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 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 events that occurred in >3% of the patients receiving LETAIRIS and were more frequent on LETAIRIS than placebo are shown in Table 1.
Table 1 Adverse Events in >3% of PAH Patients Receiving LETAIRIS and More Frequent than Placebo
| Adverse event || n (%) || n (%) || Placebo-adjusted (%) |
Note: This table includes all adverse events >3% incidence in the combined LETAIRIS treatment group and more frequent than in the placebo group, with a difference of ≥1% between the LETAIRIS and placebo groups.
|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|
|Palpitations||3 (2)||12 (5)||3|
|Nasopharyngitis||1 (1)||9 (3)||2|
|Abdominal pain||1 (1)||8 (3)||2|
|Constipation||2 (2)||10 (4)||2|
|Dyspnea||4 (3)||11 (4)||1|
|Headache||18 (14)||38 (15)||1|
Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent. Fewer patients receiving LETAIRIS had adverse events related to liver function tests compared to placebo.
Few notable differences in the incidence of adverse drug 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 pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension 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 pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension was similar for placebo (7%; 9/132 patients) and for LETAIRIS (5%; 13/261 patients).
The following adverse reaction was identified during postapproval use of LETAIRIS: Fluid retention [see Warnings and Precautions].
Because this reaction was reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency or establish a causal relationship to drug exposure.