The NEW ENGLA ND JOURNAL of MEDICINE

Perspective january 14, 2016

FDA Approval of Flibanserin Treating Hypoactive Sexual

Desire Disorder
Hylton V. Joffe, M.D., M.M.Sc., Christina Chang, M.D., M.P.H, Catherine Sewell, M.D., M.P.H, Olivia Easley, M.D.,
Christine Nguyen, M.D., Somya Dunn, M.D., Kimberly Lehrfeld, Pharm.D., LaiMing Lee, Ph.D., Myong-Jin Kim, Pharm.D.,
Ashley F. Slagle, Ph.D., and Julie Beitz, M.D.

W as the Food and Drug Administration (FDA)

approval of flibanserin (Addyi) for treatment
of hypoactive sexual desire disorder (HSDD) in pre-
convened in 2010, unanimously
recommended against approval.2
In the two phase 3 trials, one pri-
mary end point, satisfying sexual
menopausal women long overdue? Or was it an error? events, was achieved, but the oth-
er, daily sexual desire, was not.
In the face of divergent views, we Although nonpharmacologic Although the trials showed an
at the FDA think its important to approaches to HSDD are impor- effect on sexual desire over the
clarify why flibanserin was ap- tant, we recognized that some previous 4 weeks as recalled by
proved after being rejected twice. women could benefit from drug participants assessed with the
HSDD is characterized by re- therapy. Such treatments must Female Sexual Function Index
duced sexual fantasies and desire meet the statutory standard for (FSFI) the committee believed
for sexual activity that causes demonstration of effectiveness that an effect on daily recall of
marked distress or interpersonal (substantial evidence from ade- sexual desire was preferable and
difficulty and is not accounted quate, well-controlled trials) and thought that results on the FSFI,
for by coexisting conditions, use have favorable benefitrisk pro- a secondary end point, should
of medications, or relationship files. Assessing flibanserin has not override the failure to achieve
problems. At a 2014 meeting, the proven challenging; the drug has a primary end point. The commit-
FDA heard from some women been reviewed three times by the tee also expressed concern about
about the conditions effects on FDA and discussed twice at pub- adverse effects such as somno-
their sense of identity, emotional lic advisory committee meetings. lence and drug interactions. The
well-being, and relationships.1 The first advisory committee, FDA rejected the application and

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PERS PE C T IV E
requested additional studies, in-
cluding a new phase 3 trial, an
alcohol-interaction study, and
drugdrug interaction studies.
Boehringer Ingelheim, the
original applicant, completed a
new phase 3 trial with the pri-
mary end points of satisfying
sexual events and sexual desire
as assessed by the FSFI; a sec-
ondary end point was reduction
of distress related to low sexual
desire. All three were achieved,
and results were consistent with
previous findings. However, treat-
ment effects in all three phase 3
trials were small (see Table 1).
Major safety concerns regard-
ing flibanserin include risks of
hypotension, syncope, and central
nervous system (CNS) depression
(e.g., somnolence). These risks in-
crease when the drug is taken
during the day, with concomitant
use of any of the numerous mod-
erate or strong cytochrome P-450
3A4 (CYP3A4) inhibitors such as
some of the antiretroviral drugs,
antihypertensive drugs, antibiotics,
and fluconazole (which increase
systemic exposure to flibanserin
by a factor of 4.5 to 7), and with
alcohol use.
In the alcohol-interaction study,
some participants had hypotension
or syncope requiring intervention,
such as being placed supine or in
Trendelenburg position, when they
took flibanserin with the equiva-
lent of as little as two alcoholic
drinks for someone weighing 70
kg (e.g., two 5-oz glasses of wine
containing 12% alcohol). These
participants had systolic and dia-
stolic blood-pressure reductions
of 28 to 54 mm Hg and 24 to 46
mm Hg, respectively. The study
did not definitively delineate the
risk in premenopausal women
who take flibanserin at bedtime
because 23 of the 25 participants
102
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FDA Approval of Flibanserin
Table 1. Efficacy of Flibanserin in Three Phase 3 Trials.*
End Point Mean Baseline Improvement over Placebo*
Satisfying sexual events 23/mo 0.51.0/mo (median)
FSFI desire (range, 1.26.0) 1.81.9 0.30.4
Daily desire (range, 084) 1012 1.72.3
Distress (range, 04) 3.23.4 0.30.4
* Improvement data represent least-square means, unless otherwise noted. The
improvement in daily desire was not statistically significant. FSFI denotes Female
Sexual Function Index. For the FSFI and daily desire scales, the higher the num-
ber, the greater the sexual desire. For the distress scale, the higher the number,
the greater the distress.
were men, flibanserin was ad- serin for a third review. The FDA
ministered in the morning, and convened another advisory com-
alcohol was consumed rapidly mittee to obtain advice on the
(within 10 minutes). In the phase benefitrisk profile, given the new
3 trials, in which alcohol con- data. By a vote of 18 to 6, the com-
sumption was not restricted and mittee recommended approval,
flibanserin was taken at bedtime, though some members said it was
the incidence of syncope was a difficult decision. In general,
0.4% with flibanserin and 0.2% those recommending approval ac-
with placebo. Although these knowledged the small treatment
data appear more reassuring, the effects and substantial safety con-
extent of alcohol use during cerns but considered the unmet
these trials was not recorded. medical need. All votes for ap-
Because of residual concerns proval were contingent on the in-
about the benefitrisk profile, the clusion of risk-mitigation strate-
FDA rejected flibanserin again gies beyond labeling.
and requested additional data, After the advisory committee
including a study to ensure that meeting, the FDA received re-
CNS depression would not affect quests to reject flibanserin again,
next-day driving performance. This citing insufficient alcohol-inter-
rejection prompted allegations of action data in women, the infea-
gender bias at the FDA, based on sibility of abstaining indefinitely
erroneous claims that it had ap- from alcohol, drugdrug interac-
proved more than 20 drugs for tions, the importance of non-
male sexual dysfunction and none pharmacologic approaches to
for women. (Those making such HSDD, concerns about medical-
assertions included Even the Score, izing low sexual desire, and the
an advocacy campaign partly fund- change from HSDD to female
ed by Sprout Pharmaceuticals, sexual interest/arousal disorder
flibanserins sponsor after Boeh- (FSIAD) in the newest edition of
ringer Ingelheim sold the rights the Diagnostic and Statistical Manual
to the drug.) The FDA rejected of Mental Disorders. Patients with
these claims and clarified what HSDD generally meet the criteria
products had been approved (see for FSIAD if theyve had symp-
Table 2). toms for at least 6 months and
After completing the additional are typically unreceptive to a
studies, Sprout submitted fliban partners attempts to initiate sex-
n engl j med 374;2nejm.orgjanuary 14, 2016
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PE R S PE C T IV E FDA Approval of Flibanserin

Table 2. Medications for Sexual Dysfunction Approved by the FDA Prior to Flibanserin.*

Disorder Women Men

Dyspareunia Estrogen agonist/antagonist: ospemifene None
Estrogens: conjugated estrogens vaginal
cream, synthetic conjugated B estrogens
Peyronies disease Not applicable Collagenase: collagenase clostridium histo-
lyticum
Erectile dysfunction Not applicable Phosphodiesterase type 5 inhibitors: silden
afil citrate, tadalafil, vardenafil hydrochlo-
ride, avanafil
Prostaglandin E1: alprostadil urethral suppos-
itory, alprostadil for injection
Other sexual arousal disorders None None
Orgasmic disorders None None
Sexual desire disorders None None
* The list excludes testosterone drugs, which are approved only for replacement therapy in men with deficient testosterone due
to specific conditions, not for treatment of sexual dysfunction.3 Vardenafil hydrochloride is available as Levitra (an oral tablet)
and Staxyn (an orally disintegrating tablet); alprostadil for injection is available as edex, CaverJect, and CaverJect Impulse.

ual activity, but whereas HSDD
requires distress caused by low
sexual desire, the definition of
FSIAD includes distress caused
by low sexual desire, low sexual
arousal, or both. The clinical tri-
als, and therefore the FDA, eval-
uated flibanserin only for treat-
ment of HSDD.
After careful consideration, the
FDA followed the second advisory
committees recommendations,
concluding that efficacy had been
established; although the average
treatment effects were small,
about 10% more flibanserin-
treated patients than placebo-
treated patients reported clini-
cally meaningful improvement.
Assuming that the effects of
the alcohol interaction in women
are at least as severe as those ob-
served in men, the FDA required
a boxed warning and an alcohol
contraindication. In addition, tak-
ing into account the widespread
use of alcohol in the United
States,4 the agency required a
risk evaluation and mitigation
strategy (REMS) with elements
to assure safe use to ensure that
the benefits outweigh the in-
creased risk of hypotension and
syncope with alcohol. This re-
quirement means that only certi-
fied prescribers and pharmacies
that have enrolled in the REMS
program and completed training
can prescribe or dispense fliban-
serin; prescribers must counsel
patients to abstain from alcohol,
using a patientprovider agree-
After careful consideration, the FDA
followed its second advisory committees
recommendations, concluding that
efficacy had been established.
ment form that both parties sign;
and certified pharmacies must dis-
pense flibanserin only to patients
with a prescription from a certi-
fied prescriber and must counsel
the patient to abstain from alco-
hol before dispensing each pre-
scription.
As with other medications that
can cause CNS depression, that
risk will be managed with label-
ing, including a warning and a
medication guide instructing pa-
tients to take flibanserin at bed-
time and not to engage in activi-
ties requiring full alertness, such
as driving, until at least 6 hours
after taking the drug and until
they know how theyre affected
by it. As with other medications
that have dangerous drug inter-
actions, that risk will also be
managed with labeling, includ-
ing a boxed warning and a con-
traindication for moderate and
strong CYP3A4 inhibitors, and by
using existing software to screen
for drugdrug interactions be-
fore flibanserin is dispensed.
Not all members of the review
team recommended the same
regulatory action for flibanserin.

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PERS PE C T IV E
Some concluded that its benefit
risk profile was unfavorable,
even with the safety measures
described here, and recommend-
ed against approval.5 In their
view, the observed treatment ef-
fects were offset by the poten-
tially life-threatening hypoten-
sion, syncope, accidental injuries
related to CNS depression, and
the unclear clinical significance
of a drug-related increase in
malignant mammary tumors in
female mice. They also ques-
tioned the generalizability of the
phase 3 safety data to all pre-
menopausal women likely to use
flibanserin, given the trials ex-
tensive exclusion criteria. At a
minimum, they recommended a
preapproval alcohol-interaction
study in women.
Transparent, robust scientific
discussions among FDA staff are
encouraged, so that all internal
viewpoints can be considered be-
fore decisions are finalized. The
FDA also considered the recom-
mendations from advisory com-
mittee members and the public,
including letters both favoring
and opposing approval.
Shared Decision Making Finding the Sweet Spot
TerriR. Fried, M.D.
T he importance of shared de-
cision making in health care
has been increasingly recognized
over the past several decades.
Consensus has emerged that of
the various types of decisions we
make, those that involve choos-
ing among more than one rea-
sonable treatment option should
be made through a process in
which patients participate: clini-
cians provide patients with infor-
104
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The agencys approach aims
to ensure that patients and pre-
scribers know about the risks so
they can make informed deci-
sions about using flibanserin.
Because HSDD is symptomatic,
patients can directly assess
whether any improvements they
experience are worth the risks.
Flibanserin should be discon
tinued if HSDD symptoms do
not improve after 8 weeks of
treatment.
Its impossible to know any
drugs full safety profile at the
time of approval. Beyond the safe-
ty measures noted above, the
FDA is requiring three postap-
proval trials to further elucidate
the alcohol interaction in women,
plus enhanced pharmacovigilance
for hypotension, syncope, acciden-
tal injury, and death. The agency
will be able to take regulatory
action as needed on the basis of
the resulting data. We believe this
is a reasonable approach that bal-
ances safety and access. Although
the FDA does not regulate off-label
use, we encourage responsible
prescribing and emphasize that
the approval is only for the popu-
mation about all the options and
help them to identify their pref-
erences in the context of their
values.
But there are many ways in
which decision making can be
shared between clinicians and
patients. Physicians describe pro-
cesses that range from explain-
ing the clinical situation and
making a recommendation that
the patient can accept or reject to
n engl j med 374;2nejm.orgjanuary 14, 2016
The New England Journal of Medicine
FDA Approval of Flibanserin
lation that was studied pre-
menopausal women with HSDD.
Disclosure forms provided by the au-
thors are available with the full text of this
article at NEJM.org.
From the Food and Drug Administration,
Silver Spring, MD.
This article was published on December 9,
2015, at NEJM.org.
1. Food and Drug Administration. Patient-
focused drug development public meeting
and scientific workshop on female sexual
dysfunction, 2014 (http://www.fda.gov/Drugs/
NewsEvents/ucm401167.htm).
2. Transcript for the June 18, 2010, meeting of
the Advisory Committee for Reproductive
Health Drugs (http://www.fda.gov/downloads/
AdvisoryCommittees/CommitteesMeeting
Materials/Drugs/ReproductiveHealthDrugs
AdvisoryCommittee/UCM248753.pdf).
3. Nguyen CP, Hirsch MS, Moeny D, Kaul S,
Mohamoud M, Joffe HV. Testosterone and
age-related hypogonadism FDA con-
cerns. N Engl J Med 2015;373:689-91.
4. Results from the 2013 National Survey on
Drug Use and Health: summary of national
findings. Rockville, MD: Substance Abuse
and Mental Health Administration, 2014
(http://www.samhsa.gov/data/sites/
default/files/NSDUHresultsPDFWHTML2013/
Web/NSDUHresults2013.pdf).
5. Food and Drug Administration. Addyi
tablets (FDA staff reviews, REMS, labels and
action letters). 2015 (http://www.accessdata
.fda.gov/drugsatfda_docs/nda/2015/
022526Orig1s000TOC.cfm).
DOI: 10.1056/NEJMp1513686
Copyright 2015 Massachusetts Medical Society.
outlining the treatment options
and leaving the final decision to
the patient.1 In other words, the
leeway and responsibility given
to the patient for making the de-
cision can vary widely.
Unfortunately, the role the pa-
tient is asked to play in the pro-
cess is frequently not appropri-
ately matched to the clinical
circumstances underlying the de-
cision. The greater the uncertainty