization for worsening PAH, and to
`
`
`
`improve exercise ability.
`
`
`Studies establishing effectiveness included trials predominantly in
`
`
`
`patients with WHO Functional Class II–III symptoms and etiologies of
`
`
`
`
`
`
`idiopathic or heritable PAH (60%) or PAH associated with connective
`
`
`
`tissue diseases (34%) (1).
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`Initiate treatment at 5 mg once daily (2.1).
`•
`
`
`
`• May be started with tadalafil (2.1).
`
`
`
`
`Titrate at 4-week intervals as needed and tolerated (2.1).
`•
`
`
`
`
`
`
`
`Do not split, crush, or chew tablets (2.1).
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`
`•
`
`
`
`-------------------------DOSAGE FORMS AND STRENGTHS-----------------­
`
`Tablet: 5 mg and 10 mg (3)
`
`
`
`
`------------------------------CONTRAINDICATIONS-------------------------------­
`Pregnancy (4.1)
`•
`
`
`
`
`Idiopathic Pulmonary Fibrosis (4.2)
`•
`
`
`
`
`
`-------------------------WARNINGS AND PRECAUTIONS---------------------­
`
`Fluid retention may require intervention (5.3).
`•
`
`
`
`
`If patients develop acute pulmonary edema during initiation of
`•
`
`
`
`
`therapy with Letairis, consider underlying pulmonary veno­
`
`occlusive disease and discontinue treatment if necessary (5.4).
`
`
`Decreases in sperm count have been observed in patients taking
`
`
`endothelin receptor antagonists (5.5).
`
`
`Decreases in hemoglobin have been observed within the first few
`
`
`weeks; measure hemoglobin at initiation, at 1 month, and
`
`periodically thereafter (5.6).
`
`------------------------------ADVERSE REACTIONS------------------------------­
`• Most common adverse reactions (>3% compared to placebo) are
`
`
`
`
`
`
`peripheral edema, nasal congestion, sinusitis, and flushing (6.1).
`
`
`
`
`• When used in combination with tadalafil, most common adverse
`
`
`
`
`reactions (>5% compared with either monotherapy) are peripheral
`
`
`
`
`edema, headache, nasal congestion, cough, anemia, dyspepsia,
`
`
`
`
`and bronchitis (6.1).
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Gilead
`
`
`
`Sciences, Inc. at (1-800-445-3235, Option 3) or FDA at 1-800-FDA­
`
`
`
`1088 or www.fda.gov/medwatch.
`
`
`-----------------------------DRUG INTERACTIONS--------------------------------
`
`
`Cyclosporine increases ambrisentan exposure; limit ambrisentan dose
`
`
`
`
`to 5 mg once daily (7).
`
`--------------------------USE IN SPECIFIC POPULATIONS-------------------­
`
`
`Breastfeeding: Choose Letairis or breastfeeding (8.3).
`•
`
`
`
`
`
`
`Not recommended in patients with moderate or severe hepatic
`•
`
`
`
`
`
`impairment (8.8).
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`Medication Guide.
`
`
`
`Revised: 10/2015
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: EMBRYO-FETAL TOXICITY
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`2.1 Adult Dosage
`
`
`2.2 Pregnancy Testing in Females of Reproductive Potential
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`
`4.1 Pregnancy
`
`
`4.2 Idiopathic Pulmonary Fibrosis
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`5.1 Embryo-fetal Toxicity
`
`
`5.2 Letairis REMS Program
`
`
`
`
`5.3 Fluid Retention
`
`
`5.4 Pulmonary Edema with Pulmonary Veno-occlusive Disease
`
`
`
`(PVOD)
`
`
`5.5 Decreased Sperm Counts
`
`
`5.6 Hematological Changes
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`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
`
`
`
`
`
`8.7 Renal Impairment
`
`
`8.8 Hepatic 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 (PAH)
`
`
`
`
`14.2 Combination Treatment of PAH
`
`
`
`
`14.3 Long-term Treatment of PAH
`
`
`
`14.4 Adverse Effects in Idiopathic Pulmonary Fibrosis (IPF)
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`
`
`are not listed.
`
`
`
`Reference ID: 3828639
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 1 of 28
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
` WARNING: EMBRYO-FETAL TOXICITY
`
`
`
`
`
`
`
`
` Do not administer Letairis to a pregnant female because it may cause fetal harm. Letairis is
`
` very likely to produce serious birth defects if used by pregnant females, as this effect has
`
` been seen consistently when it is administered to animals [see Contraindications (4.1),
`
`
`
` Warnings and Precautions (5.1), and Use in Specific Populations (8.1)].
`
`
`
`
`
` Exclude pregnancy before the initiation of treatment with Letairis. Females of reproductive
`
`
`
`
`potential must use acceptable methods of contraception during treatment with Letairis and for
`
`
`
`
`one month after treatment. Obtain monthly pregnancy tests during treatment and 1 month
`
`
`after discontinuation of treatment [see Dosage and Administration (2.2) and Use in Specific
`
`
`Populations (8.6)].
`
`
`Because of the risk of embryo-fetal toxicity, females can only receive Letairis through a
`
`
`
`
`
`
`
`
`
`restricted program called the Letairis REMS program [see Warnings and Precautions (5.2)].
`
`1 INDICATIONS AND USAGE
`
`
`
`Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):
`
`
`
`
`
`
`
`• To improve exercise ability and delay clinical worsening.
`
`
`
`
`
`
`•
`
`
`In combination with tadalafil to reduce the risks of disease progression and hospitalization for
`
`
`
`
`
`
`
`worsening PAH, and to improve exercise ability [see Clinical Studies (14.2)].
`
`
`
`
`
`
`
`Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III
`
`
`
`
`symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective
`
`
`tissue diseases (34%).
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Adult Dosage
`
`
`
`Initiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals,
`
`
`
`
`
`either the dose of Letairis or tadalafil can be increased, as needed and tolerated, to Letairis 10 mg or
`
`
`
`tadalafil 40 mg.
`
`
`
`Do not split, crush, or chew tablets.
`
`
`
`
`2.2 Pregnancy Testing in Females of Reproductive Potential
`
`
`Initiate treatment with Letairis in females of reproductive potential only after a negative pregnancy
`
`
`
`
`
`
`test. Obtain monthly pregnancy tests during treatment [see Use in Specific Populations (8.6)].
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`5 mg and 10 mg film-coated tablets for oral administration
`
`
`
`
`
`
`• Each 5 mg tablet is square convex, pale pink, with “5” on one side and “GSI” on the other side.
`
`
`
`
`
`
`
`Reference ID: 3828639
`
`2
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 2 of 28
`
`

`

`
` • Each 10 mg tablet is oval convex, deep pink, with “10” on one side and “GSI” on the other side.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` 4.1 Pregnancy
`
` Letairis may cause fetal harm when administered to a pregnant female. Letairis is contraindicated in
`
`
`
`
`
`
`
` females who are pregnant. Letairis was consistently shown to have teratogenic effects when
`
` administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant
`
`
`
` while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings
`
`
`
` and Precautions (5.1, 5.2) and Use in Specific Populations (8.1)].
`
`
`
`
`
`
`
`
`
` 4.2 Idiopathic Pulmonary Fibrosis
`
`
`
` Letairis is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients
`
`
`
`
` with pulmonary hypertension (WHO Group 3) [see Clinical Studies (14.4)].
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
` 5.1 Embryo-fetal Toxicity
`
`
`
`
` Letairis 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)].
`
`
`
`
`
` Letairis is only available for females through a restricted program under a REMS [see Warnings and
`
`
` Precautions (5.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.2 Letairis REMS Program
`
` For all females, Letairis is available only through a restricted program called the Letairis REMS,
`
`
`
`
` 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 Letairis 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 Letairis REMS program
`
`
`
`
` prior to initiating Letairis. 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 that dispense Letairis must be certified with the program and must dispense to
`
`
`
`
` female patients who are authorized to receive Letairis.
`
`
`
`
`
`
`
` Further information is available at www.letairisrems.com or 1-866-664-5327.
`
`
`
`Reference ID: 3828639
`
`3
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 3 of 28
`
`

`

`
`
` 5.3 Fluid Retention
`
`
`
`
`
` Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical
`
`
`
` consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased
` incidence of peripheral edema in patients treated with doses of 5 or 10 mg Letairis compared to
`
`
`
`
`
`
`
` placebo [see Adverse Reactions (6.1)]. Most edema was mild to moderate in severity.
`
`
`
`
`
`
` In addition, there have been postmarketing reports of fluid retention in patients with pulmonary
`
` hypertension, occurring within weeks after starting Letairis. Patients required intervention with a
`
`
`
`
`
` diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.
`
`
`
`
` If clinically significant fluid retention develops, with or without associated weight gain, further
`
`
`
`
`
`
` evaluation should be undertaken to determine the cause, such as Letairis or underlying heart failure,
` and the possible need for specific treatment or discontinuation of Letairis therapy.
`
`
`
`
`
`
`
`
`
` Peripheral edema/fluid retention is more common with Letairis plus tadalafil than with Letairis or
`
`tadalafil alone.
`
`
`
`
`
`
`
`
`5.4 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
`
`
`
`
`
`If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such
`
`as Letairis, the possibility of PVOD should be considered, and if confirmed Letairis should be
`
`
`
`
`discontinued.
`
`
`5.5 Decreased Sperm Counts
`
`
`
`
`Decreased sperm counts have been observed in human and animal studies with another endothelin
`
`receptor antagonist and in animal fertility studies with ambrisentan. Letairis may have an adverse
`
`
`
`
`effect on spermatogenesis. Counsel patients about potential effects on fertility [see Use in Specific
`
`
`
`
`
`
`Populations (8.6) and Nonclinical Toxicology (13.1)].
`
`
`
`
`5.6 Hematological Changes
`
`
`
`Decreases in hemoglobin concentration and hematocrit have followed administration of other
`
`
`
`endothelin receptor antagonists and were observed in clinical studies with Letairis. These decreases
`
`
`were observed within the first few weeks of treatment with Letairis, and stabilized thereafter. The
`
`
`
`mean decrease in hemoglobin from baseline to end of treatment for those patients receiving Letairis
`
`
`in the 12-week placebo-controlled studies was 0.8 g/dL.
`
`
`Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower
`
`limit of normal) were observed in 7% of all patients receiving Letairis (and 10% of patients receiving
`
`
`
`
`
`
`
`10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is
`
`
`unknown, but it does not appear to result from hemorrhage or hemolysis.
`
`
`
`
`In the long-term open-label extension of the two pivotal clinical studies, mean decreases from
`
`
`baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of
`
`
`
`
`treatment.
`
`
`There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit
`
`that have resulted in anemia requiring transfusion.
`
`
`
`Measure hemoglobin prior to initiation of Letairis, at one month, and periodically thereafter. Initiation
`
`
`
`of Letairis therapy is not recommended for patients with clinically significant anemia. If a clinically
`
`
`
`
`
`
`Reference ID: 3828639
`
`4
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 4 of 28
`
`

`

`
` significant decrease in hemoglobin is observed and other causes have been excluded, consider
`
`
` discontinuing Letairis.
`
`
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`
` Clinically significant adverse reactions that appear in other sections of the labeling include:
`
`
`
`
`
`
`
`
` • Embryo-fetal Toxicity [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)]
`
`
`
`
`
`
`
`
`
` • Fluid Retention [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Pulmonary Edema with PVOD [see Warnings and Precautions (5.4)]
`
`
`
`
`
`
`
`
`
` • Decreased Sperm Count [see Warnings and Precautions (5.5)]
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Hematologic Changes [see Warnings and Precautions (5.6)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.1 Clinical Trials 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.
`
`
`
`
`
`
`
`
`
`
` Safety data for Letairis are presented from two 12-week, placebo-controlled studies (ARIES-1 and
` ARIES-2) in patients with pulmonary arterial hypertension (PAH), and one randomized, double-blind,
`
`
`
` active-controlled trial in 605 patients with PAH (AMBITION) comparing Letairis plus tadalafil to
`
`
`
`
`
`
` Letairis or tadalafil alone. The exposure to Letairis in these studies ranged from 1 day to 4 years
`
`
`
`
`
`
`
` (N=357 for at least 6 months and N=279 for at least 1 year).
`
`
`
`
`
`
`
`
`
`
`
`
` In ARIES-1 and ARIES-2, a total of 261 patients received Letairis at doses of 2.5, 5, or 10 mg once
`
` daily and 132 patients received placebo. The adverse reactions that occurred in >3% more patients
`
`
`
`
`
` receiving Letairis than receiving placebo are shown in Table 1.
`
`
`
`
`
`
`
`Table 1
`
`
`
`Adverse Reactions with Placebo-Adjusted Rates >3% in ARIES-1 and ARIES-2
`
`
`
`
`
` Adverse Reaction
`
`
`Peripheral edema
`
`Nasal congestion
`
`Sinusitis
`
`Flushing
`
`
`Placebo
`
`(N=132)
`
`
`
` n (%)
`
`
`
`14 (11)
`
`2 (2)
`
`0 (0)
`
`1 (1)
`
`
`Letairis
`
`(N=261)
`Placebo-adjusted
`
` (%)
`
`6
`
`4
`
`3
`
`3
`
`
`
` n (%)
`
`
`45 (17)
`
`15 (6)
`
`8 (3)
`
`10 (4)
`
`
`
`Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.
`
`
`
`Few notable differences in the incidence of adverse reactions were observed for patients by age or
`
`
`
`
`
`
`sex. Peripheral edema was similar in younger patients (<65 years) receiving Letairis (14%; 29/205) or
`
`
`
`placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving Letairis (29%; 16/56)
`Reference ID: 3828639
`
`5
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 5 of 28
`
`

`

`
`
`
`
` compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted
`
` cautiously.
`
`
`
`
`
`
`
` The incidence of treatment discontinuations due to adverse events other than those related to PAH
`
`
` during the clinical trials in patients with PAH was similar for Letairis (2%; 5/261 patients) and placebo
`
` (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related
`
`
` to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and
`
`
`
`
`
` for Letairis (5%; 13/261 patients).
`
`
`
`
`
`
`
`
` During 12-week controlled clinical trials, the incidence of aminotransferase elevations >3 x upper limit
`
` of normal (ULN) were 0% on Letairis and 2.3% on placebo. In practice, cases of hepatic injury should
`
`
`
` be carefully evaluated for cause.
`
`
`
`
` Combination Use with Tadalafil
`
`The mean exposure to Letairis + tadalafil in the AMBITION study was 78.7 weeks. The adverse
`
`
`
`
`reactions that occurred in >5% more patients receiving Letairis + tadalafil than receiving Letairis or
`
`
`
`
`
`tadalafil monotherapy in AMBITION are shown in Table 2.
`
`
`
`Table 2
`
`
`
`Adverse Reactions Reported More Commonly (>5%) on Letairis + Tadalafil than
`
`
`
`
`
`on Letairis or Tadalafil Monotherapy (ITT) in AMBITION
`
`
`
`
`
`
`Letairis + Tadalafil
`
`Combination Therapy
`
`(N=302)
`
`
`n (%)
`
`
`135 (45%)
`125 (41%)
`
`58 (19%)
`
`53 (18%)
`
`
`44 (15%)
`32 (11%)
`
`31 (10%)
`
`
`Letairis
`
`Monotherapy
`
`(N=152)
`
`n (%)
`
`
`58 (38%)
`51 (34%)
`
`25 (16%)
`
`20 (13%)
`
`
`11 (7%)
`5 (3%)
`
`6 (4%)
`
`
`Adverse Reactions
`
`
`
`Peripheral edema
`Headache
`
`Nasal congestion
`
`Cough
`
`
`Anemia
`Dyspepsia
`
`Bronchitis
`
`
`Tadalafil
`
`Monotherapy
`
`(N=151)
`
`n (%)
`
`
`43 (28%)
`53 (35%)
`
`17 (11%)
`
`24 (16%)
`
`
`17 (11%)
`18 (12%)
`
`13 (9%)
`
`
`
`Peripheral edema was more frequent on combination therapy; however, there was no notable
`
`difference observed in the incidence of peripheral edema in elderly patients (≥65 years) versus
`
`
`younger patients (<65 years) on combination therapy (44% vs. 45%) or Letairis monotherapy (37%
`
`
`
`
`
`
`
`vs. 39%) in AMBITION.
`
`
`
`
`Treatment discontinuations due to adverse events while on randomized treatment were similar across
`
`
`treatment groups: 16% for Letairis + tadalafil, 14% for Letairis alone, and 13% for tadalafil alone.
`
`
`
`
`
`
`
`
`Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme
`
`
`
`
`
`Abnormalities
`
`
`
`
` In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor
`
` antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations >3
`
`
`
`
` x ULN were treated with Letairis. Prior elevations were predominantly moderate, with 64% of the ALT
`
`
`
`
`
`Reference ID: 3828639
`
`6
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 6 of 28
`
`

`

`
`
`elevations <5 x ULN, but 9 patients had elevations >8 x ULN. Eight patients had been re-challenged
`
`
`
`
`with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase
`
`abnormalities that required discontinuation of ERA therapy. All patients had to have normal
`
`
`
`
`aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving
`
`
`prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy. Two patients discontinued
`
`
`early (including one of the patients with a prior 8 x ULN elevation). Of the remaining 34 patients, one
`
`
`
`
`patient experienced a mild aminotransferase elevation at 12 weeks on Letairis 5 mg that resolved
`
`with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a
`
`
`median follow-up of 13 months and with 50% of patients increasing the dose of Letairis to 10 mg, no
`
`
`
`
`
`patients were discontinued for aminotransferase elevations. While the uncontrolled study design does
`
`
`not provide information about what would have occurred with re-administration of previously used
`
`ERAs or show that Letairis led to fewer aminotransferase elevations than would have been seen with
`
`
`those drugs, the study indicates that Letairis may be tried in patients who have experienced
`
`
`asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have
`
`
`returned to normal.
`
`
`6.2 Postmarketing Experience
`
`
`The following adverse reactions were identified during post-approval use of Letairis. Because these
`
`
`
`reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate
`
`reliably the frequency or to establish a causal relationship to drug exposure: anemia requiring
`
`
`
`
`
`transfusion [see Warnings and Precautions (5.6)] heart failure (associated with fluid retention),
`
`
`
`
`symptomatic hypotension, and hypersensitivity (e.g., angioedema, rash).
`
`
`
`Elevations of liver aminotransferases (ALT, AST) have been reported with Letairis use; in most cases
`
`
`
`alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis,
`
`
`
`
`
`alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated
`
`
`
`with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Adverse
`
`
`
`
`
`
`
`Reactions (6.1)].
`
`
`7 DRUG INTERACTIONS
`
`
`Multiple dose coadministration of ambrisentan and cyclosporine resulted in an approximately 2-fold
`
`increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5
`
`
`mg once daily when coadministered with cyclosporine [see Clinical Pharmacology (12.3)].
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`8.1 Pregnancy
`
`
`Pregnancy Category X
`
`
`Risk Summary
`
`
`Letairis may cause fetal harm when administered to a pregnant woman and is contraindicated during
`
`
`pregnancy. Letairis was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5
`
`
`
`
`
`
`
`
`and 1.7 times, respectively, the human dose of 10 mg per day. 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), Warnings and Precautions (5.1)].
`
`
`
`
`Reference ID: 3828639
`
`7
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 7 of 28
`
`

`

`Animal Data
`
`
`
`
`Letairis was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•µg/mL) in rats and ≥7
`
`
`
`
`
`
`
`mg/kg/day (24.7 h•µg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5
`
`
`
`
`
`
`and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•µg/mL) based on AUC. In both
`
`
`
`
`
`
`
`
`species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart
`
`
`
`
`
`and great vessels, and failure of formation of the thymus and thyroid.
`
`
`
`A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages)
`and effects on testicle size and fertility of pups (high dosage) following maternal treatment with
`
`
`ambrisentan from late gestation through weaning. The mid and high dosages were 51 x, and 170 x
`
`
`
`
`
`
`
`(on a mg/m2 body surface area basis) the maximum oral human dose of 10 mg and an average adult
`
`
`
`
`
`
`
`
`body weight of 70 kg. These effects were absent at a maternal dosage 17 x the human dose based
`on mg/m2 .
`
`
`
`
`8.3 Nursing Mothers
`
`
`
`
`
`It is not known whether ambrisentan is present in human milk. Because many drugs are present in
`
`
`
`
`human milk and because of the potential for serious adverse reactions in nursing infants from Letairis,
`
`
`a decision should be made whether to discontinue nursing or discontinue Letairis, taking into account
`
`
`the importance of the drug to the mother.
`
`
`8.4 Pediatric Use
`
`
`
`
`
`Safety and effectiveness of Letairis in pediatric patients have not been established.
`
`
`8.5 Geriatric Use
`
`
`
`
`In the two placebo-controlled clinical studies of Letairis, 21% of patients were ≥65 years old and 5%
`
`were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with
`
`
`
`Letairis than younger patients did, but the results of such subgroup analyses must be interpreted
`
`
`
`cautiously. Peripheral edema was more common in the elderly than in younger patients.
`
`
`8.6 Females and Males of Reproductive Potential
`
`
`Pregnancy Testing
`
`
`
`Female patients of reproductive potential must have a negative pregnancy test prior to initiation of
`
`
`
`
`treatment, monthly pregnancy test during treatment, and 1 month after stopping treatment with
`
`
`Letairis. Advise patients to contact their healthcare 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 patient on the potential risk to the fetus and patient options [see Boxed
`
`
`
`
`Warning and Dosage and Administration (2.2)].
`
`
`Contraception
`
`
`
`Female patients of reproductive potential must use acceptable methods of contraception during
`
`
`
`
`
`
`treatment with Letairis and for 1 month after stopping treatment with Letairis. Patients may choose
`
`
`one highly effective form of contraception (intrauterine device (IUD), contraceptive implant, 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
`
`Reference ID: 3828639
`
`8
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 8 of 28
`
`

`

`prevention, including emergency contraception, or designate counseling by another healthcare
`
`
`provider trained in contraceptive counseling [see Boxed Warning].
`
`
`
`
`
`
`Infertility
`
`
`Males
`
`
`In a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO
`
`
`functional class III and IV PAH and normal baseline sperm count were evaluated for effects on
`
`
`
`
`
`
`testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3
`
`
`or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months,
`
`
`
`and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks.
`
`
`
`Bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. In
`
`22 patients who completed 6 months of treatment, sperm count remained within the normal range
`
`
`and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on
`
`
`these findings and preclinical data [see Nonclinical Toxicology (13.1)] from endothelin receptor
`
`
`
`
`
`antagonists, it cannot be excluded that endothelin receptor antagonists such as Letairis have an
`
`
`
`adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see
`
`
`
`
`
`
`Warnings and Precautions (5.5)].
`
`
`8.7 Renal Impairment
`
`
`
`The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a
`
`
`population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20
`
`and 150 mL/min. There was no significant impact of mild or moderate renal impairment on exposure
`
`
`
`
`
`to ambrisentan [see Clinical Pharmacology (12.3)]. Dose adjustment of Letairis in patients with mild or
`
`
`
`
`
`moderate renal impairment is therefore not required. There is no information on the exposure to
`
`
`ambrisentan in patients with severe renal impairment.
`
`
`The impact of hemodialysis on the disposition of ambrisentan has not been investigated.
`
`
`
`8.8 Hepatic Impairment
`
`
`Pre-existing Hepatic Impairment
`
`
`
`The influence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not
`
`
`been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary
`
`
`
`
`
`
`contribution to the elimination of ambrisentan, hepatic impairment might be expected to have
`
`
`
`significant effects on the pharmacokinetics of ambrisentan [see Clinical Pharmacology (12.3)]. Letairis
`
`
`
`is not recommended in patients with moderate or severe hepatic impairment. There is no information
`
`
`on the use of Letairis in patients with mild pre-existing impaired liver function; however, exposure to
`
`
`
`
`
`ambrisentan may be increased in these patients.
`
`
`Elevation of Liver Transaminases
`
`
`Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST,
`
`
`ALT) elevations, hepatotoxicity, and cases of liver failure [see Adverse Reactions (6.1, 6.2)]. In
`
`
`
`
`
`
`patients who develop hepatic impairment after Letairis initiation, the cause of liver injury should be
`
`
`fully investigated. Discontinue Letairis if elevations of liver aminotransferases are >5 x ULN or if
`
`
`
`
`
`
`
`elevations are accompanied by bilirubin >2 x ULN, or by signs or symptoms of liver dysfunction and
`
`other causes are excluded.
`
`
`Reference ID: 3828639
`
`9
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1119, p. 9 of 28
`
`

`

`10 OVERDOSAGE
`
`
`
`
`There is no experience with overdosage of Letairis. The highest single dose of Letairis administered
`
`
`
`
`to healthy volunteers was 100 mg, and the highest daily dose administered to patients with PAH was
`
`
`
`10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the
`
`
`
`
`maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and
`
`nasal congestion. Massive overdosage could potentially result in hypotension that may require
`
`intervention.
`
`
`11 DESCRIPTION
`
`
`Letairis is the brand name for ambrisentan, an endothelin receptor antagonist that is selective for the
`
`
`endothelin type-A (ETA) receptor. The chemical name of ambrisentan is
`
`
`
`
`
`(+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has a molecular
`
`
`
`
`
`
`formula of C22H22N2O4 and a molecular weight of 378.42. It contains a single chiral center determined
`
`
`to be the (S) configuration and has the following structural formula:
`
`
`
`Figure 1
`
`
`Ambrisentan Structural Formula
`
`H3CO
`
`COOH
`
`CH3
`
`O
`
`N
`
`N
`
`CH3
`
`
`Ambrisentan is a white to off-white, crystalline solid. It is a carboxylic acid with a pKa of 4.0.
`
`