Ambrisentan

Ambrisentan also called Letairis or Volibris, is a selective antagonist of the endothelin type-A receptor (ETAR) that is indicated for the treatment of pulmonary arterial hypertension (PAH, high blood pressure in the vessels that carry blood to the lungs) (WHO Group 1 – idiopathic pulmonary arterial hypertension) ¹. Inhibition of the endothelin type-A receptor (ETAR) disrupts the intracellular pathways that lead to vasoconstriction, thus causing vasodilation. Because endothelin type-A receptor (ETAR) is found in highest concentration in the lungs, ambrisentan primarily causes vasodilation in the pulmonary vasculature and decreases pulmonary vascular pressure. Ambrisentan (Letairis) lowers blood pressure in your lungs, helping your heart pump blood more efficiently. Ambrisentan is approved in Europe, Canada and the United States for use as a single agent to improve exercise ability and delay clinical worsening. In addition, ambrisentan is approved in the United States for use in combination with tadalafil (Adcirca, Cialis) to reduce the risks of disease progression and hospitalization for worsening pulmonary arterial hypertension and to improve exercise ability ². Ambrisentan is in a class of medications called endothelin receptor antagonists. It works by stopping the action of endothelin, a natural substance that causes blood vessels to narrow and prevents normal blood flow in people who have pulmonary arterial hypertension (PAH). Studies establishing the efficacy of ambrisentan included patients with both idiopathic or heritable pulmonary arterial hypertension (HPAP) and those with pulmonary arterial hypertension associated with connective tissue diseases. Patients studied displayed symptoms and causes predominantly of WHO Functional Class II-III. As an endothelin receptor antagonist, ambrisentan prevents endogenous endothelin peptide from constricting the muscles in blood vessels, allowing them to relax and permit a reduction in blood pressure.

DO NOT use ambrisentan if you are pregnant or think you might be pregnant. Ambrisentan can cause serious birth defects. Tell your doctor right away if you miss a menstrual period or think you may have become pregnant. Ambrisentan comes with patient instructions about acceptable forms of birth control to use while taking this medicine. Follow these directions carefully. Ask your doctor about emergency contraception if you have unprotected sex or if you believe your contraception has failed.

Ambrisentan is available in tablets of 5 and 10 mg under the brand name Letairis or Volibris and the recommended dose is 5 to 10 mg once daily to be taken by mouth. Ambrisentan is usually taken with or without food once a day. Take ambrisentan at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ambrisentan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow ambrisentan tablets whole; do not split, chew, or crush them.

Your doctor may start you on a low dose of ambrisentan and gradually increase your dose.

Ambrisentan controls the symptoms of pulmonary arterial hypertension but does not cure it. Continue to take ambrisentan even if you feel well. Do not stop taking ambrisentan without talking to your doctor. If you suddenly stop taking ambrisentan, your condition may worsen.

Ambrisentan common side effects include headaches, dizziness, edema, flushing, rhinitis and dyspepsia. Ambrisentan is generally well tolerated with side effects generally unrelated to dose with peripheral edema mostly in patients older than 65 years ³. Hepatic transaminase elevations occur at lower rate than with Bosentan (Tracleer) ³. However, get emergency medical help if you have signs of an allergic reaction such as hives, difficulty breathing, swelling of your face, lips, tongue or throat.

Ambrisentan special precautions

Before taking Ambrisentan (Letairis):

• Embryo-Fetal Toxicity:
  • DO NOT administer ambrisentan to pregnant females because it may cause fetal harm.
  • Ambrisentan is very likely to produce serious birth defects as this effect has been consistently seen in animal studies.
  • Recommendations:
    • Exclude pregnancy before treatment initiation.
    • Acceptable methods of contraception should be used during treatment and for 1 month following discontinuation of treatment.
    • A negative pregnancy test must be obtained prior to each prescription and 1 month following discontinuation of treatment.
    • Because of the risk of embryo-fetal toxicity, females can only receive drug through a restricted program called the Letairis REMS (Risk Evaluation and Mitigation Strategy) program.
• tell your doctor and pharmacist if you are allergic to ambrisentan, any other medications, or any of the ingredients in ambrisentan tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention if you are taking cyclosporine (Gengraf, Neoral, Sandimmune). Your doctor may need to change the dose of your medications or monitor you carefully for side effects.
• tell your doctor if you have idiopathic pulmonary fibrosis (scarring of the lungs with an unknown cause). Your doctor will probably tell you not to take ambrisentan.
• tell your doctor if you have or have ever had anemia (a lower than normal amount of red blood cells) or liver disease.
• tell your doctor if you are breastfeeding. Do not breastfeed if you are taking ambrisentan.

Ambrisentan mechanism of action

Ambrisentan (Letairis) is in a class of medications called endothelin receptor antagonists. It works by stopping the action of endothelin, a natural substance that causes blood vessels to narrow and prevents normal blood flow in people who have pulmonary arterial hypertension. Upon administration, ambrisentan targets and binds to endothelin type-A receptor (ETAR), which prevents the binding of endothelin-1 (ET-1) to the endothelin type-A (ETA) receptor and ET-1/ETA-mediated vasoconstriction and cell proliferation. This may lead to vasodilation. Because endothelin type-A receptor (ETAR) is found in highest concentration in the lungs, ambrisentan primarily causes vasodilation in the pulmonary vasculature and decreases pulmonary vascular pressure. Endothelin-1 (ET-1) concentrations are increased in plasma as well as lung tissue in pulmonary arterial hypertension (PAH) and ET-1 may play a key role in the pathogenesis of pulmonary arterial hypertension.

Ambrisentan uses

Ambrisentan (Letairis) is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (WHO Group 1 – idiopathic pulmonary arterial hypertension) to improve exercise ability and delay clinical worsening. Ambrisentan is also used in combination with tadalafil (Adcirca, Cialis) to treat pulmonary arterial hypertension (PAH) (WHO Group 1) to reduce the risks of disease progression and hospitalization for worsening pulmonary arterial hypertension, and to improve exercise ability. Ambrisentan may improve the ability to exercise and slow the worsening of symptoms in people with pulmonary arterial hypertension. Use of ambrisentan in other forms of pulmonary arterial hypertension (due to heart failure, thromboembolic disease, or pulmonary disease) should be considered experimental as its efficacy in these forms of pulmonary arterial hypertension has not been adequately shown. Because of the potential for teratogenicity, ambrisentan is available only as a part of a monitoring program in which documentation of adequate methods for birth control are required.

In prospective, randomized controlled trials, ambrisentan was effective in alleviating symptoms, improving exercise tolerance and prolonging the time to clinical worsening in patients with idiopathic pulmonary arterial hypertension (WHO group 1). Studies establishing the effectiveness of ambrisentan (Letairis) included predominantly patients with WHO Functional Class II-III symptoms and causes of idiopathic or heritable pulmonary arterial hypertension (60%) or pulmonary arterial hypertension associated with connective tissue diseases (34%).

Table 1. Classification of Pulmonary Hypertension Groups 1 – 5

Group 1 and 1’	Group 2	Group 3	Group 4	Group 5
Pulmonary arterial hypertension	Pulmonary hypertension due to left heart disease	Pulmonary hypertension due to lung diseases or hypoxia	Chronic thromboembolic pulmonary hypertension	Pulmonary hypertension with unclear multifactorial mechanisms
Idiopathic pulmonary arterial hypertension (iPAH) Heritable pulmonary arterial hypertension (HPAP) Drug and toxin-induced Associated with: Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Schistosomiasis Pulmonary veno-occlusive disease	Left ventricular systolic dysfunction Left ventricular diastolic dysfunction Valvular disease Congenital/acquired left heart inflow/outflow obstruction	Chronic obstructive pulmonary disease (COPD) Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental lung diseases		Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhan’s cell histiocytosis, lymphangioleiomyomatosis (LAM), neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Other: tumoral obstruction, fibrosing mediastinitis, chronic renal failure

[Source ⁴ ]

Ambrisentan dosage

Usual adult dose for pulmonary hypertension:

• Initial dose: 5 mg orally once a day.
• Comments:
  • Consider increasing the dose to 10 mg orally once a day if 5 mg is tolerated.
  • When used with tadalafil, the dose of either drug can be increased as needed and tolerated at 4-week intervals.
  • When coadministered with cyclosporine, the dose of ambrisentan should be limited to 5 mg once a day.

• Uses:
  • For the treatment of pulmonary arterial hypertension (WHO Group 1) to improve exercise ability and delay clinical worsening.
  • For the treatment of pulmonary arterial hypertension (WHO Group 1) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening pulmonary arterial hypertension, and to improve exercise ability.

Renal dose adjustments

• Mild or moderate renal impairment: No adjustment recommended.
• Severe renal impairment: Caution is recommended.

Liver dose adjustments

• Mild liver impairment: Dose adjustment may be required; however, no specific guidelines have been suggested. Caution is recommended.
• Moderate or severe liver impairment: Use not recommended.

If liver impairment develops after starting on the drug, the cause should be fully investigated and the drug should be discontinued if:

• ALT or AST elevations are greater than 5 times the upper limit of normal
• ALT or AST elevations are accompanied by bilirubin elevations of greater than 2 times the upper limit of normal
• ALT or AST elevations are accompanied by signs or symptoms of liver dysfunction and other causes have been excluded

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Ambrisentan side effects

Ambrisentan (Letairis) may cause side effects. Common side effects may include:

• swelling in your hands, legs, ankles, or feet;
• stuffy nose, sinus pain; or
• hot flashes, redness in your face.

This is not a complete list of side effects and others may occur.

Tell your doctor if any of these symptoms are severe or do not go away:

• flushing
• pale skin
• fast heartbeat
• headache

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness
• difficulty swallowing or breathing
• rash
• unusual weight gain
• extreme tiredness
• loss of appetite
• lack of energy
• nausea
• vomiting
• pain in the upper right stomach area
• yellowing of the skin or eyes
• flu-like symptoms
• itching
• dark colored urine

Some men taking a medication similar to ambrisentan developed a lower than normal sperm count (number of male reproductive cells); an effect that might affect their ability to father a child. Talk to your doctor about the risks of taking ambrisentan if you would like to have children in the future.

Ambrisentan (Letairis) may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Ambrisentan (Letairis) overdose

In case of ambrisentan (Letairis) overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number.

Symptoms of ambrisentan (Letairis) overdose may include the following:

• headache
• flushing
• dizziness
• nausea
• nasal congestion.

References

1. Rivera-Lebron, B. N., & Risbano, M. G. (2017). Ambrisentan: a review of its use in pulmonary arterial hypertension. Therapeutic advances in respiratory disease, 11(6), 233–244. https://doi.org/10.1177/1753465817696040
2. Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grünig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ; AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687
3. Kingman M, Ruggiero R, Torres F. Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2009;10(11):1847–1858.
4. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D34-41. doi: 10.1016/j.jacc.2013.10.029. Erratum in: J Am Coll Cardiol. 2014 Feb 25;63(7):746. Erratum in: J Am Coll Cardiol. 2014 Feb 25;63(7):746.