Flibanserin (Addyi; Valeant Pharmaceuticals, North America) is the first medication approved by the US Food and Drug Administration (FDA) for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD).1
HSDD is characterized by persistent or recurrent deficiency in, or absence of, sexual fantasies and desire for sexual activity associated with marked distress or interpersonal difficulty, and that cannot be better accounted for by another psychiatric disorder (eg, depression), substance abuse, medications, or medical conditions.2 Prior to flibanserin, there were no approved pharmacologic treatments for HSDD.1 In 2004, a testosterone patch (Intrinsa) was reviewed by the FDA for HSDD, but was not approved because of low usage rates.3 The patch was available in Europe, but recently withdrawn from the market because of low usage rates.
Used off-label for premenopausal, nondepressed women with HSDD, bupropion has shown some benefit in symptom improvement, compared with placebo.4 The legitimacy of HSDD has become widely debated because of the influence of political and policy campaigns, combined with a lack of efficacious alternative therapies and recent updates to its diagnostic criteria. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders has since removed HSDD as a condition, instead incorporating the disorder’s symptoms into the criteria for Female Sexual Interest-Arousal Disorder (FSIAD).2
Mechanism of Action
Flibanserin is a nonhormonal therapy that acts in the brain and increases sexual desire.5 According to laboratory studies, flibanserin acts as an agonist of 5-HT1A, and antagonist of 5-HT2A.5,6 Flibanserin has also been shown to moderately bind to 5-HT2B, 5-HT2C, and dopamine D4 receptors.6 The relationship between selective serotonin reuptake inhibitor antidepressants, decreased sexual desire, and trouble with arousal and orgasm suggest that serotonin receptors may play a crucial role in sexual function.5,6
Flibanserin was first studied as an antidepressant, but failed to show efficacy in phase 2 trials.7 The drug, however, demonstrated superiority over an active comparator and placebo in increasing women’s sex drives during a post hoc analysis.7,8
The Researching Outcomes on Sustained Efficacy (ROSE) trial, a multicenter, prospective, withdrawal study of 1156 premenopausal women was the first phase 3 trial to evaluate this drug.9 At the end of the 24-week randomized withdrawal phase, flibanserin was superior to placebo on measures of sexually satisfying events (SSEs), sexual desire, overall sexual function, and sexual distress. Flibanserin was well-tolerated, and no withdrawal reactions were observed following discontinuation of the drug. Following the ROSE trial, there were 3 studies in premenopausal women.
Clinical Trials of Flibanserin
The August 2015 approval of flibanserin 100 mg daily at bedtime for the treatment of premenopausal women with HSDD was based on 3 trials in approximately 2400 premenopausal women (ie, DAISY, VIOLET, and BEGONIA trials); following the third trial, Sprout Pharmaceuticals sought FDA approval for flibanserin.1,10-12 Each study was prospective, multicenter, randomized, double-blind, 24 weeks in length, placebo-controlled, and conducted in North America. Participants in all 3 studies experienced more SSEs and improved scores on the female sexual function index (FSFI) with flibanserin compared with placebo (Table).10-13
The results published from the DAISY and VIOLET trials led to the BEGONIA trial. Although study designs were similar between the first 2 trials and the third, there were significant difference in the inclusion and exclusion criteria. The BEGONIA trial did not use the sexual interest and desire inventory-female for trial inclusion, required contraceptive use before and during the study, and excluded women if they felt the contraceptive was contributing to their HSDD.10-12 BEGONIA also used FSFI as their sole measure of sexual desire.12 Changes were made to the trial design based on guidance received from the FDA.
A subsequent, systematic review and meta-analysis demonstrated that flibanserin 100 mg once daily was superior to placebo in increasing SSEs, sexual desire scores, FSFI desire domain scores, FSFI total score, patient’s global impression of improvement scores, and patient benefit evaluations during 24 weeks of therapy.8 It was also shown to be superior in reducing female sexual distress scale revised (FSDS-R) total scores, and FSDS-R item 13 scores when compared with placebo. Another systematic review and meta-analysis attempted to define the clinical value of multiple statistically significant efficacy outcomes in improving sexual desire. This additional clarity was particularly needed because of potential limitations in clinical significance and risk of adverse events.14 The authors of the review reported that flibanserin resulted in a pooled, mean increase in SSE of 0.49 events per month above baseline, which suggests a minimal meaningful change.
The safety and efficacy of flibanserin has been poorly evaluated in postmenopausal women; the Table includes results from the SNOWDROP trial, which— although flibanserin has yet to be approved for this patient population because of limited data—assessed similar outcome measures in postmenopausal women as had been captured in premenopausal women.13 Unlike the rapid onset of action observed in medications for erectile dysfunction in men, improvements in SSEs and FSFI may take ≤4 weeks to be seen, with effects appearing to plateau after 8 weeks.10-12
The authors of the SUNFLOWER trial, an open-label extension study of responders from previous studies, suggested that flibanserin may be safe for ≤52 weeks.15 Patients should discontinue therapy with flibanserin if HSDD symptoms do not improve within 8 weeks.1 Patients may be able to discontinue flibanserin safely without tapering.9
Adverse Events and Safety Concerns
Adverse events occurring ≥5% in flibanserin treatment arms were dizziness, somnolence, fatigue, nausea, headache, upper respiratory tract infection, nasopharyngitis, sinusitis, and insomnia.10-12,14
In a systematic review and meta-analysis, patients who received flibanserin had a significantly higher occurrence of adverse events, nervous system disorders, and fatigue compared with placebo.8 Flibanserin should be administered at bedtime to reduce adverse events and related sequelae.1 Boxed warnings and current contraindications include the risks for severe hypotension and syncope in patients who drink alcohol during treatment; concomitant use with moderate or strong cytochrome P450 (CYP)3A4 inhibitors; and use in patients with hepatic impairment. Regarding alcohol-related warnings, the FDA is requiring that Valeant Pharmaceuticals conduct 3 additional studies elucidating potentially serious interactions between flibanserin and alcohol.1,16
Furthermore, the FDA has established a risk evaluation and mitigation strategy (REMS) that requires prescribers and pharmacies be trained and certified prior to prescribing and dispensing flibanserin, creating an opportunity for clinicians to counsel patients about risks related to severe hypotension and concomitant alcohol use.1,16 Outpatient and inpatient pharmacies may only fill a flibanserin prescription written by a certified prescriber; this is verified electronically each time a flibanserin prescription is processed by calling the Addyi REMS Program Support Center, or through an integrated computer network linked to the Support Center databases. Clinicians may become trained and certified by completing the requirements at www.AddyiREMS.com; enrollment may be completed online or via fax.17
In addition to safety concerns, there are a lack of objective outcome measures for diagnosing HSDD and FSIAD, potentially imparting bias to relatively new, industry-supported questionnaires used in trials.4 Additional concerns include a marginal benefit compared with placebo, the potential for unpublished negative trial data, and the perception of external pressure on the FDA to approve medications for sexual dysfunction in women, even those which may provide limited efficacy (eg, flibanserin).4
Flibanserin should be avoided with concomitant use of moderate-to-strong CYP3A4 inhibitors.18 There are also significant concerns for off-label flibanserin use, especially in postmenopausal women. Older patients may be at greater risk for particular adverse events experienced with flibanserin; these patients are also more likely to take additional medications, increasing their risk for adverse events and drug−drug interactions, in addition to being at an increased risk for injury caused by falls sustained when hypotension or syncope occur. Flibanserin has not been approved for postmenopausal women at this time, and off-label use is not recommended.7
Using Multidisciplinary Treatment Approaches
The development of pharmacologic treatments for HSDD has highlighted the complexity and multidimensional nature of these disorders. There is a lack of information available concerning the biological determinants of sexual desire in women, and what may affect them.19 Desire disorders in women are very frequent—5.4% to 13.6% according to the American College of Obstetricians and Gynecologists20—and often do not respond to available treatments.19 HSDD and FSIAD may significantly affect quality of life, and be underestimated in women.21 Flibanserin offers a novel therapy for premenopausal women with HSDD, and is currently being studied in postmenopausal women.13 Clinicians must keep in mind that this is a multifactorial disorder, and that a prescription medication may not be helpful to all patients. Women with HSDD or FSIAD may benefit from an approach which includes medical, psychiatric, psychological, couple−relationship, and sociocultural approaches.14 Flibanserin has demonstrated marginal benefits and significant adverse events in female study particpants with HSDD. Ongoing studies with flibanserin in combination with sex therapy may help to provide an integrative approach.22
- US Food and Drug Administration. FDA approves first treatment for sexual desire disorder. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm. Updated August 18, 2015. Accessed August 30th, 2015.
- American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edition. Washington, DC: American Psychiatric Press, 2000.
- Nappi RE. Why are there no FDA-approved treatments for female sexual dysfunction? Expert Opin Pharmacother. 2015;16:1735-1738.
- Robinson K, Cutler JBR, Carris NW. First pharmacological therapy for hypoactive sexual desire disorder in premenopausal women: flibanserin. Ann Pharmacother. 2016;50:125-132.
- Lodise NM. Hypoactive sexual desire disorder in women: treatment options beyond testosterone and approaches to communicating with patients on sexual health. Pharmacotherapy. 2013;33:411-421.
- Thorp J Jr, Palacios S, Symons J, et al. Improving prospects for treating hypoactive sexual desire disorder (HSDD): development status of flibanserin. BJOG. 2014;121:1328-1331.
- Kennedy S. Flibanserin: initial evidence of efficacy on sexual dysfunction, in patients with major depressive disorder. J Sex Med. 2010;7:3449-3459.
- Gao Z, Yang D, Yu L, Cui Y. Efficacy and safety of flibanserin in women with hypoactive sexual desire disorder: a systematic review and meta-analysis. J Sex Med.2015;12:2095-2104.
- Goldfischer ER, Breaux J, Katz M, et al. Continued efficacy and safety of flibanserin in premenopausal women with hypoactive sexual desire disorder (HSDD): results from a randomized withdrawal trial. J Sex Med. 2011;8:3160-3172.
- Thorp J, Simon J, Dattani D, et al. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the DAISY study. J Sex Med. 2012;9:793-804.
- DeRogatis LR, Komer L, Katz M, et al. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET study. J Sex Med. 2012;9:1074-1085.
- Katz M, DeRogatis LR, Ackerman R, et al. Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial. J Sex Med. 2013;10:1807-1815.
- Simon JA, Kingsberg SA, Shumel B, et al. Efficacy and safety of flibanserin in postmenopausal women with hypoactive sexual desire disorder: results of the SNOWDROP trial. Menopause. 2014;21:633-640.
- Jaspers L, Feys F, Bramer WM, et al. Efficacy and safety of flibanserin for the treatment of hypoactive sexual desire disorder in women: a systematic review and meta-analysis. JAMA Intern Med. 2016;176:453-462.
- Jayne C, Simon JA, Taylor LV, et al. Open-label extension study of flibanserin in women with hypoactive sexual desire disorder. J Sex Med. 2012;9:3180-3188.
- Valeant Pharmaceuticals to Acquire Sprout Pharmaceuticals. Laval, Quebec and Raleigh, NC: Valeant Pharmaceuticals International, Inc. and Sprout Pharmaceuticals, Inc; August 20, 2015. http://ir.valeant.com/news-releases/2015/20-08-2015. Accessed May 4, 2016.
- Addyi REMS Homepage. https://www.addyirems.com/AddyiUI/rems/home.action. Accessed May 17, 2016. 
- Raleigh NC. Sprout Pharmaceuticals, Inc. Addyi (flibanserin) [package insert]. Raleigh, NC: Sprout Pharmaceuticals, Inc; 2015. 
- Corman A. What are we trying to cure when treating a woman for HSDD? Sexologies. 2011:20;12-14. 
- American College of Obstetricians and Gynecologists Committee on Practice Bulletins−Gynecology. ACOG Practice Bulletin No. 119: female sexual dysfunction. Obstet Gynecol. 2011;117:996-1007. 
- Meixel A, Yanchar E, Fugh-Berman A. Hypoactive sexual desire disorder: inventing a disease to sell low libido. J Med Ethics. 2015;0:1-4. 
- ClinicalTrials.govFlibanserin (Addyi) vs. flibanserin and sex therapy; https://clinicaltrials.gov/ct2/show/NCT02714049?term=flibanserin&rank=1. Published March 11, 2016. Accessed May 17, 2016.