Ambrisentan

Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adult patients: 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%). Letairis is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adult patients: 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 ).

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. Each 10 mg tablet is oval convex, deep pink, with “10” on one side and “GSI” on the other side. Tablet: 5 mg and 10 mg ( 3 )

Pregnancy ( 4.1 ) Idiopathic Pulmonary Fibrosis ( 4.2 )

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 Dosage and Administration (2.2) , Warnings and Precautions (5.1) , 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) ].

Fluid retention may require intervention ( 5.2 ). If patients develop acute pulmonary edema during initiation of therapy with Letairis, consider underlying pulmonary veno-occlusive disease and discontinue treatment if necessary ( 5.3 ). Decreases in sperm count have been observed in patients taking endothelin receptor antagonists ( 5.4 ). Decreases in hemoglobin have been observed within the first few weeks; measure hemoglobin at initiation, at 1 month, and periodically thereafter ( 5.5 ).

5.1 Embryo-fetal Toxicity Based on data from animal reproduction studies, Letairis may cause fetal harm when administered during pregnancy and is contraindicated during pregnancy. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of Letairis. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of treatment with Letairis. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with Letairis. When pregnancy is detected, discontinue use as soon as possible [see Dosage and Administration (2.2) , and Use in Specific Populations (8.1 , 8.3) ] .

5.2 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.

5.3 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.

5.4 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) ].

5.5 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 significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing Letairis.

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 (5.2) ] Pulmonary Edema with PVOD [see Warnings and Precautions (5.3) ] Decreased Sperm Count [see Warnings and Precautions (5.4) ] Hematologic Changes [see Warnings and Precautions (5.5) ] 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 .

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 Placebo (N=132) Letairis (N=261) Adverse Reaction n (%) n (%) Placebo-adjusted (%) Peripheral edema 14 (11) 45 (17) 6 Nasal congestion 2 (2) 15 (6) 4 Sinusitis 0 (0) 8 (3) 3 Flushing 1 (1) 10 (4) 3 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) 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 × 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 Adverse Reactions Letairis + Tadalafil Combination Therapy (N=302) n (%) Letairis Monotherapy (N=152) n (%) Tadalafil Monotherapy (N=151) n (%) Peripheral edema 135 (45%) 58 (38%) 43 (28%) Headache 125 (41%) 51 (34%) 53 (35%) Nasal congestion 58 (19%) 25 (16%) 17 (11%) Cough 53 (18%) 20 (13%) 24 (16%) Anemia 44 (15%) 11 (7%) 17 (11%) Dyspepsia 32 (11%) 5 (3%) 18 (12%) Bronchitis 31 (10%) 6 (4%) 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 × ULN were treated with Letairis. Prior elevations were predominantly moderate, with 64% of the ALT elevations <5 × ULN, but 9 patients had elevations >8 × 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 × 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 (5.5) ] 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) ].

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) ] . Cyclosporine increases ambrisentan exposure; limit ambrisentan dose to 5 mg once daily ( 7 ).

Breastfeeding: Choose Letairis or breastfeeding ( 8.2 ). Not recommended in patients with moderate or severe hepatic impairment ( 8.7 ).

8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, Letairis may cause fetal harm, including birth defects and fetal death, when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on Letairis use in pregnant women. Available data from post-marketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as Letairis have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. In animal reproduction studies, 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 [see Animal Data ] . 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) ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 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 ×, and 170 × (on a mg/m 2 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 × the human dose based on mg/m 2 .

8.2 Lactation Risk Summary 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 breastfed infants from Letairis, a decision should be made whether to discontinue breastfeeding or discontinue Letairis, taking into account the importance of the drug to the mother.

8.3 Females and Males of Reproductive Potential Based on data from animal reproductive toxicity studies, ambrisentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1) , Use in Specific Populations (8.1) ] . Pregnancy Testing Verify that patients who can become pregnant are not pregnant prior to initiating ambrisentan. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient should discuss the risks to the pregnancy and the fetus. Contraception Patients who can become pregnant who are using ambrisentan should use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with ambrisentan to prevent pregnancy [see Warnings and Precautions (5.1) ] . 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) ] .

8.4 Pediatric Use Safety and effectiveness of Letairis in pediatric patients have not been established . Juvenile Animal Data In juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36, or 62, a decrease in brain weight (−3% to −8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on AUC .

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 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.

8.7 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. […]

Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ET A and ET B , mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ET A are vasoconstriction and cell proliferation, while the predominant actions of ET B are vasodilation, antiproliferation, and ET-1 clearance. In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH. Ambrisentan is a high-affinity (K i =0.011 nM) ET A receptor antagonist with a high selectivity for the ET A versus ET B receptor (>4000-fold). The clinical impact of high selectivity for ET A is not known.