Hepatic Injury

• Ambrisentan can cause elevation of liver aminotransferases (ALT and AST) to at least 3 times the upper limit of normal (ULN). This drug has been 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. This drug 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 ambrisentan in these circumstances. 

Pregnancy Contraindication

• This drug 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 (4.1)].
• Pregnancy must therefore be excluded before the initiation of treatment 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.

Restricted Distribution Program

• Because of the risks of liver injury and birth defects, ambrisentan 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 (ambrisentan) may be dispensed only to patients who are enrolled in and meet all conditions of LEAP

Approved Risk Evaluation and Mitigation Strategies (REMS)

Letairis (ambrisentan) Tablets (PDF - 1120KB)

Patient Counseling Information

• Letairis

Medication Guides

Patient Medication Guide

Package Inserts

Ambrisentan