FDA Clears Two-Drug Combo as First-Line Treatment for PAH

Megan Brooks

October 05, 2015

The US Food and Drug Administration (FDA) has approved the use of ambrisentan (Letairis, Gilead Sciences) in combination with tadalafil (Adcirca, Eli Lilly) as up-front therapy for pulmonary arterial hypertension (PAH) to reduce the risk of worsening disease and improve exercise ability, according to Gilead Sciences.

Ambrisentan is a selective endothelin type A receptor antagonist approved in 2007 in the United States as monotherapy for PAH. Tadalafil is a phosphodiesterase type 5 inhibitor approved for PAH in the United States in 2009. (Cialis, another form of tadalafil, is marketed by Eli Lilly for erectile dysfunction and is not approved for PAH.)

"The evidence to support the use of ambrisentan and tadalafil in PAH is well-established, however an outstanding question has been whether combining these two medications up front may further delay the progression of this disease over the long term for patients who are newly starting PAH therapy," said Ronald J. Oudiz, MD, director of the Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, in a company news release.

"Based on the data supporting today's approval, we now know that patients receiving ambrisentan and tadalafil up front are less likely to experience disease progression or be hospitalized, and have more improvement in exercise ability than patients receiving either effective therapy alone. As such, this combination represents a new treatment strategy for patients living with this debilitating and life-threatening disease," Dr Oudiz said.

Approval of the first-line ambrisentan/tadalafil combination for PAH is based on results of the AMBITION trial involving 605 patients with World Health Organization functional class II or III PAH. Patients were randomly assigned to receive once-daily ambrisentan plus tadalafil or to either drug alone. Doses were titrated from 5 mg to 10 mg daily for of ambrisentan and from 20 mg to 40 mg once daily for tadalafil.

As reported by Medscape Medical News, treatment with the two-drug combination was associated with about a 50% reduction in risk for clinical failure compared with either drug alone.

The combination group had no new adverse effects compared with the monotherapy groups, but some adverse effects occurred more frequently in the combined group, including peripheral edema, headache, nasal congestion, and anemia. Rates of serious adverse events and events leading to discontinuation of the drugs were similar across treatment groups.

Ambrisentan is contraindicated in pregnant women. It carries a boxed warning and an associated risk evaluation and mitigation strategy program regarding the risk for embryo-fetal toxicity.


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