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.
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.
Study of Ambrisentan and Phosphodiesterase Type-5 Inhibitor (PDE-5i) to Treat Pulmonary Arterial Hypertension [Recruiting]
To evaluate the change from baseline in pulmonary vascular resistance (PVR), and other
hemodynamic parameters, following the addition of ambrisentan to background
phosphodiesterase type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial
hypertension (PAH) who have demonstrated a sub-optimal response to PDE-5i monotherapy.
Efficacy and Safety of Ambrisentan in Children 8-18yrs [Recruiting]
A 6-month (24-week), randomized, open label evaluation of the safety, tolerability, and
efficacy of a high and low dose ambrisentan (adjusted for body weight) treatment group in
subjects aged 8 years up to 18 years with pulmonary arterial hypertension (PAH). An
additional objective is to determine the ambrisentan population pharmacokinetics in the
paediatric population. The study will include a screening/baseline period and a treatment
period. The treatment period will be 24 weeks or until the subject's clinical condition
deteriorates to the point that alternative/additional treatment is necessary. Patients who
participate in the study and in whom continued treatment with ambrisentan is desired will be
eligible to enrol into a long term follow-up study. The primary comparison will be the
safety and tolerability of the two ambrisentan dose groups (Low vs. High) in the paediatric
PAH population The secondary comparison will be the change from baseline for the efficacy
parameters between the two treatment groups.
(ARTEMIS-IPF)Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF [Recruiting]
The ARTEMIS-IPF study is for people who have been diagnosed with IPF and are between 40-80
years of age. People who have been diagnosed early in the disease may be more responsive to
treatment. This is a randomized study (which means the participants will be selected by
chance (like flipping a coin) to receive one of two treatments (ambrisentan or placebo).
This is a double-blind study which means participants and their study doctor won't know what
treatment they are assigned to receive. Participants will have 2 out of 3 chances to receive
ambrisentan, or 1 out of 3 chances to receive placebo (which is a tablet that looks like the
active medicine but contains no active medicine)Taking part in the study could be up to 4
years depending on how long it takes to enroll and observe study events. After
randomization, visits take place every 3 months. Laboratory visits occur every month.
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