WARNING: POTENTIAL LIVER INJURY
LETAIRIS (ambrisentan) can cause elevation of liver aminotransferases (ALT and AST) to at least 3 times the upper limit of normal (ULN). LETAIRIS treatment was associated with aminotransferase elevations >3 x ULN in 0.8% of patients in 12-week trials and 2.8% of patients including long-term open-label trials out to one year. One case of aminotransferase elevations >3 x ULN has been accompanied by bilirubin elevations >2 x ULN. Because these changes are a marker for potentially serious liver injury, serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) must be measured prior to initiation of treatment and then monthly.
In the post-marketing period with another endothelin receptor antagonist (ERA), bosentan, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy. In at least one case with bosentan, a late presentation (after >20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of the suspect drug. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment.
Elevations in aminotransferases require close attention. LETAIRIS should generally be avoided in patients with elevated aminotransferases (>3 x ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin >2 x ULN, treatment should be stopped. There is no experience with the re-introduction of LETAIRIS in these circumstances.
LETAIRIS is very likely to produce serious birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals [see Contraindications ]. Pregnancy must therefore be excluded before the initiation of treatment with LETAIRIS and prevented thereafter by the use of at least two reliable methods of contraception unless the patient has had a tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception is needed. Obtain monthly pregnancy tests.
Because of the risks of liver injury and birth defects, LETAIRIS is available only through a special restricted distribution program called the LETAIRIS Education and Access Program (LEAP), by calling 1-866-664-LEAP (5327). Only prescribers and pharmacies registered with LEAP may prescribe and distribute LETAIRIS. In addition, LETAIRIS may be dispensed only to patients who are enrolled in and meet all conditions of LEAP [see WARNINGS, Prescribing and Distribution Program for LETAIRIS ].
LETAIRIS (ambrisentan) tablets for oral use
LETAIRIS is the brand name for ambrisentan, an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor.
LETAIRIS is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.
Published Studies Related to Letairis (Ambrisentan)
Long-term outcomes with ambrisentan monotherapy in pulmonary arterial hypertension. [2010.02]
CONCLUSIONS: Ambrisentan monotherapy led to improvements in catheterization, 6MWD, and RV ejection fraction, and shows promise as a long-term treatment for pulmonary arterial hypertension. Copyright 2010 Elsevier Inc. All rights reserved.
Long-term outcomes with ambrisentan monotherapy in pulmonary arterial
CONCLUSIONS: Ambrisentan monotherapy led to improvements in catheterization,
No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. [2009.12]
Ambrisentan is a nonsulfonamide, ET(A)-selective endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), and tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor under investigation for treatment of PAH...
Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. [2009.11.17]
OBJECTIVES: This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH... CONCLUSIONS: Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786).
Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. [2008.12]
The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ET(A)-selective, propanoic acid-based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC(0-infinity)) and maximum plasma concentration (C(max)) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily...
Clinical Trials Related to Letairis (Ambrisentan)
A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis [Recruiting]
This will be a 36-week, randomized, double-blind, parallel group study comparing the effects
of tadalafil monotherapy, ambrisentan monotherapy and combination therapy with tadalafil
and ambrisentan in patients with PAH-SSc. Standard outcome measures such as six-minute walk
distance (6MWD), NYHA classification, and hemodynamic measurements will be assessed, as well
as novel functional measures of RV-PV function including the transthoracic echocardiogram
parameter tricuspid annular plane systolic ejection (TAPSE), contrast-enhanced cardiac MRI
and heart rate variability assessed by Holter monitoring. This design (excluding a
placebo-placebo arm) was selected for ethical concerns and to provide optimal efficiency and
active therapy to all study subjects. It also allows for comparisons between the two
monotherapies and with combination therapy.
Ambrisentan in Patients With Porto-pulmonary Hypertension A Multicenter Open Label Trial [Recruiting]
This is an Open Label, Multicenter, pilot clinical trial to assess the efficacy and safety
of an oral selective Endothelin Receptor Antagonist (ambrisentan) in patients with
Preliminary evidence suggests that ambrisentan is safe and effective in patients with
portopulmonary hypertension. The goal of therapy for these patients is to improve symptoms
of dyspnea and to improve pulmonary hemodynamics to a mean pulmonary artery pressure <35 mm
Hg in order to make patients eligible for liver transplantation. Therefore, the primary
endpoints for this study will include 6 minute walk distance (6MWD) and pulmonary vascular
Eligible subjects will receive 5 mg ambrisentan once-daily for the first 4 weeks. After the
initial 4-week period, investigators will increase study drug dose to 10 mg once daily (both
5 mg and 10 mg doses are FDA approved). If 10 mg is not tolerated in the opinion of
investigator, then the investigator may decrease the dose back to 5 mg once daily. Primary
outcome is a change in both the 6MWD and in PVR from baseline to Week 24. Subjects will be
monitored with liver function tests (LFT) every 2 weeks for the first 8 weeks, then every 4
weeks thereafter. These safety laboratory tests may be performed at a local phlebotomy
laboratory or at the Investigator clinic. In addition, the Investigator will assess each
subject for safety and efficacy at Week 4, Week 12, and Week 24. Following Week 24, subjects
will be assessed for safety and efficacy every 12 weeks. Patients will be followed for a
total of 1 year. After 1 year, if the Investigator feels that continuing the treatment will
be beneficial to the patients, they will be provided with ambrisentan by Gilead
Pharmaceuticals, free of charge.
Ambrisentan (Letairis) for Sarcoidosis Associated Pulmonary Hypertension [Recruiting]
Hypothesis: Ambrisentan (Letairis ®) is safe and effective in treating pulmonary
hypertension in patients with Sarcoidosis
Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Diffuse Systemic Sclerosis [Recruiting]
Systemic sclerosis is a chronic autoimmune connective tissue disorder with no universally
accepted disease modifying regimen. Recruiting patients for systemic sclerosis treatment
studies is difficult due to the limited availability of such patients and furthermore the
use of a placebo arm is often deemed unethical due to the poor survival of diffuse systemic
Long-term controlled trials examining functional outcomes and survival from novel
therapeutic agents for systemic sclerosis are often difficult to undertake because of costs,
rarity of the disease and ethical issues with the use of a true placebo. Open label single
center studies while inferior to multicenter placebo controlled studies, have helped
establish the benefits of certain pharmaceutical agents in systemic sclerosis, and while not
universally accepted as disease modifying agents, have been used with some success to treat
The hypothesis on which we are basing this study is that an endothelin receptor antagonist
and disease modifying agent with antifibrotic properties will have additive influence on
fibrosis, inhibit cellular and humoral hyperactivity and interfere with smooth muscle
proliferation in the vessel wall. The combination of these two agents will also be the first
regimen to address the heterogeneity of scleroderma manifestations including ILD, pulmonary
arterial hypertension and skin manifestations
ARTEMIS-PH - Study of Ambrisentan in Subjects With Pulmonary Hypertension Associated With Idiopathic Pulmonary Fibrosis [Recruiting]
This Phase 3, randomized, double-blind, placebo-controlled, multicenter study will compare
the efficacy and safety of ambrisentan to placebo in subjects with pulmonary hypertension
associated with idiopathic pulmonary fibrosis.
Reports of Suspected Letairis (Ambrisentan) Side Effects
Unevaluable Event (248),
Fluid Retention (184),
Cardiac Failure Congestive (182),
Pulmonary Arterial Hypertension (181),
Chest Pain (150),
Fall (135), more >>
Page last updated: 2013-02-10