Flibanserin, sold under the brand name Addyi, is a medication approved for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD). The medication improves sexual desire, increases the number of satisfying sexual events, and decreases the distress associated with low sexual desire. The most common side effects are dizziness, sleepiness, nausea, difficulty falling asleep or staying asleep and dry mouth.
Development by Boehringer Ingelheim was halted in October 2010, following a negative evaluation by the US Food and Drug Administration (FDA). The rights to the drug were then transferred to Sprout Pharmaceuticals, which achieved approval of the drug by the US FDA in August 2015.
Addyi is approved for medical use in the US for premenopausal women with HSDD and in Canada for premenopausal and postmenopausal women with HSDD.
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
Flibanserin is used for hypoactive sexual desire disorder among women. 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 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.
Supportive analyses based on the patient's perspective of her symptoms at the end of the study showed that improvements in symptoms of HSDD were not only statistically significant but also clinically meaningful to women.
Side effects
The majority of adverse events were mild to moderate in severity. The most commonly reported adverse events included dizziness, nausea, feeling tired, sleepiness, and trouble sleeping.
Drinking alcohol while on flibanserin may increase the risk of severe low blood pressure. The Addyi Prescribing Information was updated in 2019 following the FDA's review of three postmarketing alcohol interaction studies which led to increased understanding of this drug interaction. This new data led to a removal of the contraindication with alcohol and new recommendations on how to safely consume alcohol while receiving Addyi therapy.
Current recommendations are to wait at least two hours after consuming one or two standard alcoholic drinks before taking ADDYI at bedtime or to skip their ADDYI dose if they have consumed three or more standard alcoholic drinks that evening.
Mechanism of action
Activity profile
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 of the 5-HT1A receptor (serotonin receptor) (Ki = 1 nM in cells, but only 15–50 nM in cortex, hippocampus and dorsal raphe) 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, Ki = 8–650 nM ). 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. 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).