Letairis Drug Information

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.

Pregnancy Testing in Females of Reproductive Potential Exclude pregnancy before initiating treatment

with Letairis in females of reproductive potential.

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 45 6 Nasal congestion 2 15 4 Sinusitis 0 8 3 Flushing 1 10 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.

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 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.

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 . Cyclosporine increases ambrisentan exposure; limit ambrisentan dose to 5 mg once daily.

• 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 .

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.

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 .

Idiopathic Pulmonary Fibrosis Letairis is contraindicated in patients with Idiopathic Pulmonary Fibrosis

(IPF), including IPF patients with pulmonary hypertension (WHO Group 3).

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.