FDA, Regulatory

FDA tells Sprout Pharma, like it or not the black box on Addyi stays, but we will dilute the warning

When the controversial first drug for low sexual desire in women was finally granted approval in 2015, critics accused the FDA of bowing to pressure from advocates by sanctioning the use of a drug that was found to be marginally effective in clinical trials, and dangerous when taken with alcohol. On Thursday, the agency rebuked the maker of the drug, Addyi, by refusing to entertain the company’s quest to discard the black box warning carried by the treatment, but agreed to dampen the strong warning on the basis of postmarketing data.

Addyi, known chemically as flibanserin, is designed for premenopausal women whose lack of sexual desire causes distress. Patients who took Addyi in a clinical trial had an increase of about one sexually satisfying event per month, versus those given a placebo.

The pink pill — nicknamed the “female Viagra” — has little in common with the Pfizer $PFE blockbuster, which was approved decades ago as the pioneering erectile dysfunction treatment. While Viagra impacts blood flow and is taken as-needed, Addyi was designed to activate sexual impulses in the brain and must be taken everyday.

In particular, Addyi’s label carries a black box warning, highlighting the risk of potentially dangerous low blood pressure and fainting, notably when taken with alcohol.

On Thursday, the regulator made clear that Addyi’s label must be modified to clarify there is still a concern about consuming alcohol close in time to taking Addyi, but that it does not have to be avoided completely. After analyzing data from postmarketing studies, the FDA said the warning inside the black box should reflect that women should discontinue drinking alcohol at least two hours before taking Addyi at bedtime or to skip the dose that evening, and that women should not consume alcohol at least until the morning after taking Addyi at bedtime.

The regulator has proverbially put its foot down, and is compelling Addyi maker Sprout Pharmaceuticals to make the change, after the two parties were unable to reach an agreement. “We work diligently with companies to make labeling updates but occasionally are unable to reach agreement. In those rare cases…we have important authorities to compel companies to make safety labeling changes that are critical for the safe use of an approved product,” the agency said in a statement.

Cindy Eckert and Robert Whitehead

The founders of Sprout Pharmaceuticals have long had a strained relationship with the FDA. Chief Cindy Whitehead (now Cindy Eckert) co-founded the company with her then-husband Robert Whitehead in 2011, after selling another drug company they had spawned together after it was issued multiple FDA warnings related to its marketing tactics.

Sprout purchased flibanserin from Germany’s Boehringer Ingelheim, which originally developed it and took it to the FDA, only to be denied approval in 2010. Under Sprout, the drug was evaluated in additional studies, but the FDA rejected it again in 2013. Incensed by the rejection, Sprout — with the support of some women’s groups —  aggressively lobbied the FDA to get the drug across the finish line, by accusing the US agency of gender bias (a charge the regulator denied).

The FDA finally approved the treatment — with a boxed warning — on August 19, 2015, the very next day Sprout announced it was being sold to Valeant (now Bausch Health) for a tidy $1 billion. The honeymoon didn’t last long — in 2017, an embattled Valeant returned Sprout to its original owners.

Last month, Sprout issued an cheerful press release, suggesting postmarketing data indicated that treatment with Addyi did not result in fainting or hypotension that required medical attention. But the FDA took issue with that assessment, saying the safety precautions built into the trial did not allow for an adequate assessment of this risk. “For example, women with low blood pressure while lying down…were not permitted to stand up to have blood pressure measurements taken or had to have repeated blood pressure measurements while lying down until they were high enough for the women to safely stand up. As a result, the data collected had missing or delayed blood pressure measurements from these women while standing.”

The regulator was also not satisfied with how the postmarketing trials were conducted, pointing out that in one trial, there were “missing or delayed measurements for blood pressure from when the women were first laying down to when they stood up that are critical in determining the risk of hypotension and syncope when taking Addyi and alcohol together.” The agency also flagged that many more women had missing or delayed blood pressure measurements when they took Addyi and alcohol together, compared to when they consumed alcohol or Addyi alone.

Altogether, the “pattern of the missing or delayed measurements” provides further evidence of an interaction between Addyi and alcohol that can enhance the risk of hypotension and fainting, the agency underscored.

Sprout must comply with the FDA’s labeling decision or risk monetary fines and/or enforcement in the form of product seizure and injunction. The company has until April 16 to appeal.

Endpoints News has contacted Sprout for comment.

Image source: AP

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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