GAITHERSBURG, MD. — A Food and Drug Administration advisory panel unanimously agreed that concerns about the risks of flibanserin outweighed any evidence that the drug was effective as a treatment for premenopausal women with hypoactive sexual desire disorder.
Moreover, the evidence provided by Boehringer Ingelheim Pharmaceuticals that flibanserin (Girosa) is effective treatment for hypoactive sexual desire disorder (HSDD) did not sway the FDA's Reproductive Health Drugs Advisory Committee, reflected by their 10 to 1 no vote on that question.
The panel was not asked to vote on a separate safety question, but members expressed concerns about adverse effects associated with the drug in clinical trials, including high rates of somnolence and fatigue, a slightly higher rate of depression, the potential for drug and alcohol interactions, the lack of safety data on long-term use and during nursing and pregnancy—as well as the high withdrawal rate for adverse events in clinical trials.
However, panelists encouraged the company to continue studying the drug, noting the importance of finding treatments for HSDD, defined as a persistent or recurrent deficiency or absence of desire for sexual activity.
Boehringer Ingelheim has proposed that 100 mg of flibanserin, a centrally acting drug, taken orally every night at bedtime be approved for the treatment of HSDD in premenopausal women. The drug, first studied for depression, is a postsynaptic 5-HT1A agonist and 5-HT2A antagonist, and results in increases in dopamine and norepinephrine and decreases serotonin. No drug on the market has this neurotransmitter activity, according to the FDA.
In two pivotal, randomized, double-blind trials in the United States and Canada, the 100-mg dose was compared with placebo in healthy, premenopausal adult women (almost 700 patients were in each group with an average age of 35-36 years). Participants were in stable, heterosexual, monogamous relationships and were diagnosed with HSDD based on DSM–IV-TR criteria; most were white and 78% were married and had been with their partner for at least 10 years; exclusions included having a psychiatric disorder or taking a medication that could affect sexual functioning.
The primary end points were the changes from baseline in the number of Satisfying Sexual Events (SSEs), and the sexual desire score (the “eDiary Sexual Desire score), based on answers to questions answered on an online diary every day, regarding the respondent's level of sexual desire, whether she had sex, and whether it was satisfying.
The study failed to meet these two coprimary end points: After 24 weeks, the increase in SSEs was slightly less than one satisfactory event per month more than those in placebo group, in the two studies. (The increase in the mean number of SSEs over placebo was 0.8 per month in both studies.) Changes over 24 weeks in the eDiary Sexual Desire Score increased among those on flibanserin but were not significantly different from those on placebo in the two studies.
A secondary end point, the change in the total distress score on a scale measuring female sexual distress, showed a statistically significant effect of treatment over placebo.
The most common side effects of treatment were dizziness, nausea, fatigue, somnolence, insomnia, dry mouth, and anxiety. Safety concerns raised by the FDA were a higher rate of accidental injuries, syncope, and depression among those treated with the 100-mg dose, compared with lower doses in other studies and placebo, as well as the effects of hepatic impairment and coadministration with drugs that are strong CYP3A4 inhibitors on the concentration of flibanserin.
“I'm concerned about the safety signals that we saw. I'm especially concerned about the risk and the generalizability in a very heterogeneous population that would take this drug if we were to approve it,” committee member Valerie Montgomery Rice, professor of obstetrics and gynecology at Meharry Medical College, Nashville, said. She also cited doubts about generalizability of the efficacy findings to a more heterogeneous population than was studied in the pivotal trials.
The FDA usually follows the recommendations of its advisory panels. Currently, no drug is approved for HSDD, but testosterone and bupropion are used off-label for this indication.
Disclosures: Members of FDA advisory panels have been cleared of conflicts related to the topic under discussion.
Sue Sutter of Elsevier's “The Pink Sheet” contributed to this report.
'I'm especially concerned about the risk and the generalizability in a very heterogeneous population.'
Source DR. RICE