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FDA Drug Safety Communication: Liver injury warning to be removed from Letairis (ambrisentan) tablets


Safety Announcement

Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary

Safety Announcement

[03-04-2011] The U.S. Food and Drug Administration (FDA) is removing the warning related to liver injury from the boxed warning of the Letairis (ambrisentan) tablet label. Further evaluation of the clinical trial data and post-marketing safety information has led the FDA to conclude that the risk of liver injury in patients treated with this drug is low.

FDA has also concluded that routine monthly serum liver enzyme testing for patients taking Letairis is not necessary.  Healthcare professionals should still continue to order liver enzyme tests when they consider it clinically necessary.

The boxed warning on the risk of serious birth defects and the contraindication for use during pregnancy will remain in the Letairis label.  Monthly pregnancy tests will still be required before Letairis shipment.

Letairis will continue to be prescribed and dispensed only through the special restricted distribution program called the Letairis Education and Access Program (LEAP).

Letairis is used to treat pulmonary arterial hypertension (PAH or high blood pressure in the vessels that carry blood to the lungs). 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. 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.

(see Data Summary)
 

Additional Information for Patients

  • Monthly liver enzyme testing (a blood test) is not required while taking Letairis.
  • Your healthcare professional may still order a liver enzyme test when it is considered clinically necessary.
  • Monthly pregnancy tests are still required for females of childbearing age.
  • Females of childbearing age must still use 2 acceptable methods of birth control while taking Letairis.
  • Do not stop taking Letairis without talking to your healthcare professional.
  • Discuss any questions or concerns about Letairis with your healthcare professional.
  • Report any side effects you experience to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page.


Additional Information for Healthcare Professionals

  • Be aware that monthly testing of serum liver enzymes is no longer required and drug shipment is no longer contingent upon completion of this testing.
  • You should continue to order and review serum liver enzyme tests if you consider it clinically necessary.
  • Be aware that a boxed warning on the risk of serious birth defects and the contraindication for use during pregnancy remains in the label. 
  • Monthly pregnancy tests will still be required in females of childbearing potential before each shipment of Letairis through the LEAP program.
  • Females of childbearing age must still use 2 effective methods of contraception while taking Letairis unless that patient has had a tubal sterilization or uses an intrauterine device (IUD).
  • Report adverse events involving Letairis to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.


Data Summary

Letairis (ambrisentan) was approved in 2007 with a Risk Minimization Action Plan (RiskMAP) to manage liver injury and teratogenicity because these effects were thought to be common to all members of its drug class, the endothelin receptor antagonists (ERA). The Letairis RiskMAP was subsequently converted to a Risk Evaluation and Mitigation Strategy (REMS) and approved in May 2009. The Letairis REMS linked drug access with patient-reported monthly liver testing and pregnancy testing for females of childbearing potential. For a more complete discussion of FDA’s rationale and regulatory decisions regarding Letairis, refer to the Letairis Question and Answer document.

The new revisions in the Letairis label and modifications to the Letairis REMS are based on FDA’s thorough review of all available results from clinical trials and post-marketing data.  This body of data has shown a low risk of hepatotoxicity.

The 12-week controlled clinical studies showed the incidence of aminotransferase elevations was 0.0% for patients on Letairis compared to 2.3% for patients on placebo. Post-marketing observational data from the Adverse Event Reporting System (AERS) database reported some elevations in serum liver aminotransferases with Letairis use, but in nearly all cases, alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, or hepatotoxic medications). Likewise, in preliminary data from an observational study in Europe, alternative causes were identified for cases of liver injury.  FDA has concluded that reports of liver injury are consistent with the background rate of such events in the general PAH population.

Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure.

The label for Letairis contains a report of a study in which 36 patients who had discontinued an endothelin antagonist because of liver toxicity were given Letairis, with none of those patients experiencing recurrent toxicity. In contrast, eight similar patients reexposed to another provoking endothelin antagonist (bosentan or an investigational agent) all had recurrent liver injury.

The Letairis label now recommends that healthcare professionals order and review tests for serum liver enzymes as clinically indicated. Letairis should be discontinued if serum 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. Other causes for liver impairment should be investigated. Letairis is not recommended in patients with moderate or severe hepatic impairment. There is no information on its use in patients with mild hepatic impairment; however, ambrisentan blood levels may be increased in these patients.

 

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