Ambrisentan (Letairis® in the U.S. and Volibris® in Canada) is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.

June 15, 2007

This is an oral medication, available in 5 mg and 10 mg tablets. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension.

Physicians most likely will initiate treatment at 5 mg once daily with or without food and may consider increasing dose to 10 mg daily if 5 mg is tolerated.

Letairis s not recommended in patients with moderate or severe hepatic impairment and caution should be used in patients with mild hepatic impairment.

Possible Liver Damage:

• Elevations of liver aminotransferases (ALT/AST) have been reported with Letairis® and serious liver injury has been reported with related drugs.
• Liver aminotransferases should be monitored monthly and Letairis® should be discontinued if >5 X ULN or if elevations are accompanied by bilirubin >2 X ULN or by signs or symptoms of liver dysfunction.

Serious birth defects:

• Very likely to cause fetal harm if taken during pregnancy.
• Must exclude pregnancy before the start of treatment of Letairis® and each month following treatment
• Pregnancy must be prevented by the use of two reliable methods of contraception during Letairis® treatments and for one month after stopping Letairis®

Drug Interactions:

• No significant interactions of Letairis® with warfarin or sildenafil have been observed.
• Caution should be taken when Letairis® is co-administerd with cyclosporine A because cyclosporine A may cause increased exposure to Letairis®.
• Caution should be taken when Letairis® is co-administered with strong CYP3A-inhibitors (e.g., ketoconazole) and CYP2C19-inhibitors (e.g., omeprazole).

Serious side effects:

• Possible liver injury
• Serious birth defects
• Low sperm count - Letairis® can lower sperm count in animals. If this happens in men, they may lose the ability to father children.

Common Side Effects:

• Peripheral edema
• Nasal congestion
• Sinusitis
• Flushing

Most common reactions were mild to moderate and only nasal congestion was dose-dependent.

In clinical trials, treatment with Letairis  resulted in a significant improvement in 6-minute walk distance for each dose of Letairis and the improvements increased with dose. An increase in 6-mnute walk distance was observed after 4 weeks of treatment.

Improvements in walk distance with  Letairis were smaller for elderly (age >65 years) patients than younger patients and for patients with secondary PAH than for patients with idiopathic PAH.

Letairis studies show a significant delay in the time to clinical worsening for those treated with the medication compared to placebo.

Endothelin receptor antagonists (ERAs) act on the endothelin pathway by blocking binding of endothelin-1 to its receptors (endothelin type-A [ETA] and/or type-B [ETB]) on the surface of endothelial and smooth muscle cells.

Letairis as a once-a-day pill, will cost $3,940* a month, about the same as Tracleer®, which is also known as bosentan. Gilead will be establishing programs to help uninsured or underinsured patients to obtain the drug.

* Costs are subject to change

Gilead Sciences

In clinical trials, an increase in 6-mnute walk distance was observed after 4 weeks of treatment, with a dose-response observed after 12 weeks of treatment.

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 1-888-684-LEAP (5327). Only prescribers and pharmacies registered with LEAP may prescribe or distribute Letairis. Letairis may be dispensed ONLY to patients who are enrolled in and meet all condition of LEAP.

• DailyMed
• U.S. Food and Drug Administration
• Gilead
• Medscape