Treatments for Pulmonary Hypertension
Issued by PHA’s Scientific Leadership Council. Information is based on the United States Food and Drug Administration drug labeling.
Last Updated February 2012
What is ambrisentan?
Ambrisentan is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Group 1 patients to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).
Ambrisentan is an oral medication and was approved by the United States Food and Drug Administration (FDA) in 2007.
How does ambrisentan work?
Ambrisentan works by blocking the effects of a substance called endothelin, which is made by the body in increased amounts in patients with PAH. Endothelin causes blood vessels to narrow (constrict). It also causes overgrowth of the muscle in the walls of the blood vessels in the lungs. By blocking the action of endothelin, ambrisentan can reduce blood pressure in the lungs and improve activity level and well being in PAH patients.
Short-term randomized studies demonstrate that ambrisentan improves exercise capacity and delays clinical worsening in PAH patients. Long-term open label trials of the drug showed sustained benefit in exercise capacity.
How is ambrisentan given?
Ambrisentan is taken orally with or without food. The initial dose for most patients is 5-mg once daily. If there are no problems or side effects, the dose may be increased to 10 mg once daily. Both doses are FDA approved.
How is ambrisentan supplied?
5 and 10 mg, film-coated, convex, unscored tablets. The 5 mg tablet is pale pink and square. The 10 mg tablet is deep pink and oval.
How do patients obtain ambrisentan?
Ambrisentan must be prescribed by a physician. Ambrisentan is sent directly to patients by any of the following specialty pharmacies: Accredo Health Inc., Aetna Specialty Pharmacy, CVS Caremark, Cigna Tel-Drug, CuraScript, Kaiser Permanente Specialty Pharmacy, Walgreens Specialty Pharmacy (Medmark), and WellCare. Ambrisentan can only be obtained through the Letairis® Education and Access Program (LEAP).
Will insurance pay for ambrisentan?
It is expected that most insurance plans will pay for ambrisentan prescriptions; however, plans with a set co-payment may result in substantial cost to the patient.
Medicaid and most state-run insurance plans will pay for ambrisentan. Medicare will also cover ambrisentan in most cases under the part D component of that program.
Gilead Solutions™ (866-664-5327) offers a variety of options to cover either partial or full drug costs for any patient with qualifying financial circumstances. Caring Voice Coalition (888-267-1440), an organization that provides grants to assist with drug cost for patients with chronic illnesses, may also provide coverage if the patient qualifies for such assistance.
What are the frequent side effects of ambrisentan?
Ambrisentan is generally well tolerated.
The most frequent side effects of ambrisentan are fluid retention (ranging from swelling of the extremities to heart failure), nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain and constipation.
Fluid retention is a known side effect of ERAs. In the clinical studies of ambrisentan, there was an increased prevalence of peripheral edema (swelling) with doses of 5 or 10 mg. The swelling was generally mild or moderate in severity and occurred with greater frequency and severity in the elderly. It is important to notify your doctor if you experience swelling. Treatment may be required including sodium and fluid restriction as well as a diuretic.
The red blood cell count or hemoglobin (hematocrit) may decrease in some patients but is rarely severe enough to require transfusion.
The development of abnormal liver function tests (LFTs), measured in blood samples to greater than three times the upper limit of normal may occur in patients taking ERAs but appears to be less common with ambrisentan compared to bosentan.
Decreases in sperm count have been observed in men taking bosentan, another type of ERA. Based on this information and preclinical data from animal studies, it cannot be excluded that ERA’s such as ambrisentan have an adverse effect on spermatogenesis.
How are side effects of ambrisentan monitored?
Because of the potential harm to the fetus, women of childbearing potential must have a pregnancy test before initiating therapy and subsequently on a monthly basis as long as a patient is receiving ambrisentan.
Hemoglobin (red blood cell count) should be assessed prior to initiating therapy and after 1 month then monitored periodically as long as a patient is receiving ambrisentan.
The FDA recently removed the black box warning related to liver injury for ambrisentan because of a low observed incidence of liver toxicity. Although monthly LFT monitoring is no longer mandatory for ambrisentan treatment, it is prudent to test liver function at the outset of all treatments for PAH and, at the prescriber's discretion, at periodic intervals thereafter.
Ambrisentan should be discontinued if the liver enzymes (hepatic aminotransferases) rise to more than 5 times the upper limit of normal or if elevations are accompanied by an increased total bilirubin to more than 2 times the upper limit of normal or by signs and symptoms of liver dysfunction and other causes are excluded.
What are considerations for use of ambrisentan in special populations?
Use of ambrisentan is contraindicated in pregnancy. Ambrisentan has been shown to be harmful to the growing fetus in rats and rabbits. Patients should not become pregnant while taking ambrisentan; therefore, two forms of contraception are recommended in order to be sure to prevent pregnancy. An exception to this recommendation would be for patients who have had a surgical sterilization procedure such as a tubal ligation or for women who use a Copper T380A or LNg 20 intrauterine device (IUD) as a form of contraception. In addition, a pregnancy test prior to the initiation and monthly thereafter while taking ambrisentan is advised. If a patient becomes pregnant while taking ambrisentan, she should immediately notify the prescribing physician. It is not known whether ambrisentan passes into breast milk; therefore, nursing mothers should not take ambrisentan.
The safety and effectiveness of ambrisentan has not been studied in children.
Ambrisentan is not recommended in patients with moderate to severe hepatic (liver) impairment.
Dose adjustment for ambrisentan is not required for patients with mild to moderate renal (kidney) impairment.
Could a patient be allergic to ambrisentan?
This is possible, although such reports are rare.
What are important drug interactions with ambrisentan?
Ambrisentan can interact with cyclosporine, a medication given to prevent transplant rejection. When ambrisentan and cyclosporine are used together, the dose of ambrisentan should be limited to 5 mg daily.
Co-administration of ambrisentan and sildenafil or tadalafil does not result in clinically relevant interaction.
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