FDA: Monthly liver enzyme tests no longer needed for PAH drug

March 11, 2011

FDA has approved a change to the prescribing information for ambrisentan 5-mg and 10-mg tablets (Letairis, Gilead Sciences) once-daily treatment to improve exercise ability and delay clinical worsening in patients with pulmonary arterial hypertension (PAH, WHO Group 1) and predominantly WHO Functional Class II-III symptoms.

FDA has approved a change to the prescribing information for ambrisentan 5-mg and 10-mg tablets (Letairis, Gilead Sciences) once-daily treatment to improve exercise ability and delay clinical worsening in patients with pulmonary arterial hypertension (PAH, WHO Group 1) and predominantly WHO Functional Class II-III symptoms.

This change removes language concerning the potential risk of liver injury from the boxed warning. In conjunction with this label update, patients with PAH who are receiving ambrisentan are no longer required to obtain monthly liver function tests. FDA advises that healthcare professionals should order and review tests for liver function as necessary based on the patient’s condition and history.

FDA approved the new labeling based on its review of postmarketing data reflecting use of ambrisentan over more than 7,800 patient years, which were collected through the Letairis Education and Access Program (LEAP). These data were consistent with clinical trial data used to support the registration of ambrisentan. During 12-week controlled clinical trials, the incidence of liver function abnormalities was 0% on ambrisentan and 2.3% on placebo.

FDA said that the drug poses only a low risk of liver injury. Information related to potential serious liver injury and the need to monitor for such serious injury is being removed from the drug’s boxed warning.

In patients with PAH, ambrisentan, an endothelin receptor antagonist, slows the worsening of symptoms and improves the ability to exercise. It was approved in 2007.

Ambrisentan was approved with a Risk Minimization Action Plan (RiskMAP) to manage liver damage and fetal malformation. The RiskMAP called for liver enzyme testing prior to treatment and monthly during treatment for all patients. It also required monthly pregnancy testing for women of childbearing potential because ambrisentan causes birth defects in animals, like other drugs in this class. The ambrisentan RiskMAP was converted to a Risk Evaluation and Mitigation Strategy (REMS) in 2009.

The boxed warning on the risk of serious birth defects and the contraindication for use during pregnancy will remain in the labeling. Letairis will continue to be available only through LEAP. For women who can become pregnant, monthly pregnancy tests will still be required before ambrisentan is shipped.

The liver warnings were based on experience with other drugs in ambrisentan’s drug class, as well as a few observed instances of increased liver enzymes in people treated with ambrisentan. FDA’s further evaluation has shown that rates of liver problems in ambrisentan-treated patients are consistent with rates within the general PAH population. In the controlled clinical trials, the rates of liver problems in ambrisentan-treated patients are similar to the rates in people receiving an inactive pill (placebo).

“The removal of the warning related to liver injury from the boxed warning for Letairis should be welcome news for providers and patients interested in PAH,” Robert T. Taketomo, PharmD, MBA, president/CEO and chairman of the board, of Glendale, Calif.-based Ventegra, told Formulary. “This change eliminates the need for monthly liver enzyme testing but it’s interesting that the REMS program remains. This implies that, while concern over liver injury was largely unfounded, other significant risks remain with this agent.”