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U.S. Department of Health and Human Services

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Questions & Answers: Liver injury warning to be removed from Letairis (ambrisentan) tablets

On March 4, 2011, the U.S. Food and Drug Administration (FDA) informed the public that the warning related to liver injury will be removed from the Letairis (ambrisentan) label.  A thorough evaluation of all available clinical trial data and post-market information has shown that Letairis does not increase the risk of livery injury.  The warning against the use of Letairis in pregnancy has not been altered.

Q1.  What is Letairis (ambrisentan)?
Q2.  Why is FDA removing the liver injury warning from the Letairis label?
Q3. Why was the risk of liver injury originally included in the Letairis label?
Q4. What does the change in the label of Letairis mean for the use of this drug?
Q5.  What should patients currently taking Letairis know about FDA’s action?
Q6.  What should healthcare professionals do if they are currently prescribing Letairis?
Q7. Does removal of the liver injury warning from the label mean that Letairis is safer than other drugs used to treat pulmonary arterial hypertension (PAH)?

Q1.  What is Letairis (ambrisentan)?

Letairis is a medication used to treat pulmonary arterial hypertension (PAH or high blood pressure in the vessels that carry blood to the lungs).  PAH is a serious condition that can cause breathlessness, chest tightness, limited exercise capacity, fatigue, and death. Letairis has been shown to improve the ability to exercise and slow the worsening of symptoms in patients with PAH.  

Letairis is in a class of medications called endothelin receptor antagonists (ERAs).  These drugs work by stopping the action of endothelin, a natural substance that causes blood vessels to narrow, which prevents normal blood flow in people who have PAH.  

Q2.  Why is FDA removing the liver injury warning from the Letairis label?

FDA is removing the liver injury warning from Letairis’s boxed warning based on a thorough review of all available clinical trials and post-market safety data.

Further evaluation of the studies that led to the approval of Letairis showed there was no significant increase in liver enzymes in patients taking Letairis compared to patients taking a placebo. In addition, the frequency of liver impairment reported in patients taking Letairis after its approval is similar to that seen in the general PAH population.

Q3. Why was the risk of liver injury originally included in the Letairis label?

The risk of liver injury (hepatotoxicity) was included in the original Letairis label based on experience with other members of Letairis’s drug class (the ERAs).  The other ERAs have been associated with liver enzyme elevations, more severe liver injury, and cases of liver failure.   As a result, Letairis was approved with a boxed warning and a requirement that patients have their liver enzymes monitored monthly - the same as the first ERA drug that was approved.

Healthcare professionals and patients should note that Letairis is still not recommended in patients with moderate or severe liver problems because such patients have not been studied. Healthcare professionals should also note that the contraindication against use during pregnancy remains the same for the entire class of ERAs.  

Q4. What does the change in the label of Letairis mean for the use of this drug?

When Letairis was approved in 2007, it was approved with a Risk Minimization Action Plan, which has since been approved as a Risk Evaluation and Mitigation Strategy (REMS), to manage the liver injury and pregnancy risks thought to be common to all members of its drug class.  The Letairis REMS, a restricted distribution program called the Letairis Education and Access Program (LEAP), required that all patients taking the drug have monthly liver enzyme testing to ensure patients were not experiencing a liver injury. Letairis will still be available only through the  LEAP program.  However, with the removal of the liver injury warning, patients will no longer be required to take monthly serum liver enzyme tests. 

The other requirements of the REMS related to pregnancy risks will remain the same. Monthly pregnancy tests will still be required in females of childbearing potential before each shipment of Letairis through the LEAP program.

Q5.  What should patients currently taking Letairis know about FDA’s action?

Patients currently taking Letairis should be aware that monthly liver enzyme testing will no longer be required. 

Patients should be aware that there are serious risks to the fetus when Letairis is taken during pregnancy.  Females of childbearing potential will still be required to take monthly pregnancy tests in before each shipment of Letairis through the LEAP program. These women must also continue to use two (2) acceptable methods of birth control when taking this medication.

Patients should not stop taking Letairis unless told to do so by a healthcare professional, including women who become pregnant while taking this medication. Patients should discuss any questions or concerns they may have about Letairis with their healthcare professional.  

Patients should report any side effects they experience while taking Letairis to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page. 

Q6.  What should healthcare professionals do if they are currently prescribing Letairis?

Healthcare professionals should be aware that monthly testing of liver enzymes is no longer required of patients taking Letairis, and drug shipment is no longer contingent on this testing.  However, liver enzyme tests should still be ordered and reviewed when considered clinically necessary.  Letairis should be discontinued if liver aminotransferases greater than 5 times the upper limit of normal (ULN) are observed, if aminotransferase elevations are accompanied by bilirubin greater than 2 times ULN, or if signs or symptoms of liver impairment are reported.  Letairis is not recommended in patients with moderate or severe hepatic impairment. 

Healthcare professionals should also be aware that the boxed warning on the risk of serious birth defects and the contraindication for use during pregnancy remain in the Letairis label.  Females of childbearing potential are still required to undergo monthly pregnancy tests in order to receive Letairis through the LEAP program.  Females of childbearing potential must also still use 2 effective methods of contraception while taking Letairis, unless the patient has had a tubal sterilization or uses an intrauterine device (IUD).

Healthcare professionals should continue to report adverse events involving Letairis to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page.

Q7. Does removal of the liver injury warning from the label mean that Letairis is safer than other drugs used to treat pulmonary arterial hypertension (PAH)?

All drugs have risks and benefits, and these risks and benefits should always be carefully weighed when deciding which drug is appropriate for treatment.  Although recent data suggest that Letairis has a low risk for liver injury risk, patients should talk to their healthcare professional to determine which treatment option is most appropriate for them.