Flibanserin

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Flibanserin
Flibanserin.svg
Flibanserin ball-and-stick model.png
Systematic (IUPAC) name
1-(2-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one
Clinical data
Trade names Addyi
Pregnancy
category
  • C
Legal status
  • (Prescription only)
Routes of
administration
Oral
Pharmacokinetic data
Biological half-life ~11 hours[1]
Identifiers
CAS Registry Number 167933-07-5 YesY
ATC code None
PubChem CID: 6918248
IUPHAR/BPS 8182
ChemSpider 5293454 YesY
UNII 37JK4STR6Z YesY
KEGG D02577 YesY
ChEMBL CHEMBL231068 YesY
Chemical data
Formula C20H21F3N4O
Molecular mass 390.40 g/mol
 YesY (what is this?)  (verify)

Flibanserin (INN, USAN), sold under the trade name Addyi, is a medication approved for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD).[1][2] The medication increases the number of satisfying sexual events per month by about one half to one over placebo from a starting point of about two to three.[3]

Development by Boehringer Ingelheim was halted in October 2010 following a negative evaluation by the U.S. Food and Drug Administration.[4] The rights to the drug were then transferred to Sprout Pharmaceuticals, which achieved approval of the drug by the US FDA in August 2015.

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).[5][6]

Effectiveness[edit]

Some studies found that flibanserin increased sexually satisfying events, and some did not, depending on how it was measured.

Trials involving more than 5,000 pre-menopausal women with generalized acquired HSDD demonstrated that:[7][8]

Although the two North American trials that used the flibanserin 100 mg qhs dose showed a statistically significant difference between flibanserin and the placebo for the endpoint of [satisfying sexual events], they both failed to demonstrate a statistically significant improvement on the co-primary endpoint of sexual desire. Therefore, neither study met the agreed-upon criteria for success in establishing the efficacy of flibanserin for the treatment of [Hypoactive Sexual Desire Disorder].

The women receiving flibanserin reported that the average number of times they had “satisfying sexual events” rose from 2.8 to 4.5 times a month. However, women receiving placebo reported also an increase of “satisfying sexual events” from 2.7 to 3.7 times a month. Evaluation of the overall improvement of their condition and whether the benefit was meaningful to the women, showed a significantly higher rate of a meaningful benefit in the flibanserin-treated people versus the placebo group.[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]

Side effects[edit]

Some adverse events were reported among women taking flibanserin. The majority of adverse events were mild to moderate and resolved during the treatment. The most commonly reported adverse events included dizziness, nausea, fatigue, sleepiness, and trouble sleeping.[8]

Mechanism of action[edit]

Flibanserin acts as a full agonist of the 5-HT1A receptor (Ki = 1 nM) 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).[11][12][13][14] Despite the much greater affinity of flibanserin for the 5-HT1A receptor, and for reasons that are unknown, flibanserin occupies the 5-HT1A and 5-HT2A receptors in vivo with similar percentages.[15][16] 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.[14] 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.[11] As such, flibanserin has been described as a norepinephrine-dopamine disinhibitor (NDDI).[14][17]

The proposed mechanism of action refers to the Kinsey dual control model of sexual response.[18] Various sex steroids, neurotransmitters, and hormones have important excitatory or inhibitory effects on the sexual response. Among the neurotransmitters, the excitatory activity is driven by dopamine and norepinephrine, while the inhibitory activity is driven by serotonin. The balance between these systems is relevant for a normal sexual response. By modulating these neurotransmitters in the brain, flibanserin may improve the balance between these neurotransmitter systems in regulation of sexual response.[19][20]

Society and culture[edit]

Flibanserin was originally developed as an antidepressant,[21][22] before being repurposed for the treatment of HSDD.

Names[edit]

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

Approval process and advocacy[edit]

On June 18, 2010, a federal advisory panel to the U.S. Food and Drug Administration (FDA) unanimously voted against recommending approval of flibanserin, citing the small effect and the risks of long-term use. 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".[23] On October 8, 2010, Boehringer announced that it would discontinue its development of flibanserin in light of the FDA advisory panel's recommendation.[24]

On June 27, 2013, Sprout Pharmaceuticals confirmed they had resubmitted flibanserin for FDA approval.[25] In December 2013, a Formal Dispute Resolution was filed,[26] 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.[26][27][28] Sprout expected to resubmit the New Drug Application (NDA) in the 3rd quarter of 2014.[26][27]

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 0-18–6.[29] 0 voted to recommend Flibanserin with label warnings, 18 voted to recommend Flibanserin with the inclusion of risk management options beyond labeling, and 6 members voted against approving the drug.[30] On August 18, 2015 the FDA approved Addyi (Flibanserin) for use in improving female sex drive.[31][32][33][34]

Even the Score[edit]

Sprout launched a campaign called Even the Score to pressure the FDA to approve flibanserin. The campaign emphasized that several approved treatments for male sexual dysfunction exist, while no such treatment for women was available.[35]

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."[36] One researcher said that the members of the FDA advisory committee "were emotionally blackmailed by the Even the Score campaign".[37] The director of the National Women's Health Network said that "Even The Score is full of lies, knowing willful lies."[38]

The Even the Score campaign was managed by Blue Engine Message & Media, a public relations firm, and their funding came from Sprout.[39]

See also[edit]

References[edit]

  1. ^ Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S (Summer 2002). "Pharmacology of flibanserin". CNS Drug Rev. 8 (2): 117–142. doi:10.1111/j.1527-3458.2002.tb00219.x. PMID 12177684. 
  2. ^ Jolly E, Clayton A, Thorp J, Lewis-D’Agostino D, Wunderlich G, Lesko L (April 2008). "Design of Phase III pivotal trials of flibanserin in female Hypoactive Sexual Desire Disorder (HSDD)". Sexologies 17 (Suppl 1): S133–4. doi:10.1016/S1158-1360(08)72886-X. 
  3. ^ "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. Retrieved 5 June 2015. 
  4. ^ Spiegel online: Pharmakonzern stoppt Lustpille für die Frau, 8 October 2010 (in German)
  5. ^ 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.
  6. ^ http://www.nytimes.com/2015/02/27/opinion/nothing-is-wrong-with-your-sex-drive.html?_r=0
  7. ^ "Proposed Indication: Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women" (PDF). May 20, 2010. p. 38. Retrieved June 17, 2010. 
  8. ^ a b "Proposed Indication: Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women" (PDF). May 20, 2010. Retrieved June 16, 2010. 
  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. ^ a b 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. 
  12. ^ Borsini F, Giraldo E, Monferini E, Antonini G, Parenti M, Bietti G et al. (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. PMID 8584042. 
  13. ^ Stahl, Stephen M. (2015). "Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder". CNS Spectrums 20 (01): 1–6. doi:10.1017/S1092852914000832. ISSN 1092-8529. 
  14. ^ a b c 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. 
  15. ^ Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S (2002). "Pharmacology of flibanserin". CNS Drug Rev 8 (2): 117–42. PMID 12177684. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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.
  19. ^ 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. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ "Drug for sexual desire disorder opposed by panel". New York Times. 18 June 2010. 
  24. ^ Burger, Ludwig (8 October 2010). "Boehringer pulls the plug on "pink Viagra"". Reuters. 
  25. ^ "Sprout Pharmaceuticals resubmits flibanserin NDA for treating HSDD in pre-menopausal women". 27 June 2013. 
  26. ^ a b c http://sproutpharma.com/sprout-pharmaceuticals-receives-clear-guidance-from-fda-on-path-forward-to-resubmit-new-drug-application-for-flibanserin-the-first-potential-medical-treatment-for-hypoactive-sexual-desire-disorder-in/
  27. ^ a b FDA seeks more tests on a female Viagra, by Matthew Perrone, The Detroit Free Press, page 2A Wednesday, Feb. 12, 2014
  28. ^ http://www.cnn.com/2014/02/11/health/female-sex-drive-drug/index.html?hpt=hp_t2
  29. ^ Stein, Rob (June 4, 2015). "Advisers To FDA Recommend Agency Approve Drug To Boost Female Libido". NPR. Retrieved June 4, 2015. 
  30. ^ "Critics: Women’s Sex Pill Approval Vote Driven By PR, Not Science". Forbes. June 7, 2015. 
  31. ^ "FDA approves first treatment for sexual desire disorder Addyi approved to treat premenopausal women". 
  32. ^ Kasperkevic, Jana. "FDA approves 'female Viagra' pill Flibanserin after two rejections". The Guardian. Retrieved 2015-08-18. 
  33. ^ "The Myth of "Female Viagra"". 
  34. ^ "F.D.A. Approves Addyi, a Libido Pill for Women". 
  35. ^ Pollack, Andrew (2015-06-04). "‘Viagra for Women’ Is Backed by an F.D.A. Panel". The New York Times. 
  36. ^ Perry, Susan (8 June 2015). "'Faux-advocacy,' not science, prompted FDA panel's OK of 'low libido' drug for women, critics charge". minnpost.com. Retrieved 18 August 2015. 
  37. ^ Cassels, Alan (5 June 2015). "Astroturfers rule the day: FDA's flibanserin reviewers were “emotionally blackmailed” by a slick lobbying campaign - HealthNewsReview.org". healthnewsreview.org. Retrieved 18 August 2015. 
  38. ^ Volsky, Igor; Fleischer, Victoria (14 August 2015). "What Big Pharma Doesn't Want You To Know About 'Female Viagra' | ThinkProgress". thinkprogress.org. Retrieved 18 August 2015. 
  39. ^ Karlin, Sarah (13 August 2015). "Women's sex drug gets political hard sell". politico.com. Retrieved 18 August 2015. 

External links[edit]