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. 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.

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.

Initiate treatment at 5 mg once daily. May be started with tadalafil. Titrate at 4-week intervals as needed and tolerated. Do not split, crush, or chew tablets.

Pregnancy. Idiopathic Pulmonary Fibrosis 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.

Boxed warning (embryo-fetal toxicity): Letairis is contraindicated for use during pregnancy because it may cause major birth defects if used by pregnant patients, based on studies in animals. Therefore, for females of reproductive potential, exclude pregnancy before the initiation of treatment with Letairis. Advise use of effective contraception before initiation, during treatment, and for one month after treatment with Letairis. Fluid retention may require intervention. If patients develop acute pulmonary edema during initiation of therapy with Letairis, consider underlying pulmonary veno-occlusive disease and discontinue treatment if necessary. Decreases in sperm count have been observed in patients taking endothelin receptor antagonists. Decreases in hemoglobin have been observed within the first few weeks, measure hemoglobin at initiation, at 1 month, and periodically thereafter.

Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal Toxicity Fluid Retention Pulmonary Edema with PVOD Decreased Sperm Count Hematologic Changes Most common adverse reactions (>3% compared to placebo) are peripheral edema, nasal congestion, sinusitis, and flushing. 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.

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.

Store at 25° C (77° F), excursions permitted to 15 – 30° C (59 – 86° F). Store Letairis in its original packaging.