Drug for low sexual desire carries significant harms, FDA advisers find

A committee of advisers to the US Food and Drug Administration has unanimously rejected an application to approve the drug flibanserin for low sexual desire in premenopausal women.

Last month an 11 member advisory committee found that flibanserin’s manufacturer, Boehringer Ingelheim, had failed to show overall efficacy for its drug, which caused worrying side effects, including dizziness, fainting, and accidental injury, leading to almost one in seven women dropping out of clinical trials.

Final approval rests with the FDA, although it is considered unlikely to overturn its advisers’ unanimous rejection.

An experimental drug that affects neurotransmitters, including serotonin, flibanserin previously failed in trials as an antidepressant but was recently tested in women said to have hypoactive sexual desire disorder, a condition that the manufacturer says may affect one in 10 women.

The advisory committee’s rejection follows a damning analysis of trial data by FDA staff, which found that neither of two pivotal studies “met the agreed-upon criteria for success in establishing the efficacy of flibanserin for the treatment of HSDD [hypoactive sexual desire disorder]” (www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM215437.pdf).

The FDA’s report says that the two company run trials showed that in comparison with placebo flibanserin 100 mg offered women about an extra 0.7 “satisfying sexual events” a month. On the co-primary end point of desire, as measured in an electronic diary, the drug did not show a significant difference from placebo.

FDA staff also criticised a number of aspects of the conduct of the trials and the way the company had analysed results. Their report raised concerns that many exclusion criteria would limit the results’ ability to be generalised to a broader population of women.

The report also said that during analysis of the trial results Boehringer Ingelheim had sought approval to change the way it measured the co-primary end point of desire, by switching to a questionnaire rather than using the electronic diaries. The agency rejected the company’s application to switch the end point, arguing that “failure to meet an efficacy endpoint does not constitute an acceptable reason to alter a pre-specified and agreed-upon endpoint.”

The report also found that common side effects included dizziness, nausea, fatigue, somnolence, and sedation, with nearly 15% of women taking flibanserin 100 mg discontinuing the trials because of adverse events. Importantly the report also uncovered “an increased frequency” of “significant adverse events,” including depression, accidental injury, and syncope, or fainting.

Hypoactive sexual desire disorder is a controversial condition, and a formal working group has recently proposed abandoning the term in the forthcoming edition of the Diagnostic and Statistical Manual of Mental Disorders in favour of a newly defined disorder combining arousal and interest complaints (BMJ 2010;340:c830, doi:10.1136/bmj.c830).

While rejecting approval for flibanserin, the advisory committee believed that the symptoms of the disorder were real, and it was supportive of ongoing work on this health issue.

Boehringer Ingelheim said it was disappointed at the decision but that it will work with the FDA on questions raised by the committee.