Flibanserin for Low Sexual Desire in Women: A Molecule From Bench to Bed?

Flibanserin, a drug with mixed effects on serotonergic and dopaminergic neurotransmitter systems, has recently been recommended for FDA approval, albeit withmany restrictions, for the treatment of low sexual desire in premenopausal women. The sexual side effects of antidepressants with at least partially known mechanisms of action indicate that flibanserin should enhance sexual response. Rather than illustrating translation of knowledge from bench to bedside, the reality is less dramatic – as is flibanserin's efficacy. Ineffective as an antidepressant, but noted to have pro-sexual side effects, flibanserin was trialed for this new indication in the early 2000's. The FDA denied Boehringer Ingelheim's application for approval of flibanserin for hypoactive sexual desire disorder (HSDD) inwomen in 2010 as two phase 3 trials failed to show statistically significant benefit on one of two co-primary endpoints — a daily diary assessment of desire. Sprout Pharmaceuticals reapplied in 2013 with data from a third trial which used a different co-primary endpoint – a retrospective assessment of desire over the previous 4 weeks. Due both to safety concerns, which include hypotension, syncope, somnolence, fatigue, and potential carcinogenicity and to the short duration of studies and questionable accuracy of 4 week recall along with marginal efficacy, approval was denied and additional safety studies recommended. Benefit across all phase 3 studies averaged a placebo-corrected increase of ‘satisfactory sexual events’ by 0.5 to 1 per month and an increase of 0.3 on the retrospective desire scale (range 1.2–6.0). Surprisingly, despite lack of additional efficacy data, but with data ruling out driving impairment and assessing alcohol's enhancement of side effects in 23 men and 2 women, on June 4, 2015, an FDA advisory committee voted 18 to 6 to accept flibanserin's approval, but with reservations. Fifteen members endorsing its approval declared their reluctance to do so. An additional concern is that trial participants had no clear diagnosis of sexual disorder as is currently understood. Growing concern that HSDD criteria are not appropriate for women led to interim definitions of low desire in 2003, and to an officially changed definition in 2013 (American Psychiatric Association, 2013). A state of ongoing sexual desire between sexual experiences is de-emphasized. Responsive desire triggered by sexual stimuli including those received during sexual encounters is now recognized (Both et al., 2007; Stoléru et al., 2012). Beginning partnered sexual activity for reasons other than ‘desire’ has been clearly documented as the most common scenario in both young (Meston and Buss, 2007) and older women (Cain et al., 2003). Pathology now focuses on the inability to trigger desire and arousal during sexual experiences. Participants in flibanserin studies, however, reported 2 to 3 rewarding sexual experiences each month at baseline.