(August 18, 2015) After three applications and ownership by two drug manufacturers, the Food and Drug Administration (FDA) has approved flibanserin (brand name Addyi) for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty that is not due to a co-existing medical or psychiatric condition, problems within a relationship, or the effects of a medication or drug. This type of HSDD occurs in patients who previously had no problems with sexual desire and occurs regardless of the type of sexual activity, the situation, or sexual partner. Flibanserin is not indicated in postmenopausal women, men, or as an agent to enhance sexual performance.
Molecular Structure of Flibanserin
Unlike the six drugs (i.e. Viagra) marketed for the treatment of erectile dysfunction, flibanserin is a first in pharmacotherapy that addresses female sexual dysfunction. And while flibanserin has been hailed as the “female Viagra”, it is much different than its male counterpart. Viagra is taken before sex to increase blood flow to the genitals which enhances physical arousal-it works almost 100% of the time.
Flibanserin is a serotonin-1A receptor agonist and serotonin-2A receptor antagonist with very weak partial agonist activity on dopamine-D4 receptors. These receptor interactions result in an increase of dopamine and norepinephrine and a decrease of serotonin levels in the prefrontal cortex and, as such, flibanserin has been described as a norepinephrine-dopamine disinhibitor (NDDI). It has antidepressant-like activity but how these mechanisms serve to increase sexual desire is not known.
The effectiveness of flibanserin has been evaluated in three 24-week randomized, double-blinded, placebo-controlled trials in 2,400 premenopausal women with acquired, generalized HSDD. In these trials, women counted the number of satisfying sexual events, reported sexual desire (and distress related to low sexual desire) over the preceding four weeks. Treatment with flibanserin increased the number of satisfying sexual events by 0.5 to one additional event per month over placebo. Approximately 10% more flibanserin-treated patients than placebo-treated patients reported meaningful improvements in satisfying sexual events, sexual desire, or distress.
Beyond concerns of efficacy, flibanserin may cause orthostatic hypotension and syncope exacerbated by alcohol, liver impairment, and moderate or strong CYP3A4 inhibitors (i.e. oral contraceptives, grapefruit juice, St. John’s Wort, etc.). Flibanserin is contraindicated in these patients and a Boxed Warning highlights these interactions. Additionally, the FDA has required the pharmaceutical company to conduct three well-designed studies in women to better understand the serious risk involved with flibanserin and alcohol co-administration (oddly enough, the original alcohol-safety study submitted to the FDA consisted of 23 males and 2 females).
Flibanserin is approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The REMS requires that prescribers be certified with the REMS program following completion of training. Certified prescribers must counsel patients about the risk of severe hypotension, syncope, and alcohol co-administration using a Patient-Provider Agreement Form. Pharmacies that dispense flibanserin must be certified with the REMS program and must dispense flibanserin only to patients with a prescription from a certified prescriber. Prior to dispensing flibanseirn, pharmacists must counsel patients not to ingest alcohol.
Flibanserin is available in 100mg tablets which are taken daily at bedtime to decrease the risk of orthostatic hypotension, syncope, and sedation. Treatment should be discontinued if there is no improvement in sexual desire after 8 weeks.
This question prepared by: Justin Loden, PharmD, CSPI (Certified Specialist in Poison Information) Tennessee Poison Center
Here are some facts. Conclusions regarding efficacy are up to you.
This drug was initially developed as an antidepressant (structurally similar to trazodone) but failed to demonstrate efficacy.
Flibanserin has been twice rejected by the FDA for treatment of HSDD due to an unfavorable risk-benefit profile. Following the second rejection in 2013, an advocacy group called “Even the Score” was formed to advocate for “gender equality” in access to treatments for sexual dysfunction.
In the first application, the primary desire end point was based on a daily diary rating. In the second application, end point was a 4-week recall of frequency and intensity of sexual desire.
The drug’s effect is “modest”, about 10% better than placebo.
Sexual desire is regulated not only by estrogen and testosterone, but also by the neurotransmitters dopamine and norepinephrine which enhance sexual desire. Serotonin inhibits sexual desire and interest (reason the SSRIs are said to decrease libido) Flibanserin theoretically improves sexual desire by enhancing downstream release of dopamine and norepinephrine while reducing serotonin release. The actual mechanism by which the drug increases sexual desire (if it does) is unknown.
And your conclusion is………
ds
I am interesting in any questions you would like answered in the Question of the Week. Please email me with any suggestion at donna.seger@vanderbilt.edu
Donna Seger, MD
Medical Director
Tennessee Poison Center
Poison Help Hotline: 1-800-222-1222