Mechanism of Action of Flibanserin
The exact mechanism by which flibanserin improves sexual function and libido in premenopausal women with hypoactive sexual desire disorder (HSDD) is not fully understood, but it acts as a postsynaptic 5-HT1A receptor agonist and 5-HT2A receptor antagonist, with additional moderate antagonist activity at 5-HT2B, 5-HT2C, and dopamine D4 receptors. 1
Receptor Pharmacology
The FDA-approved drug label explicitly states that "the mechanism of action of ADDYI in the treatment of premenopausal women with hypoactive sexual desire disorder is not known," despite well-characterized receptor binding profiles. 1
In vitro receptor binding studies demonstrate:
- High affinity agonist activity at 5-HT1A receptors 1
- High affinity antagonist activity at 5-HT2A receptors 1
- Moderate antagonist activity at 5-HT2B, 5-HT2C, and dopamine D4 receptors 1
Theoretical Neurochemical Basis
While the precise mechanism remains unclear, the dual action on serotonin receptors is thought to modulate neurotransmitter pathways involved in sexual desire. 2, 3 The 5-HT1A agonism and 5-HT2A antagonism may work synergistically to influence dopamine and norepinephrine levels in brain regions associated with sexual motivation, though this has not been definitively proven in humans. 4, 5
Clinical Efficacy Evidence
The clinical effects of flibanserin 100 mg once daily at bedtime in premenopausal women with HSDD include:
- Approximately 1 additional satisfying sexual event every 2 months compared to placebo 6, 7
- Statistically significant improvements in sexual desire measured by the Female Sexual Function Index (FSFI) desire domain score 8, 2
- Significant reductions in distress associated with low sexual desire 8, 3
In pooled analysis of three pivotal trials (VIOLET, DAISY, BEGONIA) involving 2,465 premenopausal women, flibanserin demonstrated mean increases of 2.1 satisfying sexual events over 28 days versus 1.2 for placebo (p<0.0001). 2
Important Clinical Caveats
Flibanserin has NOT been evaluated in women with a history of cancer or those on endocrine therapy, and the risk/benefit ratio in these populations remains uncertain. 7 This is a critical limitation given that many guidelines discussing flibanserin are in the context of cancer survivorship care. 7
The most common adverse events include dizziness (10.5%), somnolence (11.8%), and fatigue (10.3%), which are likely related to its serotonergic and dopaminergic receptor activities. 2, 3
Pharmacokinetic Considerations
Flibanserin is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, with approximately 98% protein binding to albumin. 1 Food increases the extent of absorption by 1.18- to 1.56-fold depending on fat content, though the clinical significance of this is modest. 1