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 every day.

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 an 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

Click on the im­age to see the full-sized ver­sion

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 a 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: Allen G. Breed AP

Paul Hudson, Sanofi CEO (Getty Images)

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Pablo Legorreta, founder and CEO of Royalty Pharma AG, speaks at the annual Milken Institute Global Conference in Beverly Hills, California (Patrick T. Fallon/Bloomberg via Getty Images)

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About Avance Clinical

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As oncology sponsors look internationally to speed-up trials after unprecedented COVID-19 suspensions and delays, Australia, which has led the world in minimizing the pandemic’s impact, stands out as an attractive destination for early phase trials. This in combination with the streamlined regulatory system and the financial benefits including a very favourable exchange rate and the R & D cash rebate makes Australia the perfect location for accelerating biotech clinical programs.

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Dan O'Day, Gilead CEO (Andrew Harnik, AP Images)

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Bris­tol My­ers Squibb fi­nal­ly gets in the front­line NSCLC game dom­i­nat­ed by Mer­ck, adding a sec­ond Op­di­vo/Yer­voy-based op­tion

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Bryan Roberts, Venrock

Ven­rock sur­vey shows grow­ing recog­ni­tion of coro­n­avirus toll, wan­ing con­fi­dence in ar­rival of vac­cines and treat­ments

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The venture firm had sent their form out to hundreds of insurance and health tech executives, investors, officials and academics on February 24 and gave them two weeks to fill it out. No Americans had died at that point but the coronavirus had become enough of a global crisis that they included two questions about the virus, including “Total U.S. deaths in 2020 from the novel coronavirus will be:”.

Roger Perlmutter, Merck R&D chief (YouTube)

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