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Female sexual dysfunction: a focus on flibanserin

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This article was published in the following Dove Press journal:

International Journal of Women’s Health
11 October 2017
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Nicole M Lodise Abstract: Flibanserin is the first US Food and Drug Administration (FDA)-approved option for
Department of Pharmacy Practice, sexual dysfunction, specifically low sexual desire. Until recently, there were no FDA-approved
Albany College of Pharmacy and medication options to assist the ~40% of women affected by female sexual dysfunction (FSD).
Health Sciences, Albany, NY, USA Often, patients report feeling uncomfortable discussing sexual health, identifying a strong
need for health care professionals (HCPs) to proactively reach out to patients to identify
concerns and initiate a discussion about sexual health and the available treatment options.
Within the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DMS-5),
the criteria of female sexual interest/arousal disorder (FSIAD) are outlined, encompassing
one of the most common sexual concerns, formerly in its own category defined as hypoac-
For personal use only.

tive sexual desire disorder (HSDD) or low sexual desire. HSDD is the absence or deficiency
of sexual interest and/or desire leading to significant distress and interpersonal difficulties.
HCPs offer an important service in assessing their patients and providing information about
treatment considerations while ensuring patient comfort with this topic. This article provides
an overview of the types and potential causes associated with FSD and the role of flibanserin
in practice as a treatment option. Despite a need for additional study in diverse populations,
flibanserin has demonstrated efficacy with increased female sexual function index (FSFI)
total and desire domain scores in clinical studies indicating benefit in sexual desire. Common
patient or provider-administered assessment tools to assist in identifying affected patients and
patient counseling strategies are reviewed.
Keywords: female sexual dysfunction, low sexual desire, hypoactive sexual desire disorder,
pharmacotherapy, flibanserin

Introduction
Female sexual dysfunction (FSD) is patient specific and may present as changes
in a patient’s orgasm, concerns with vaginal pain and penetration and/or female
sexual interest/arousal disorder (FSIAD), including low sexual desire or hypoactive
sexual desire disorder (HSDD).1 Table 1 provides a summary of the Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for FSD. A 2006
review by Hayes et al2 estimated the prevalence of female concerns with desire to be
64%, orgasm to be 35%, arousal to be 31% and pain concerns estimated to be 26%.
In comparison, Shifren et al3 surveyed more than 30,000 females in the US noting a
prevalence of any type of sexual dysfunction in ~40% of respondents. Patients may
present with one type of sexual dysfunction or a combination, although less common,
with the possibility of personal distress associated with each. Low sexual desire is the
Correspondence: Nicole M Lodise most commonly reported sexual health problem with a prevalence of 38.7% compared
Albany College of Pharmacy and Health
Sciences, Department of Pharmacy to a 10% approximate prevalence when patients experience low desire and associated
Practice, 106 New Scotland Avenue, personal distress.3 The Women’s International Study of Health and Sexuality (WISHeS)
Albany, NY 12208, USA
Tel +1 518 694 7345
study in 2006 estimated a prevalence of low sexual desire in premenopausal and post-
Email [email protected] menopausal women of 14% and 9%–26%, respectively.4 More recently, Rosen et al5

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Table 1 Summary of DSM-5 criteria for female sexual dysfunction

Female sexual dysfunction types DSM-5 criteria
Female sexual interest/arousal disorder A. Lack of, or significantly reduced, sexual interest/arousal, as manifested by at least three of the
following:
1. Absent/reduced interest in sexual activity
2. Absent/reduced sexual/erotic thoughts or fantasies
3. No/reduced initiation of sexual activity and typically unreceptive to a partner’s attempts to initiate
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4. Absent/reduced sexual excitement/pleasure during sexual activity in almost all or all (75%–100%)
sexual encounters (in identified situational contexts or, if generalized, in all contexts)
5. Absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues
(eg, written, verbal, visual)
6. Absent/reduced genital or non-genital sensations during sexual activity in almost all or all (75%–100%)
sexual encounters (in identified situational contexts or, if generalized, in all contexts)
B. The symptoms in Criterion A have persisted for a minimum duration of approximately 6 months
C. The symptoms in Criterion A cause clinically significant distress in the individual
D. The sexual dysfunction is not better explained by a non-sexual mental disorder or as a consequence of
severe relationship distress (eg, partner violence) or other significant stressors and is not attributable
to the effects of a substance/medication or another medical condition.
Specify whether:
Lifelong: The disturbance has been present since the individual became sexually active.
Acquired: The disturbance began after a period of relatively normal sexual function.
Specify whether:
For personal use only.

Generalized: Not limited to certain types of stimulation, situations or partners.

Situational: Only occurs with certain types of stimulation, situations or partners.
Specify current severity:
Mild: Evidence of mild stress over the symptoms in Criterion A.
Moderate: Evidence of moderate distress over the symptoms in Criterion A.
Severe: Evidence of severe or extreme distress over the symptoms in Criterion A.
Female orgasmic disorder A. Presence of either of the following symptoms and experienced on almost all or all (approximately
75%–100%) occasions of sexual activity (in identified situational contexts or, if generalized, in all contexts):
1. Marked delay in, marked infrequency of, or absence of orgasm
2. Markedly reduced intensity of orgasmic sensations
B. The symptoms in Criterion A have persisted for a minimum duration of approximately 6 months
C. The symptoms in Criterion A cause clinically significant distress in the individual
D. The sexual dysfunction is not better explained by a non-sexual mental disorder or as a consequence of
severe relationship distress (eg, partner violence) or other significant stressors and is not attributable
to the effects of a substance/medication or another medical condition.
Specify whether:
Lifelong: The disturbance has been present since the individual became sexually active.
Acquired: The disturbance began after a period of relatively normal sexual function.
Specify whether:
Generalized: Not limited to certain types of stimulation, situations or partners.
Situational: Only occurs with certain types of stimulation, situations or partners.
Specify if:
Never experienced an orgasm under any situation.
Specify current severity:
Mild: Evidence of mild stress over the symptoms in Criterion A.
Moderate: Evidence of moderate distress over the symptoms in Criterion A.
Severe: Evidence of severe or extreme distress over the symptoms in Criterion A.
Genito-pelvic pain/penetration disorder A. Persistent or recurrent difficulties with one (or more) of the following:
1. Vaginal penetration during intercourse
2. Marked vulvovaginal or pelvic pain during vaginal intercourse or penetration attempts
3. Marked fear or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of
vaginal penetration
4. Marked tensing or tightening of the pelvic floor muscles during attempted vaginal penetration
B. The symptoms in Criterion A have persisted for a minimum duration of approximately 6 months
C. The symptoms in Criterion A cause clinically significant distress in the individual
D. The sexual dysfunction is not better explained by a non-sexual mental disorder or as a consequence of
severe relationship distress (eg, partner violence) or other significant stressors and is not attributable
to the effects of a substance/medication or another medical condition.
(Continued)

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Table 1 (Continued)
Female sexual dysfunction types DSM-5 criteria
Specify whether:
Lifelong: The disturbance has been present since the individual became sexually active.
Acquired: The disturbance began after a period of relatively normal sexual function.
Specify current severity:
Mild: Evidence of mild stress over the symptoms in Criterion A.
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Moderate: Evidence of moderate distress over the symptoms in Criterion A.

Severe: Evidence of severe or extreme distress over the symptoms in Criterion A.
Note: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©2013). American Psychiatric Association. All Rights
Reserved.1
Abbreviation: DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.

surveyed ~700 women across the US at multiple clinical FSD can possibly affect any woman at any age.11,12
sites identifying ~7.4% of women reporting low sexual Existing factors such as medication use, current medical
desire, specifically HSDD. Although a range of prevalence conditions and psychological factors also contribute to the
rates exist, sexual dysfunction among women is commonly possibility of FSD. Medications and current medical condi-
reported and may represent a significant concern and oppor- tions such as cardiovascular disease, diabetes mellitus and
tunity for education. Low sexual desire is the most common gynecologic cancers in addition to the use of antidepressants
For personal use only.

type and identifies a key area for clinicians to proactively or the use of recreational drugs may increase the possible risk
engage their patients in open communication to ensure that for sexual dysfunction.11,13,14 Relationship issues as well as
affected patients are identified and recommended options, life stressors may also demonstrate a psychological impact
as necessary, are discussed with the patient. on a patient’s sexual health and functioning.12,13,15
Normal sexual response has been defined through various One of the most common types of sexual dysfunction is
models. One of the initial models from Masters and Johnson low sexual desire with associated distress, formerly known
proposed a linear model to describe the sexual response iden- as HSDD. Within the DSM-5, HSDD is now a part of the
tifying the following four stages: excitement, plateau, orgasm criteria for FSIAD; however, this terminology may still be
and resolution.6 In comparison, the model by Kaplan expanded referred to in clinical practice and has been utilized within
on this model from Masters and Johnson to further incorporate the criteria of several previous studies evaluating medications
the importance of desire and modified the phases to focus on to treat low sexual desire. Treatment approaches for low
desire, excitement and orgasm.6 More recently, the model by sexual desire have focused on the use of behavioral modifica-
Basson et al presented a further variation of the earlier models tions, possible use of testosterone, off-label pharmacologic
with a combined circular and linear focused model that cen- options and complementary therapies. Until recently, with
ters on sexual stimuli, emotional intimacy and psychological the availability of flibanserin, there were no available
components as factors contributing to overall sexual activity FDA-approved treatment options. A literature search was
demonstrating the complexity and ever-evolving assessment completed utilizing PubMed to identify published articles
of sexual response.6 Each of these models, although differing within the last 10 years (2006–2016) in humans and available
in their area of focus, represent the complexity and multifacto- in English for evaluating the safety, efficacy and patient
rial nature of an individual’s sexual response. counseling considerations associated with flibanserin as a
The pathophysiology of sexual functioning, and therefore treatment option for low sexual desire. Key search words
dysfunction, involves the role of neurotransmitters in addition included flibanserin, HSDD and FSD. A total of 58 articles
to possible hormonal contributors. Neurotransmitters such as were identified.
dopamine, norepinephrine and serotonin have involvement in This article focuses solely on key features regarding fli-
a patient’s sexual response, with dopamine and norepinephrine banserin, while the use of additional pharmacologic options
providing an excitatory effect versus serotonin having an inhibi- investigated to treat FSD or low sexual desire is described
tory effect.7,8 Hormonal changes, associated with estrogen in in previous publications.7,16–23
naturally occurring or surgically induced menopausal patients,
may also alter a patient’s sexual activity and interest. Specifi- Patient assessment tools
cally, estrogen reductions may increase vaginal dryness and dys- The DSM-5 classifies female sexual disorders as female
pareunia, increasing the potential for sexual dysfunction.9,10 orgasmic disorder, FSIAD and genito-pelvic pain/penetration

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disorder (Table 1).1 The DSM-5 further includes four specific DSDS provides questions focused on desire using a “yes/no”
subtypes to categorize dysfunction onset as follows: lifelong format such as “Are you bothered by your decreased sexual
dysfunction indicating a sexual problem present from the first desire or interest”.29 With each tool, clinicians are encour-
sexual experience; acquired dysfunction identifying sexual aged to engage in a more detailed discussion with a patient
health issues that arise after a time of normal sexual activity; regarding their sexual health including the use of open-ended
generalized dysfunction referring to sexual issues not limited questioning on when and how the dysfunction is occurring
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to a specific situation or partner, while situational dysfunction while using the responses from the administered question-
occurs with specific partners or situations.1 As a complement naires to facilitate the interaction.
to DSM-5, health care professionals (HCPs) may successfully More recently, Weinfurt et al30 described the development
incorporate additional tools to assess a patient. These tools process of a lengthier assessment tool to assess sexual func-
may be administered either by the patient or the provider tioning in males and females, the PROMIS Sexual Function
to assist in collecting information or initially identifying a and Satisfaction Measures version 2.0 tool. This tool offers
patient’s possible sexual health concerns. Despite possible another option to broadly assess patients regarding overall
tools and patient interest for additional sexual health sexual health. Another tool, described by Flynn et al,31 in
information from HCPs, challenges in initiating communica- comparison to the brief option of the DSDS, is a nonspe-
tion on sexual health continue to be present in clinical practice cific tool, called the “checklist screener” to assess sexual
across patient ages with identified concerns such as a need functioning. This tool includes an initial question regarding
for further HCP sexual health knowledge and limitations on if a patient has had any problems or concerns over the past
For personal use only.

available time to discuss with patients.24–26 It is important for year for a minimum of 3  months such as “pain during or
HCPs to remain cognizant of these considerations to optimize after sexual activity”; “difficulty having an orgasm” and
the patient–HCP interaction regarding sexual health. “whether the patient enjoyed sexual activity”.31 Despite this
When screening for FSD, specifically low sexual desire, tool’s general focus, it does provide another opportunity to
available tools may assist HCPs and often have had demon- gather this type of information from patients to further initiate
strated use within clinical studies. Several validated ques- a patient discussion.
tionnaires may be used including the brief sexual symptom
checklist, the female sexual function index (FSFI) and the Treatment
decreased sexual desire screener (DSDS).27–29 The brief The multifactorial nature of FSD and low sexual desire indi-
sexual symptom checklist uses one initial question to assess a cates a need for various approaches to assist patients. Upon
patient’s satisfaction with their sexual functioning and based completion of the use of a patient assessment tool or through
on this response, patients may provide further information to general open-ended questioning within a visit, it is important
identify possible sexual problems and interest in discussing for HCPs to consider possible causes, if known, regarding a
further with their HCP.27 The FSFI is a 19-question tool patient’s identified low sexual desire to best target possible,
covering six domains assessing desire, arousal, orgasm, customized treatment options whether nonpharmacologic or
lubrication, pain and satisfaction. Each domain is associated pharmacologic to assist the patient. For example, if the cause
with a maximum score of up to six points out of the total FSFI is medication related, an initial approach may be to seek out
score (maximum total score on all domains is 36 points). The alternative agents not known to increase the risk of sexual
FSFI desire score is based on 2 of the 19 questions within dysfunction. If a patient has described relationship or stress
the tool focused on sexual desire: “Over the past four weeks, considerations, a recommendation referring the patient to
how often did you feel sexual desire or interest?” and “Over a couple’s counselor may be an initial step in the overall
the past four weeks, how would you rate your level of sexual treatment approach. Given the number of factors that may
desire or interest?”28 The FSFI desire score has also been affect low sexual desire, it is critical for the HCP to create a
used as a primary or secondary end point in studies evalu- treatment plan addressing any of the possible contributors.
ating the efficacy of medications used to treat low sexual
desire. The lower the FSFI score, the higher the likelihood Nonpharmacologic and behavioral
of sexual dysfunction. The FSFI is a longer questionnaire recommendations
assessing each type of sexual dysfunction including desire; Nonpharmacologic and behavioral recommendations
in comparison, the DSDS offers a condensed option for offer an important step in a patient’s treatment plan to
HCPs to solely assess low sexual desire. Although brief, the consider, especially in patients uncomfortable in trying

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pharmacologic options. One of the goals of an HCP is to HSDD in premenopausal women.39,40 Although there are
assess nonpharmacologic avenues that may offer possible important safety considerations and monitoring associated
improvement in low sexual desire. As described earlier, with this agent, it does fill a gap and opens the opportunity
for example, recommendation for couple’s counseling may for further medication approvals in this therapeutic area.
be advantageous if relationship issues are identified. Other Furthermore, with patient and clinician awareness about the
nonpharmacologic options are also being explored. Recent availability of this medication, it may serve as a way to further
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studies evaluating the use of a sacral nerve stimulator for its facilitate the discussion about sexual health with patients.
use in treating FSD symptoms have demonstrated statisti-
cally significant benefits with desire, orgasm, lubrication and Flibanserin – dosing and pharmacokinetics
satisfaction.16,32,33 In addition, Oakley et al34 evaluated the use Flibanserin is available as a 100  mg tablet and is recom-
of twice weekly acupuncture for 5 weeks to treat low sexual mended to be taken orally once daily at bedtime.41,42 Dosing
desire in a small patient population of premenopausal females at bedtime is advised to minimize side effects including
(N=15). Despite the lack of blinding and small patient enroll- somnolence, hypotension and syncope.42 Administration
ment as limitations, improvements in FSFI desire and total of flibanserin with food does increase the extent of absorp-
scores were noted, indicating the need for further evaluation tion while slowing the rate of absorption.42 Flibanserin’s
of acupuncture in larger patient samples to assess its role in bioavailability is 33% and is 98% protein bound; has a half-
low sexual desire. With the significant potential for psycho- life of 11 hours and is extensively metabolized by the liver
logical and lifestyle causes, behavioral strategies represent an through cytochrome P450 3A4 (CYP3A4); however, it is also
For personal use only.

integral component in a patient’s plan.10 The use of cognitive metabolized by CYP2C19.42 Flibanserin’s exposure increases
behavioral therapy or use of a sex therapist has demonstrated 4.5-fold resulting in an increased risk of hypotension and
positive benefits in sexual dysfunction including low sexual syncope in patients with hepatic impairment.42 Given the dra-
desire.35 With the use of either of these approaches, the focus matic increase in exposure, use in patients with any level of
centers on addressing the behaviors and thoughts associated hepatic impairment should be avoided. Although metabolism
with sexual activity in an effort to establish new routines and is less with CYP2C19, patients who are poor metabolizers
associations to address sexual concerns. With any patient of CYP2C19 should also receive additional counseling, but
experiencing sexual health concerns, the importance of may continue to use as tolerated, regarding increased side
incorporating behavioral strategies with or without the use effects due to elevated exposure.42 Use in geriatric patients
of medications will be critical in a patient’s overall treatment is currently not advised due to a lack of safety and efficacy
plan to address concerns.36 data in this specific population.42

Pharmacologic – flibanserin Flibanserin – safety and cost considerations

There are several agents that have been investigated as The side effect profile of flibanserin includes a potential for diz-
possible treatment options to assist patients with FSD, specifi- ziness, somnolence, nausea and fatigue as the most commonly
cally low sexual desire. These agents include testosterone, reported in clinical trials (~10% incidence of each).43–47 The pos-
bupropion, sildenafil, melanocortin receptor agonists and the sibility for drug interactions with strong CYP3A4 inhibitors (eg,
use of complementary products such as dehydroepiandroster- itraconazole and ketoconazole) is also present with flibanserin.
one (DHEA); however, until recently, there were no FDA- This interaction warrants proactive patient counseling on the
approved options specifically for FSD.7,16–23 Flibanserin is risk and the importance in comprehensively reviewing all other
now the first FDA-approved pharmacologic option for low current medications utilized by the patient. The combination
sexual desire or HSDD. Flibanserin focuses on the role of with CYP3A4 inhibitors increase flibanserin levels and related
neurotransmitters within the sexual response. It acts as a side effects such as hypotension and syncope.41,42 In addition to
serotonin 5-HT1A agonist in addition to a 5-HT2A antagonist. interactions with CYP3A4 inhibitors, flibanserin also presents a
Through this action, it reduces the inhibitory effect of sero- significant interaction when used in combination with alcohol.
tonin while increasing the excitatory effect of dopamine.37,38 This combination increases the risk of hypotension and syncope
Flibanserin has had prior submissions and denials with its and is contraindicated.42 Given this interaction, flibanserin use
approval secondary to side effects; however, in 2015, the is restricted through a risk evaluation and mitigation strategy
US Food and Drug Administration (FDA) voted 18 to 6 to (REMS) program requiring both the prescriber and the phar-
recommend the approval of Flibanserin as a treatment for macy to be certified (www.AddyiREMS.com).48

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In addition to use restrictions due to adverse effects, cost placebo (N=295). Improvements in the number of sexually
may also present an important factor, with patients consid- satisfying events, FSFI desire and total scores and overall dis-
ering flibanserin use as the availability of insurance cover- tress reported with the Female Sexual Distress Scale-Revised
age and the depth of coverage varying greatly. Therefore, (FSDS-R) total and Item 13 scores were noted in both trials,
flibanserin’s manufacturer established flibanserin-affordable specifically demonstrating improvements with the 100 mg
access cards to assist in reducing patient cost burden.48 once daily dosing.43,44 The ROSE and SUNFLOWER studies
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further assessed continued efficacy versus possible with-

Flibanserin – efficacy drawal effects and overall adverse effects, respectively.45,47
The efficacy of flibanserin continues to be debated regarding Within the ROSE trial, participants who responded positively
its overall clinical significance and the potential for vari- to an open-label 24-week trial taking either 50  mg or
ability with its effect among patients; however, statistical 100  mg per day of flibanserin (N=333) were randomized
significance has been demonstrated within several efficacy and blinded to receive additional 24 weeks of their optimal
and safety studies available on flibanserin. Most recently, a flibanserin dose (N=163) versus placebo (N=170). Although
thoughtful review and meta-analysis focused on this debate a decline in primary and secondary outcomes was reported
analyzing previous published and unpublished randomized in both the flibanserin and placebo groups, there continued
clinical trials on flibanserin indicating an overall modest to be a statistically significant difference between flibanserin
clinically significant efficacy.49 The analysis considered and placebo in the number of sexually satisfying events and
important limitations in the clinical trials including the limited the FSFI desire score demonstrating less of a decline in the
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diversity among study populations since many medical condi- flibanserin group at 48 weeks.47 The SUNFLOWER study
tions and the use of various medications were excluded among was a 52-week open-label study focused on the safety and
study participants potentially reducing generalizability.49 tolerability of flibanserin. Participants involved with earlier
In addition, the possible limitations with the broad use of flibanserin randomized trials were invited to participate
flibanserin were identified due to the higher risk of adverse within the SUNFLOWER trial (N=1,725 eligible to include
effects versus placebo such as hypotension and syncope due with 962 completing the full 52  weeks).45 Primary end
to the interaction with alcohol. This analysis demonstrates points included incidence of somnolence, sedation, fatigue,
the need for continued evaluation of flibanserin in patients dizziness, nausea and vomiting in addition to serious adverse
with expanded medical and medication histories beyond what effects and discontinuations. Somnolence was reported most
was represented in study populations to further assist HCPs commonly followed by fatigue, dizziness, nausea, sedation
in better defining the role of flibanserin.49 Despite concerns, and vomiting. More than 95% of the adverse effects were
currently, this medication represents the only approved option reported as mild or moderate; however, ~10% of participants
for patients but does require strong patient-specific counseling discontinued treatment due to adverse effects. Although a
regarding adverse effects and drug and alcohol interactions secondary end point in this trial, efficacy was demonstrated
with use. As the primary randomized clinical trials evaluating by increased FSFI total and desire scores indicating improve-
flibanserin use have been reviewed in great detail elsewhere, ments in sexual desire compared to baseline.45 Another trial
this article provides a brief review of select end point results focusing on the efficacy and safety of flibanserin in premeno-
for comparison among recent studies used in assessing fliban- pausal women was the BEGONIA study.46 BEGONIA was
serin’s safety and efficacy in supporting flibanserin’s FDA a randomized placebo-controlled 24-week study evaluating
approval.49 Flibanserin has been evaluated predominantly in flibanserin 100 mg at bedtime (N=542) compared to placebo
premenopausal female patients with an initial study focusing (N=545). At study completion, improvements were noted in
on postmenopausal patients. Table 2 recaps select end points the number of sexually satisfying events, FSFI desire and
from each of these trials for comparison.43–47,50 The DAISY and total scores in addition to reported distress within the FSDS-R
VIOLET trials were both 24-week randomized, double-blind, total and Item 13 scores. Somnolence and dizziness were
placebo-controlled studies evaluating the use of flibanserin in identified as the most common adverse effects associated
premenopausal females. Both trials included various dosing with flibanserin use.
options with DAISY evaluating 50 mg twice daily (N=392) Although the majority of data available is specific for
and 100  mg once daily at bedtime (N=395) compared to premenopausal females and the current approval is for
placebo (N=398) and VIOLET evaluating 50 mg once daily use only in premenopausal patients, flibanserin is also
(N=295) and 100 mg once daily (N=290) at bedtime versus evaluated in postmenopausal patients. The SNOWDROP

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Table 2 Comparison of select endpoints evaluating the use of flibanserin treatment

Study and population Dose(s) Comparator Select end point(s) (FSFI – desire Commonly reported
domain score and total score) flibanserin adverse effects
DAISY study Flibanserin 25 mg Placebo Mean change (SE) from baseline to week Somnolence (11.8%)
Premenopausal women43 twice daily (N=398) 24 in the FSFI – desire domain score: Dizziness (10.5%)
4-week baseline followed by Flibanserin 50 mg Placebo – 0.6 (0.1) Fatigue (10.3%)
24-week randomized, double- twice daily Flibanserin 25 mg twice daily – 0.8 (0.1)
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blind, placebo-controlled Flibanserin 100 mg (P,0.01 vs placebo)

once daily at bedtime Flibanserin 50 mg twice daily – 0.8 (0.1)
(total flibanserin (P,0.01 vs placebo)
N=1,183) Flibanserin 100 mg once daily – 0.9 (0.1)
(P,0.0001 vs placebo)
Mean change (SE) from baseline to week
24 in the FSFI – total score:
Placebo – 2.6 (0.3)
Flibanserin 25 mg twice daily – 3.9 (0.3)
(P,0.01 vs placebo)
Flibanserin 50 mg twice daily – 3.8 (0.3)
(P,0.01 vs placebo)
Flibanserin 100 mg once daily – 4.1 (0.3)
(P,0.01 vs placebo)
VIOLET study Flibanserin 50 mg Placebo Mean change (SE) from baseline to week Somnolence (9.9%)
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Premenopausal women44 once daily at bedtime (N=295) 24 in the FSFI – desire domain score: Nausea (9.6%)
4-week baseline followed by Flibanserin 100 mg Placebo – 0.5 (0.1) Dizziness (7%)
24-week randomized, double- once daily at bedtime Flibanserin 50 mg once daily – 0.8 (0.1) Fatigue (4.8%)
blind, placebo-controlled (total flibanserin (P,0.05 vs placebo)
N=585) Flibanserin 100 mg once daily – 0.9 (0.1)
(P,0.0001 vs placebo)
Mean change (SE) from baseline to week
24 in the FSFI – total score:
Placebo – 2.4 (0.4)
Flibanserin 50 mg once daily – 3.9 (0.4)
(P,0.01 vs placebo)
Flibanserin 100 mg once daily – 5.0 (0.4)
(P,0.0001 vs placebo)
ROSE study Flibanserin (50 mg Placebo Mean (SE) decrease from weeks 21–24 Open label: (8%–14%)
Premenopausal women47 or 100 mg/d) (N=170) (randomization baseline) to weeks Somnolence, nausea,
Continued efficacy study (N=738, open label) 45–48 in the FSFI – desire domain score: dizziness, headache, fatigue
evaluating an additional 24 weeks After open label, Placebo – 0.8 (0.1) vs Double-blind: (5%–13%)
of double-blind treatment additional 24 weeks Flibanserin – 0.5 (0.1) Nasopharyngitis, upper
vs placebo in patients with a of double-blind (P,0.01) respiratory infection, urinary
predefined response after an initial treatment: Mean (SE) decrease from weeks 21–24 tract infection, sinusitis and
24 weeks of open-label treatment Flibanserin therapy at (randomization baseline) to weeks headache
with flibanserin optimized dosage 45–48 in the FSFI – total score: (similar adverse effects and
(N=163) Placebo – 4.0 (0.5) vs incidence rates as placebo)
Flibanserin – 1.9 (0.5) (P,0.01)
SUNFLOWER study Flexible-dose – Mean change (±SD) from baseline to Somnolence (15.8%)
Premenopausal women45 flibanserin (50 or week 52 in the FSFI – desire domain Fatigue (7.6%)
52-week open-label extension 100 mg once daily score: Dizziness (6.9%)
study to assess safety with at bedtime or 25 or Flibanserin remitters at baseline: Nausea (6.3%)
flibanserin flexible dose in women 50 mg twice daily) Increased from 2.7±1.0 to 3.6±1.4 Sedation (1.6%)
with HSDD who had completed a (N=1,723) Flibanserin nonremitters at baseline: Vomiting (1.4%)
trial of flibanserin or placebo prior Increased from 1.8±0.7 to 2.9±1.3
(patients were classified as Mean change (±SD) from baseline to
flibanserin remitters [FSFI total week 52 in the FSFI – total score:
score at baseline indicating no clinical Flibanserin remitters and nonremitters:
sexual dysfunction] and flibanserin Increased from 20.1±7.6 at baseline to
nonremitters [FSFI total score at 25.0±8.1 at week 52
baseline indicating dysfunction])
(Continued)

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Table 2 (Continued)
Study and population Dose(s) Comparator Select end point(s) (FSFI – desire Commonly reported
domain score and total score) flibanserin adverse effects
BEGONIA study Flibanserin 100 mg Placebo Mean change (SE) from baseline to week Somnolence (14.4%)
Premenopausal women46 once daily at bedtime (N=545) 24 in the FSFI – desire domain score: Dizziness (10.3%)
24-week randomized, double- (N=542) Placebo 0.7 Nausea (7.6%)
blind, placebo-controlled trial Flibanserin 100 mg once daily – 1.0 (0.1) Fatigue (5.7%)
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(P,0.001 vs placebo)
Mean change (SE) from baseline to week
24 in the FSFI – total score:
Placebo 3.5 (0.3)
Flibanserin 100 mg once daily – 5.3 (0.3)
(P,0.001 vs placebo)
SNOWDROP study Flibanserin 100 mg Placebo Mean change (SE) from baseline to week Dizziness (9.9%)
Naturally menopausal women50 once daily at bedtime (N=481) 24 in the FSFI – desire domain score: Somnolence (8.8%)
24-week randomized, double- (N=468) Placebo – 0.4 (0.1) Nausea (7.5%)
blind, placebo-controlled trial Flibanserin 100 mg once daily – 0.7 (0.1) Headache (6.0%)
(P,0.001 vs placebo)
Mean change (SE) from baseline to week
24 in the FSFI – total score:
Placebo – 2.7 (0.4)
Flibanserin 100 mg once daily – 4.2 (0.4)
For personal use only.

(P=0.003 vs placebo)
Note: Data from.43–47,50
Abbreviations: FSFI, female sexual function index; SD, standard deviation; SE, standard error; HSDD, hypoactive sexual desire disorder.

trial was a randomized, double-blind, placebo-controlled end points and potential concerns identified regarding the
trial in naturally postmenopausal women assessing the use usefulness of the information collected by tools such as
of flibanserin 100  mg at bedtime (N=468) compared to the e-Diary to demonstrate a significant clinical outcome.52
placebo (N=481) in postmenopausal women for 24 weeks. Common tools used in clinical trials to evaluate a medica-
The number of sexually satisfying events, FSFI desire tion’s effectiveness for sexual dysfunction have included the
scores and distress based on the FSDS-R total and Item 13 use of patient diaries, the number of satisfying sexual events
scores showed a statistically significant improvement in the (SSEs), the FSFI tool assessing reduced desire and overall
flibanserin group compared to placebo at 24 weeks.50 The sexual dysfunction and the FSDS-R total and Item 13 score
FDA has summarized flibanserin’s overall demonstrated to assess personal distress. Despite use in study trials, there
efficacy as statistically significant improvements in sexual may be challenges in determining the significance of the
desire with an estimated increase of ~0.5–1.0 additional information collected through tools such as e-Diaries.53 The
sexually satisfying event per month.51 Given the modest use of patient-reported outcomes such as the FSFI tool may
efficacy and potential for significant side effects, discus- be considered more beneficial in not only collecting compo-
sion is ongoing to further define the clinical significance nents of sexual health but also evaluating treatment options
of efficacy results and the broad applicability and use of versus the use of e-Diaries.52,53 In flibanserin studies, patient
flibanserin across diverse patient populations. Despite this, diaries were used as primary outcomes while the FSFI tool
flibanserin does offer the first approved option for female was used as a secondary outcome (DAISY, VIOLET trials)
patients with low sexual desire and opens an opportunity compared to later studies (BEGONIA, SNOWDROP tri-
to further engage in patient-specific dialogue regarding als), the FSFI tool was identified as a primary outcome
sexual health. instead.43,44,46,50,53
With potential concerns of inconsistency in the assess-
Flibanserin – study limitations ment of clinical outcomes based on the varied measurement
One of the limitations when assessing the efficacy of fliban- tools used across trials, Table 2 focuses on the FSFI desire
serin across available studies involves the different tools used and total scores for the reader to consider in assessing similar
(objective versus patient reported) as primary and secondary outcomes across select trials.

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Patient counseling strategies and Flibanserin use in practice

flibanserin use in practice Low sexual desire is a commonly reported sexual health
Patient counseling strategies problem with a prevalence ranging from 10% to over
As described earlier, there may be challenges for patients 30%. Although several investigated agents have been
and HCPs when considering discussions regarding sexual explored, currently, there is only one FDA-approved option,
health.24–26 At a minimum, HCPs may simply engage patients flibanserin. Flibanserin is approved to treat low sexual desire
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in open-ended questions regarding whether a patient has any in premenopausal females. The combination with the use
sexual health concerns in addition to the use of available of behavioral approaches should be considered. Despite
tools or communication models to further assist in initiating concerns regarding the impact and clinical significance of
a conversation. HCPs play a pivotal role in offering guidance flibanserin’s efficacy, there are demonstrated improvements
addressing specific questions and discussion on possible showing an increase, although small, in sexual desire in
select patients. If flibanserin is selected as a treatment
treatment approaches to consider.
option, patients must also receive counseling regarding the
When additional tools are considered for use, as previ-
concomitant use with strong CYP3A4 inhibitors and be
ously described, the checklist screener or the brief DSDS
advised to avoid use with alcohol due to an increased risk
screener may be possible options to incorporate to initiate
of hypotension and syncope.
a patient conversation and collect information.29,31 In addi-
As the first approved medication for low sexual desire,
tion, structured models such as the Sexual Health Model
even with counseling considerations and concerns regarding
(SHM) and the Permission, Limited Information, Specific
For personal use only.

broad use and efficacy, flibanserin provides an option for

Suggestions and Intensive Therapy (PLISSIT) model have
patients desiring an FDA-approved medication to address
been used to assist in discussing sexual health concerns.54
low sexual desire. As described in the Jaspers et al’s article,49
Annon’s widely referenced PLISSIT model focuses on the
additional study of flibanserin in diverse populations will
abovementioned four components within individual patient
be advantageous to further define flibanserin’s role and the
interactions to assist the patient and the HCP in reviewing
patients best suited for use to ensure optimal efficacy.
the patient’s sexual health considerations.55 This model has
The approval of flibanserin is an opportunity and a
been consistently identified as a possible option to assist
call to HCPs to further engage in discussion with their
health professionals in providing a guide to a comprehensive
patients regarding sexual health while promoting the ongo-
discussion on sexual health but may also be consulted as an
ing investigation of additional pharmacologic options to
approach to enhance patient care.56–59 This model also offers
address FSD.
the HCP the opportunity to provide additional information
on resources, treatment options and possible referrals within
Acknowledgment
a comfortable environment. SHM is another approach that
No grants, equipment or drugs were received by the author
offers an opportunity to engage patients.60 This model uses
in support of this publication.
a group approach to discuss sexual health with a focus cen-
tered on behavioral modifications. The use of this model, Disclosure
however, may be limited based on a patient’s comfort level The author reports no conflicts of interest in this work.
to participate in a group environment but does offer a cost-
effective method to target several patients.54 Although the References
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