Flibanserin for hypoactive sexual desire disorder in premenopausal women

As noted in the package insert, these trials each had 2 co-primary efficacy endpoints, SSEs and sexual desire:

• change from baseline to Week 24 in the number of monthly SSEs (ie, sexual intercourse, oral sex, masturbation, or genital stimulation by the partner)
• change in sexual desire from baseline to 24-week endpoint.

In Study 1 and 2, change in sexual desire from baseline to Week 24 was measured daily by using an electronic diary. Every day, patients rated their sexual desire level by answering the question, “Indicate your most intense level of sexual desire” from 0 (no desire) to 3 (strong desire). These responses were totaled over a 28-day period to yield the monthly sexual desire score, which ranged from 0 to 84. These 2 studies also used the Female Sexual Function Index (FSFI) Desire domain as a secondary endpoint.

Study 3 used the FSFI Desire domain, comprising 2 questions, as the sexual desire co-primary endpoint:

• “Over the past 4 weeks, how often did you feel sexual desire or interest?” Responses ranged from 1 (almost never or never) to 5 (almost always or always).
• “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?” Responses ranged from 1 (very low or none at all) to 5 (very high).

In all 3 trials, flibanserin was associated with a small, yet statistically significant, improvement in change in monthly SSEs from baseline to Week 24 compared with placebo. In Study 1 and 2, there were no statistically significant differences between flibanserin and placebo for the electronic diary sexual desire endpoint. In the third study, there was statistically significant improvement in the change in sexual desire using the FSFI Desire domain with flibanserin compared with placebo. The FSFI Desire domain findings were consistent across all 3 trials. Flibanserin was associated with a decrease in sexual distress compared with placebo in all 3 studies.

Tolerability
Flibanserin was well tolerated in the 3 clinical trials. As the FDA noted, clinical trials are conducted under widely varying conditions and therefore adverse reaction rates observed in trials of flibanserin cannot be directly compared with those reported in clinical trials of another drug and might not reflect rates observed in clinical practice.

The discontinuation rate due to adverse reactions was 13% among patients treated with flibanserin, 100 mg at bedtime, and 6% among those taking placebo. The most common side effects were somnolence, dizziness, fatigue, nausea, insomnia, and dry mouth, which appear dose-dependent. Onset of most of these adverse events was within 14 days after the start of treatment.

Although hypotension and syncope rarely were seen with flibanserin alone in clinical trials, these adverse events occurred more frequently in the morning and when taken with alcohol and with some drugs (moderate or strong CYP3A4 inhibitors), and in patients with hepatic impairment. Therefore, women who drink alcohol or take a moderate or strong inhibitor of CYP3A4—both of which are contraindicated—and those with hepatic impairment should not take flibanserin.

Flibanserin should be taken at bedtime, because the risk of hypotension and syncope is higher when flibanserin is taken in the morning and because of associated sedation and somnolence.

Unique clinical issues
Flibanserin is the first FDA-approved medication for treating HSDD. It is important to note that the drug originally was developed as an antidepressant, but failed to show efficacy. Researchers noted that the drug was more effective than placebo when patients were asked, “How strong is your sexual desire?” The focus of development then shifted to a potential treatment of HSDD.

Flibanserin was not approved at 2 previous FDA hearings, mainly because of safety concerns. For the second hearing, the manufacturer, Boehringer Ingelheim, which sold the rights to the drug to Sprout Pharmaceuticals in 2011,⁶ did not present any new efficacy data, but provided additional safety data, such as research suggesting the absence of next-day driving impairment and data related to alcohol use (the study confirming hypotension associated with alcohol abuse used a small sample, and only 2 of 25 participants were women).

Contraindications
Flibanserin is contraindicated in patients using alcohol because of an increased risk of hypotension and syncope. A patient’s alcohol use should be evaluated before administering flibanserin, and patients should be counseled about the importance of abstaining from alcohol.

Similarly, concomitant use of flibanserin with a moderate or strong inhibitor of CYP3A4 increases the concentration of flibanserin and raises the risk of hypotension and syncope. Therefore, the use of a moderate or strong inhibitor of CYP3A4 in patients taking flibanserin is contraindicated. Similarly, patients with liver impairment should not take this drug.