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Revision as of 03:39, 25 October 2015 edit73.162.132.47 (talk) →Even the Score: closer to language of source, which notes several funding sources and clearly states it does not know all the funding details← Previous edit Revision as of 03:42, 25 October 2015 edit undo73.162.132.47 (talk) →Even the Score: removed non-notable quote from blog - Unnamed "researcher" is an assistant professor inNext edit →
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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.<ref>{{Cite news|title = ‘Viagra for Women’ Is Backed by an F.D.A. Panel|url = http://www.nytimes.com/2015/06/05/business/panel-backs-a-drug-to-increase-womens-sex-drive.html|newspaper = The New York Times|date = 2015-06-04|first = Andrew|last = Pollack}}</ref> The group successfully obtained letters of support from the President of the ], the editor of the ], and several members of Congress.<ref>{{cite web | url = http://www.theatlantic.com/health/archive/2015/08/why-flibanserin-is-not-the-female-viagra/401789/ | title = Why Flibanserin Is Not the ‘Female Viagra’ - The Atlantic | format = | work = | accessdate = }}</ref> 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.<ref>{{Cite news|title = ‘Viagra for Women’ Is Backed by an F.D.A. Panel|url = http://www.nytimes.com/2015/06/05/business/panel-backs-a-drug-to-increase-womens-sex-drive.html|newspaper = The New York Times|date = 2015-06-04|first = Andrew|last = Pollack}}</ref> The group successfully obtained letters of support from the President of the ], the editor of the ], and several members of Congress.<ref>{{cite web | url = http://www.theatlantic.com/health/archive/2015/08/why-flibanserin-is-not-the-female-viagra/401789/ | title = Why Flibanserin Is Not the ‘Female Viagra’ - The Atlantic | format = | work = | accessdate = }}</ref>


A representative of ] 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."<ref>{{cite web |url= https://www.minnpost.com/second-opinion/2015/06/faux-advocacy-not-science-prompted-fda-panels-ok-low-libido-drug-women-critic |title='Faux-advocacy,' not science, prompted FDA panel's OK of 'low libido' drug for women, critics charge |first=Susan |last=Perry |work=minnpost.com |date=8 June 2015 |accessdate=18 August 2015}}</ref> One researcher said that the members of the FDA advisory committee "were emotionally blackmailed by the Even the Score campaign".<ref>{{cite web |url= http://www.healthnewsreview.org/2015/06/astroturfers-rule-the-day-fdas-flibanserin-reviewers-were-emotionally-blackmailed-by-a-slick-lobbying-campaign/ |title=Astroturfers rule the day: FDA's flibanserin reviewers were "emotionally blackmailed" by a slick lobbying campaign - HealthNewsReview.org |first=Alan |last=Cassels |work=healthnewsreview.org |date=5 June 2015 |accessdate=18 August 2015}}</ref> A representative of ] 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."<ref>{{cite web |url= https://www.minnpost.com/second-opinion/2015/06/faux-advocacy-not-science-prompted-fda-panels-ok-low-libido-drug-women-critic |title='Faux-advocacy,' not science, prompted FDA panel's OK of 'low libido' drug for women, critics charge |first=Susan |last=Perry |work=minnpost.com |date=8 June 2015 |accessdate=18 August 2015}}</ref>


The Even the Score campaign was managed by Blue Engine Message & Media, a public relations firm, and recieved funding from Sprout, the .<ref>{{cite web |url= http://www.politico.com/story/2015/08/sexual-politics-boosts-bid-for-pink-viagra-121310.html |title=Women's sex drug gets political hard sell |first=Sarah |last=Karlin |work=politico.com |date=13 August 2015 |accessdate=18 August 2015}}</ref> The Even the Score campaign was managed by Blue Engine Message & Media, a public relations firm, and recieved funding from Sprout, the .<ref>{{cite web |url= http://www.politico.com/story/2015/08/sexual-politics-boosts-bid-for-pink-viagra-121310.html |title=Women's sex drug gets political hard sell |first=Sarah |last=Karlin |work=politico.com |date=13 August 2015 |accessdate=18 August 2015}}</ref>

Revision as of 03:42, 25 October 2015

{{Drugbox | Watchedfields = changed | verifiedrevid = 437139289 | IUPAC_name = 1-(2-{4-piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one | image = Flibanserin.svg | image2 = Flibanserin ball-and-stick model.png

| tradename = Addyi | pregnancy_category = C | legal_status = Rx only | routes_of_administration = Oral

| bioavailability = 33% | protein_bound = ~98% | metabolism = extensive hepatic (mainly by CYP3A4 and CYP2C19) | elimination_half-life = ~11 hours | excretion = biliary (51%), renal (44%)

| IUPHAR_ligand = 8182 | CAS_number_Ref = | CAS_number = 167933-07-5 | ATC_prefix = none | ATC_suffix = | PubChem = 6918248 | ChemSpiderID_Ref = | ChemSpiderID = 5293454 | UNII_Ref = | UNII = 37JK4STR6Z | KEGG_Ref = | KEGG = D02577 | ChEMBL_Ref = | ChEMBL = 231068

| C=20 | H=21 | F=3 | N=4 | O=1 | molecular_weight = 390.40 g/mol | smiles = FC(F)(F)c4cc(N3CCN(CCN2c1ccccc1NC2=O)CC3)ccc4 | InChI = 1/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) | InChIKey = PPRRDFIXUUSXRA-UHFFFAOYAA | StdInChI_Ref = | StdInChI = 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) | StdInChIKey_Ref = | StdInChIKey = PPRRDFIXUUSXRA-UHFFFAOYSA-N }} 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). 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.

Development by Boehringer Ingelheim was halted in October 2010 following a negative evaluation by the U.S. Food and Drug Administration. 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).

Medical uses

Fibanserin is used for hypoactive sexual desire disorder among women. Those receiving flibanserin report 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. The onset of the flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period.

The effectiveness of flibanserin was evaluated in three phase 3 clinical trials. Each of the three trials had two co-primary endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire. Each of the 3 trials also had a secondary endpoint that measured distress related to sexual desire.

All three trials showed that flibanserin produced a statistically significant 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 a statistically significant increase relative to women treated with a placebo. These two trials also measured sexual desire using the Female Sexual Function index (FSFI) as a secondary endpoint, and a statistically significant 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.

Side effects

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.

Drinking alcohol while on flibanserin may result in severely low blood pressure (low blood pressure that produced symptoms occurred after only 2 glasses of wine occurred in 17%).

Mechanism of action

Activity profile

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). 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. 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. 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. As such, flibanserin has been described as a norepinephrine-dopamine disinhibitor (NDDI).

The proposed mechanism of action refers to the Kinsey dual control model of sexual response. 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.

Society and culture

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

Names

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

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". On October 8, 2010, Boehringer announced that it would discontinue its development of flibanserin in light of the FDA advisory panel's recommendation.

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

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. 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. On August 18, 2015 the FDA approved Addyi (Flibanserin) for use in improving female sex drive.

Even the Score

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. 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.

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."

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

References

  1. "Addyi™ (flibanserin) Tablets, for Oral Use. Full Prescribing Information" (PDF). Addyi REMS (Risk Evaluation and Mitigation Strategy). Sprout Pharmaceuticals, Inc. Raleigh, NC 27609 USA. Retrieved 21 October 2015.
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  3. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. Retrieved 5 June 2015.
  5. Spiegel online: Pharmakonzern stoppt Lustpille für die Frau, 8 October 2010 (in German)
  6. Mullard, Asher (1 October 2015). "FDA approves female sexual dysfunction drug". Nature Drug Discovery. doi:10.1038/nrd4757. Retrieved 3 October 2015.
  7. 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.
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  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.
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  17. 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.
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  20. 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.
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  25. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. "Drug for sexual desire disorder opposed by panel". New York Times. 18 June 2010.
  28. Burger, Ludwig (8 October 2010). "Boehringer pulls the plug on "pink Viagra"". Reuters.
  29. "Sprout Pharmaceuticals resubmits flibanserin NDA for treating HSDD in pre-menopausal women". 27 June 2013.
  30. ^ 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/
  31. ^ FDA seeks more tests on a female Viagra, by Matthew Perrone, The Detroit Free Press, page 2A Wednesday, Feb. 12, 2014
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  33. Stein, Rob (June 4, 2015). "Advisers To FDA Recommend Agency Approve Drug To Boost Female Libido". NPR. Retrieved June 4, 2015.
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  41. 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.
  42. Karlin, Sarah (13 August 2015). "Women's sex drug gets political hard sell". politico.com. Retrieved 18 August 2015.

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