FDA Advisors: No to Nebivolol/Valsartan Combo Pill for HTN

September 10, 2014

SILVER SPRING, MD — An FDA advisory panel has recommended by a six-to-four vote that a dual-agent medication combining a beta-blocker and an angiotensin-receptor blocker (ARB) not be approved for the treatment of hypertension.

Predominant among reasons cited against approval by a majority on the panel: the fixed-dose combination of nebivolol (Bystolic, Actavis) and valsartan didn't show enough of a blood-pressure-lowering effect in the medication's pivotal trial[1], especially given combination agents with a more pronounced effect already on the market for the same indication.

"I voted no because I thought the size of the effect just wasn't robust enough, and actually, from a public-health standpoint, it might delay patients in either getting to [BP] goal more efficiently or getting to goal at all, depending on the number of steps [their] physicians want to go through," said Dr Philip Sager (Stanford University and the Cardiac Safety Research Consortium, San Francisco, CA) from the panel.

"Approving a drug with a very small effect like this will lead to choosing this agent over other combinations or individual agents that work better," agreed Dr James De Lemos (University of Texas Southwestern, Dallas). "We don't need 47 combinations of blood-pressure medicines; we need a fewer number that offer advantages, and I think the ones that get approved should offer clear advantages over the individual components."

Forest Laboratories, acquired earlier this year by Actavis, had applied to the FDA for the agent's approval based largely on a phase 3 randomized controlled trial with >4000 patients that compared three fixed-dose nebivolol/valsartan combinations against two dosages each of the component drugs vs placebo. The fixed-dose combinations showed an edge over BP reductions from treatment with nebivolol and valsartan individually over the trial's eight weeks.

Panelists voting in support of approval included Dr Linda F Fried (University of Pittsburgh, PA), who said the combination pill appeared safe and pointed out that some individual patients showed a much better BP response to it than others. "I think this isn't the drug for everybody," she said, but "there might be a good response for certain individuals, and if you don't see a response, it's time to move on."

Panel chair Dr A Michael Lincoff, who voted to recommend approval, said the nebivolol/valsartan combination "clearly has less of an effect" on BP than other combo pills for hypertension, but that the effect on systolic BP, at least, seemed "clinically relevant."

He said he doubted, "from a regulatory standpoint," whether the panel should declare that "this drug combination isn't as good as some other combination, so it shouldn't be approved. I think it gets to be difficult where you draw that line."

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