Clinically significant adverse reactions that appear in other sections of the labeling include:
- Embryo-fetal Toxicity [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]
- Fluid Retention [see WARNINGS AND PRECAUTIONS]
- Pulmonary Edema with PVOD [see WARNINGS AND PRECAUTIONS]
- Decreased Sperm Count [see WARNINGS AND PRECAUTIONS]
- Hematologic Changes [see WARNINGS AND PRECAUTIONS]
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 were obtained from two 12-week, placebo-controlled studies in patients with pulmonary arterial hypertension (PAH) (ARIES-1 and ARIES-2) and four nonplacebo-controlled studies in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily. The exposure to Letairis in these studies ranged from 1 day to 4 years (N = 418 for at least 6 months and N = 343 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%
(N = 132)
(N = 261)
|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 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.
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 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.
The following adverse reactions were identified during postapproval 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 [see WARNINGS AND PRECAUTIONS], asthenia, dizziness, fatigue, fluid retention [see WARNINGS AND PRECAUTIONS], heart failure (associated with fluid retention), hypersensitivity (eg, angioedema, rash), nausea, and vomiting.
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.