Flibanserin

Flibanserin
Names
Trade namesAddyi
IUPAC name
  • 1-(2-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one
Clinical data
Main usesHypoactive sexual desire disorder (HSDD)[1]
Side effectsDizziness, sleepiness, nausea, tiredness[2]
InteractionsAlcohol[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: N (Not classified yet)
    Routes of
    use    		By mouth
    Typical dose100 mg at HS[1]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability33%[3]
    Protein binding~98%
    MetabolismExtensive by liver (mainly by CYP3A4 and CYP2C19)
    Elimination half-life~11 hours
    ExcretionBiliary (51%), kidney (44%)
    Chemical and physical data
    FormulaC20H21F3N4O
    Molar mass390.410 g·mol−1
    3D model (JSmol)
    SMILES
    • FC(F)(F)c4cc(N3CCN(CCN2c1ccccc1NC2=O)CC3)ccc4
    InChI
    • InChI=1S/C20H21F3N4O/c21-20(22,23)15-4-3-5-16(14-15)26-11-8-25(9-12-26)10-13-27-18-7-2-1-6-17(18)24-19(27)28/h1-7,14H,8-13H2,(H,24,28) checkY
    • Key:PPRRDFIXUUSXRA-UHFFFAOYSA-N checkY

    Flibanserin, sold under the brand name Addyi, is a medication used to treat women with hypoactive sexual desire disorder (HSDD).[1] It increases the number of satisfying sexual events per month by about one half from a starting point of about two to three.[2][4] The certainty of this estimate is low.[2] It is taken by mouth.[1]

    Common side effects include dizziness, sleepiness, nausea, and tiredness.[2] Other side effects may include low blood pressure.[1] Use with alcohol or in those with liver problems is not recommended.[1] There are concerns that use in pregnancy may harm the baby.[5] It is a 5-HT1A receptor activator and 5-HT2A receptor inhibitor.[1]

    Flibanserin was approved for medical use in the United States in 2015 and Canada in 2018.[1][6] As of 2021 it is not approved in the United Kingdom.[7] In the United States it costs about 490 USD per month as of 2021.[8]

    Medical uses

    Flibanserin is used for hypoactive sexual desire disorder among women. Those receiving flibanserin report a 0.5 increase compared to placebo in the number of times they had "satisfying sexual events".[2] In those on flibanserin it rose from 2.8 to 4.5 times a month while women receiving placebo reported also an increase of "satisfying sexual events" from 2.7 to 3.7 times a month.[9] The onset of the flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period.[10][3]

    The effectiveness was evaluated in three phase 3 clinical trials. Each of the trials had two co-primary endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire. Each of the trials also had a secondary endpoint that measured distress related to sexual desire. All three trials showed that flibanserin produced an increase in the number of SSEs and reduced distress related to sexual desire. The first two trials used an electronic diary to measure sexual desire, and did not find an increase. These two trials also measured sexual desire using the Female Sexual Function index (FSFI) as a secondary endpoint, and an increase was observed using this latter measure. The FSFI was used as the co-primary endpoint for sexual desire in the third trial, and again showed a statistically significant increase.[3]

    Women's overall feeling of improvement was small to none.[2] The overall quality of the evidence was low.[2]

    HSDD was recognized as a distinct sexual function disorder for more than 30 years, but was removed from the Diagnostic and Statistical Manual of Mental Disorders in 2013, and replaced with a new diagnosis called female sexual interest/arousal disorder (FSIAD).[11][12]

    Dosage

    It is taken at a dose of 100 mg per night.[1]

    Side effects

    Side effects are more common among women taking flibanserin. The majority of adverse events were mild to moderate. The most commonly reported adverse events included dizziness, nausea, feeling tired, sleepiness, and trouble sleeping.[13]

    Drinking alcohol while on flibanserin may result in severely low blood pressure (low blood pressure that produced symptoms after two glasses of wine occurred in 17%).[14]

    Mechanism of action

    Flibanserin acts as a full agonist in the frontal cortex and the raphe dorsalis, but only as a partial agonist in the CA3 region of the hippocampus[15] of the 5-HT1A receptor (serotonin receptor) (Ki = 1 nM in CHO cells, but only 15–50 nM in cortex, hippocampus and dorsal raphe)[16] and, with lower affinity, as an antagonist of the 5-HT2A receptor (Ki = 49 nM) and antagonist or very weak partial agonist of the D4 receptor (Ki = 4–24 nM).[17][18][19][20] Despite the much greater affinity of flibanserin for the 5-HT1A receptor, and for reasons that are unknown (although it might be caused by the competition with endogenous serotonin), flibanserin occupies the 5-HT1A and 5-HT2A receptors in vivo with similar percentages.[16][21] Flibanserin also has low affinity for the 5-HT2B receptor (Ki = 89.3 nM) and the 5-HT2C receptor (Ki = 88.3 nM), both of which it behaves as an antagonist of.[20] Flibanserin preferentially activates 5-HT1A receptors in the prefrontal cortex, demonstrating regional selectivity, and has been found to increase dopamine and norepinephrine levels and decrease serotonin levels in the rat prefrontal cortex, actions that were determined to be mediated by activation of the 5-HT1A receptor.[17] As such, flibanserin has been described as a norepinephrine–dopamine disinhibitor (NDDI).[20][22]

    The proposed mechanism of action refers to the Kinsey dual control model of sexual response.[23] Various neurotransmitters, sex steroids, and other hormones have important excitatory or inhibitory effects on the sexual response. Among neurotransmitters, excitatory activity is driven by dopamine and norepinephrine, while inhibitory activity is driven by serotonin. The balance between these systems is of significance for a normal sexual response. By modulating serotonin and dopamine activity in certain parts of the brain, flibanserin may improve the balance between these neurotransmitter systems in the regulation of sexual response.[24][25]

    Society and culture

    Flibanserin was originally developed as an antidepressant,[26][27] before being repurposed for the treatment of HSDD.

    Names

    Former proposed but abandoned brand names of flibanserin include Ectris and Girosa, and its former developmental code name was BIMT-17. The brand name is Addyi.

    Approval

    On June 18, 2010, a federal advisory panel to the US Food and Drug Administration (FDA) unanimously voted against recommending approval of flibanserin, citing an inadequate risk-benefit ratio. The Committee acknowledged the validity of hypoactive sexual desire as a diagnosis, but expressed concern with the drug's side effects and insufficient evidence for efficacy, especially the drug's failure to show a statistically significant effect on the co-primary endpoint of sexual desire.[28] Earlier in the week, a FDA staff report also recommended non-approval of the drug. Ahead of the votes, Boehringer Ingelheim had mounted a publicity campaign to promote the controversial disorder of "hypoactive sexual desire".[29] In 2010 the FDA issued a Complete Response Letter, stating that the New Drug Application could not be approved in its current form. The letter cited several concerns, including the failure to demonstrate a statistical effect on the co-primary endpoint of sexual desire and overly restrictive entry criteria for the two Phase 3 trials. The Agency recommended performing a new Phase 3 trial with less restrictive entry criteria.[30] On October 8, 2010, Boehringer announced that it would discontinue its development of flibanserin in light of the FDA's decision.[31]

    Sprout responded to the FDA's cited deficiencies and refiled the NDA in 2013. The submission included data from a new Phase 3 trial and several Phase 1 drug-drug interaction studies.[30][32] The FDA again refused the application, citing an uncertain risk/benefit ratio. In December 2013, a Formal Dispute Resolution was filed,[33] which contained the requirements of the FDA for further studies. These include two studies in healthy subjects to determine if flibanserin impairs their ability to drive, and to determine if it interferes with other biochemical pathways. The Agency agreed to call a new Advisory Committee meeting to consider whether the risk-benefit ratio of flibanserin was favorable after this additional data was obtained.[33][34][35] Sprout expected to resubmit the New Drug Application (NDA) in the 3rd quarter of 2014.[33][34]

    On June 4, 2015, the US FDA Advisory Committee, which includes the Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSRM), recommended approval of the drug by 18–6, with the proviso that measures be taken to inform women of the drug's side effects.[36][37] On August 18, 2015 the FDA approved Addyi (Flibanserin) for the treatment of premenopausal women with low sexual desire that causes personal distress or relationship difficulties. The approval specified that flibanserin should not be used to treat low sexual desire caused by co-existing psychiatric or medical problems; low sexual desire caused by problems in the relationship; or low sexual desire due to medication side effects.[3]

    As of 21 August 2015, The Pharmaceutical Journal reported that Sprout Pharmaceuticals had not yet made an application to the European Medicines Agency for a marketing authorisation.[38]

    Even the Score, a coalition of women's group's brought together by a Sprout consultant, actively campaigned for the approval of flibanserin. The campaign emphasized that several approved treatments for male sexual dysfunction exist, while no such treatment for women was available.[39] The group successfully obtained letters of support from the President of the National Organization for Women, the editor of the Journal of Sexual Medicine, and several members of Congress.[40]

    Other organizations supporting the approval of flibanserin included the National Council of Women's Organizations, the Black Women’s Health Imperative, the Association of Reproductive Health Professionals, National Consumers League, and the American Sexual Health Association.[41][42][43][44]

    The approval was opposed by the National Women's Health Network, the National Center for Health Research and Our Bodies Ourselves.[45] A representative of PharmedOut said "To approve this drug will set the worst kind of precedent — that companies that spend enough money can force the FDA to approve useless or dangerous drugs."[46] An editorial in JAMA noted that, "Although flibanserin is not the first product to be supported by a consumer advocacy group in turn supported by pharmaceutical manufacturers, claims of gender bias regarding the FDA’s regulation have been particularly noteworthy, as have the extent of advocacy efforts ranging from social media campaigns to letters from members of Congress".[47]

    The Even the Score campaign was managed by Blue Engine Message & Media, a public relations firm, and received funding from Sprout.[48]

    Commercialization

    On 20 August 2015 Valeant Pharmaceuticals and Sprout Pharmaceuticals announced that Valeant will acquire Sprout, on a debt-free basis, for approximately $1 billion in cash, plus a share of future profits based upon the achievement of certain milestones.[49]

    Reception

    The initial response since the 2015 introduction of flibanserin to the U.S. market was slow with 227 prescriptions written during the first three weeks.[50] The slow response may be related to a number of factors: physicians require an about 10 minute online training to get certified, the medication has to be taken daily and costs about US$400 per month,[51] and questions about the drug's efficacy and need.[50] Prescriptions for the drug continue to be few with less than 4,000 being made as of February 2016.[52]

    References

    1. 1 2 3 4 5 6 7 8 9 10 "Flibanserin Monograph for Professionals". Drugs.com. Retrieved 11 December 2021.
    2. 1 2 3 4 5 6 7 Jaspers, Loes; Feys, Frederik; Bramer, Wichor M.; Franco, Oscar H.; Leusink, Peter; Laan, Ellen T. M. (29 February 2016). "Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women". JAMA Internal Medicine. 176 (4): 453–62. doi:10.1001/jamainternmed.2015.8565. PMID 26927498.
    3. 1 2 3 4 5 "Addyi- flibanserin tablet, film coated". DailyMed. 10 October 2019. Archived from the original on 20 October 2020. Retrieved 20 October 2020.
    4. ↑ "Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee" (PDF). June 4, 2015. Archived (PDF) from the original on 5 June 2015. Retrieved 5 June 2015.
    5. ↑ "Flibanserin (Addyi) Use During Pregnancy". Drugs.com. Archived from the original on 4 December 2020. Retrieved 11 December 2021.
    6. ↑ Government of Canada, Health Canada (25 April 2012). "Drug Product Database Online Query". health-products.canada.ca. Archived from the original on 11 December 2021. Retrieved 11 December 2021.
    7. ↑ Nast, Condé (6 August 2021). "Is there a female equivalent of Viagra? And if so, does it actually work?". Glamour UK. Archived from the original on 11 December 2021. Retrieved 11 December 2021.
    8. ↑ "Flibanserin Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 11 May 2016. Retrieved 11 December 2021.
    9. ↑ Jolly E, Thorp J, Clayton AH, et al. Patients’ Perspective of Efficacy of Flibanserin in Premenopausal Women with HSDD. Oral presentation at the 58th Annual Clinical Meeting of The American College of Obstetricians and Gynecologists, May 2010.
    10. ↑ Simon JA, Thorp J, Katz M et al. Onset of Efficacy of Flibanserin in Premenopausal Women with Hypoactive Sexual Desire Disorder. Abstract presented at the 58th Annual Clinical Meeting of The American College of Obstetricians and Gynecologists, May 2010.
    11. ↑ American Psychiatric Association. Sexual and gender identity disorders. In: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000:493–538.
    12. ↑ Nagoski, Emily (27 February 2015). "Nothing Is Wrong With Your Sex Drive". The New York Times. Archived from the original on 15 July 2017. Retrieved 31 July 2017.
    13. ↑ "Proposed Indication: Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women" (PDF). May 20, 2010. Archived (PDF) from the original on May 9, 2017. Retrieved June 16, 2010.
    14. ↑ "FDA Risk Evaluation and Mitigation Strategy of Addyi" (PDF). p. 42. Archived (PDF) from the original on 2021-07-14. Retrieved 2021-08-29. Public Domain This article incorporates text from this source, which is in the public domain.
    15. ↑ Rueter LE, de Montigny C, Blier P (1998). "In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre- and postsynaptic 5-HT1A receptors in the rat brain". Synapse. 29 (4): 392–405. doi:10.1002/(SICI)1098-2396(199808)29:4<392::AID-SYN11>3.0.CO;2-T. PMID 9661257.
    16. 1 2 Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S (2002). "Pharmacology of flibanserin". CNS Drug Reviews. 8 (2): 117–42. doi:10.1111/j.1527-3458.2002.tb00219.x. PMC 6741686. PMID 12177684.
    17. 1 2 Invernizzi, Roberto William; Sacchetti, Giuseppina; Parini, Stefania; Acconcia, Sabrina; Samanin, Rosario (2003). "Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT1Areceptors". British Journal of Pharmacology. 139 (7): 1281–1288. doi:10.1038/sj.bjp.0705341. ISSN 0007-1188. PMC 1573953. PMID 12890707.
    18. ↑ Borsini F, Giraldo E, Monferini E, Antonini G, Parenti M, Bietti G, Donetti A (1995). "BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex". Naunyn Schmiedebergs Arch. Pharmacol. 352 (3): 276–82. doi:10.1007/bf00168557. PMID 8584042. S2CID 19340842.
    19. ↑ Stahl, Stephen M. (2015). "Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder". CNS Spectrums. 20 (1): 1–6. doi:10.1017/S1092852914000832. ISSN 1092-8529. PMID 25659981.
    20. 1 2 3 Stahl, Stephen M.; Sommer, Bernd; Allers, Kelly A. (2011). "Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder". The Journal of Sexual Medicine. 8 (1): 15–27. doi:10.1111/j.1743-6109.2010.02032.x. ISSN 1743-6095. PMID 20840530.
    21. ↑ Scandroglio A, Monferini E, Borsini F (2001). "Ex vivo binding of flibanserin to serotonin 5-HT1A and 5-HT2A receptors". Pharmacol. Res. 43 (2): 179–83. doi:10.1006/phrs.2000.0762. PMID 11243720.
    22. ↑ Stephen M. Stahl; S. M. Stahl (17 March 2008). Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press. p. 658. ISBN 978-0-521-67376-1. Retrieved 23 April 2012.
    23. ↑ Janssen, E, Bancroft J. The dual control model: The role of sexual inhibition & excitation in sexual arousal and behavior In Janssen, E. (Ed). (2006). The Psychophysiology of Sex. Bloomington, IN:Indiana University press.
    24. ↑ Pfaus JG (June 2009). "Pathways of sexual desire". J Sex Med. 6 (6): 1506–33. doi:10.1111/j.1743-6109.2009.01309.x. PMID 19453889. S2CID 3427784.
    25. ↑ Allers K, Dremencov E, Ceci A, et al. (May 2010). "Acute and repeated flibanserin administration in female rats modulates monoamines differentially across brain areas: a microdialysis study". J Sex Med. 7 (5): 1757–67. doi:10.1111/j.1743-6109.2010.01763.x. PMID 20163532.
    26. ↑ D'Aquila P, Monleon S, Borsini F, Brain P, Willner P (December 1997). "Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant". European Journal of Pharmacology. 340 (2–3): 121–32. doi:10.1016/S0014-2999(97)01412-X. PMID 9537806.
    27. ↑ Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R (August 2003). "Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT1A receptors". Br J Pharmacol. 139 (7): 1281–8. doi:10.1038/sj.bjp.0705341. PMC 1573953. PMID 12890707.
    28. ↑ "June 18, 2010 meeting of the FDA Advisory Committee for Reproductive Health Drugs" (PDF), Minutes, archived (PDF) from the original on 2016-09-13, retrieved 2015-11-18
    29. ↑ "Drug for sexual desire disorder opposed by panel". The New York Times. 18 June 2010. Archived from the original on 11 February 2021. Retrieved 29 August 2021.
    30. 1 2 "Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee" (PDF). Archived (PDF) from the original on 2015-06-05. Retrieved 2021-08-29.
    31. ↑ Burger, Ludwig (8 October 2010). "Boehringer pulls the plug on "pink Viagra"". Reuters. Archived from the original on 15 October 2010. Retrieved 29 August 2021.
    32. ↑ "Sprout Pharmaceuticals resubmits flibanserin NDA for treating HSDD in pre-menopausal women". 27 June 2013. Archived from the original on 12 September 2015. Retrieved 29 August 2021.
    33. 1 2 3 "ADDYI® (flibanserin) - Home". sproutpharma.com. Archived from the original on 10 August 2015. Retrieved 31 July 2017.
    34. 1 2 FDA seeks more tests on a female Viagra, by Matthew Perrone, The Detroit Free Press, page 2A Wednesday, Feb. 12, 2014
    35. ↑ Elizabeth Landau (11 February 2014). "FDA: Female sex drive drug needs more research - CNN.com". CNN. Archived from the original on 1 August 2017. Retrieved 31 July 2017.
    36. ↑ Stein, Rob (June 4, 2015). "Advisers To FDA Recommend Agency Approve Drug To Boost Female Libido". NPR. Archived from the original on June 4, 2015. Retrieved June 4, 2015.
    37. ↑ "Critics: Women's Sex Pill Approval Vote Driven By PR, Not Science". Forbes. June 7, 2015. Archived from the original on March 4, 2021. Retrieved August 29, 2021.
    38. ↑ Torjesen I (21 August 2015). "First drug to improve sexual desire in women approved in the United States". The Pharmaceutical Journal. 295 (7878). doi:10.1211/PJ.2015.20069201.
    39. ↑ Pollack, Andrew (2015-06-04). "'Viagra for Women' Is Backed by an F.D.A. Panel". The New York Times. Archived from the original on 2021-02-13. Retrieved 2021-08-29.
    40. ↑ "Why Flibanserin Is Not the 'Female Viagra' - The Atlantic". 19 August 2015. Archived from the original on 7 April 2021. Retrieved 29 August 2021.
    41. ↑ "F.D.A. Approves Addyi, a Libido Pill for Women". The New York Times. Archived from the original on 2021-03-26. Retrieved 2021-08-29.
    42. ↑ "Association of Reproductive Health Professionals". Archived from the original on 2015-11-18. Retrieved 2015-11-17.
    43. ↑ "National Consumers League". 4 June 2015. Archived from the original on 2015-11-18. Retrieved 2015-11-17.
    44. ↑ "American Sexual Health Association". 19 August 2015. Archived from the original on 2015-11-06. Retrieved 2015-11-17.
    45. ↑ "Raleigh's Sprout Pharmaceuticals awaits FDA ruling on female libido drug | News & Observer". Archived from the original on 2019-06-03. Retrieved 2021-08-29.
    46. ↑ Perry, Susan (8 June 2015). "'Faux-advocacy,' not science, prompted FDA panel's OK of 'low libido' drug for women, critics charge". minnpost.com. Archived from the original on 30 August 2015. Retrieved 18 August 2015.
    47. ↑ Gellad WF, Flynn KE, Alexander GC (2015). "Evaluation of Flibanserin: Science and Advocacy at the FDA". JAMA. 314 (9): 869–70. doi:10.1001/jama.2015.8405. PMID 26148201.
    48. ↑ Karlin, Sarah (13 August 2015). "Women's sex drug gets political hard sell". politico.com. Archived from the original on 16 August 2015. Retrieved 18 August 2015.
    49. ↑ "Archived copy". Archived from the original on 2015-08-22. Retrieved 2015-10-25.{{cite web}}: CS1 maint: archived copy as title (link)
    50. 1 2 Anna Edney; Laura Colbey (November 17, 2015). "The Female Libido Pill Is No Viagra". Bloomberg Business. Archived from the original on November 17, 2015. Retrieved November 18, 2015.
    51. ↑ "Addyi Flibanserin". GoodRx. Archived from the original on 2021-01-29. Retrieved 2021-08-29.
    52. ↑ Thomas, Katie. "The Female Viagra, Undone by a Drug Maker's Dysfunction". The New York Times. Archived from the original on 25 May 2016. Retrieved 9 April 2016.
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