Flibanserin approved for low female sexual desire.
Conditions of the drug's third--and successful--bid for approval, however, include a risk evaluation and mitigation strategy (REMS), postmarketing research, and a boxed warning to highlight the risk of severe hypotension and syncope for some patients.
The decision adheres to the recommendations of two FDA advisory panels--the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee --which met jointly on June 4 and voted 18-6 for approval of the non-hormonal, centrally acting drug. The panels advised that additional measures beyond labeling language be put in place to address concerns about serious adverse events associated with flibanserin. Unpredictable episodes of syncope have been reported, and significant interactions with alcohol can worsen the hypotension and syncope flibanserin can cause.
Flibanserin, a mixed agonist/antagonist for serotonin and dopamine receptors, is meant to be taken orally at bedtime on a chronic basis; the dose is 100 mg. Previous applications for approval in 2009 by then-manufacturer Boehringer Ingelheim, and in 2013 by current manufacturer Sprout Pharmaceuticals, were denied.
The REMS requires that prescribers of flibanserin complete training about the risks of severe hypotension and syncope when the drug is taken with alcohol, and that a patient-provider agreement form about these risks be signed. Pharmacies also must certify with the REMS program.
Avoiding alcohol critical
The boxed warning will state that the use of alcohol is contraindicated when taking flibanserin, that it is contraindicated for those with liver impairment, and that it should not be taken with moderate or strong CYP3A4 inhibitors, which include selective serotonin reuptake inhibitors, benzodiazepines, and antifungals.
The FDA also is requiring more study of flibanserin and alcohol in women.
In a series of three phase III clinical trials in North America, premenopausal women who met the DSM-IV diagnostic criteria for hypoactive sexual desire disorder (HSDD) and who were in a stable monogamous relationship took flibanserin or placebo. Of the more than 1,200 women in each study arm, those taking flibanserin had a statistically significant improvement in the number of satisfying sexual events (SSEs) per month, and also showed a significant increase in sexual desire, though overall effect sizes were modest. Women on placebo experienced an increase of 1.5 SSEs per month, compared to 2.5 SSEs per month in those taking flibanserin.
The primary endpoint for sexual desire in the first two studies was a response on an electronic diary reporting the highest level of desire over the last 24 hours. For the final study, the primary desire endpoint was the desire domain of the Female Sexual Function Index, which asked respondents to reflect on their desire over the previous 28 days. In the third clinical trial, women taking flibanserin showed a significantly greater increase in desire than those taking placebo.
Side effects and adverse events associated with flibanserin included drowsiness, hypotension, and syncope. Since the drug is metabolized through the CYP3A4 system, the potential for drug-drug and drug-alcohol interaction exists.
These interactions and the potential for adverse events are concerning, said Dr. Adriane Fugh-Berman, associate professor of pharmacology, physiology and family medicine at Georgetown University, Washington, and director of Georgetown's Pharmed Out, a project to advance evidence-based prescribing.
"Clinical trial populations are always healthier than the general population," she said. "In some clinical trial subjects, this drug caused diastolic blood pressure to drop into the 40s. For patients with cardiovascular disease, this is very worrisome."
And Dr. Fugh-Berman noted that many medications, including commonly prescribed antidepressants and oral contraceptives, can cause a decrease in libido. "We would be doing our patients a much better service by doing a thorough medication review and referring patients for counselling," she said. "Psychosexual therapy should precede prescribing this drug."
Some factors still unaddressed
Lori A. Brotto, Ph.D., agreed that low sexual desire in women often is not "exclusively biological." "In fact, large scale, population-based studies find the pivotal role of mood, relationship quality, feelings for partner, and stress in these women's desire, and it is unlikely for flibanserin to directly address any of these factors," Dr. Brotto, of the department of obstetrics and/gynaecology at the University of British Columbia, Vancouver, said in an interview.
"That said, my hope is for the small subgroup of premenopausal women with 'acquired HSDD' who abstain from alcohol, are not using antifungal medications, and are psychologically and relationally 'healthy," flibanserin addresses their difficulty and restores their sexual desire," said Dr. Brotto, who served as text coordinator of the DSM-5's Sexual and Gender Identity Disorders Work Group.
Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, was on the FDA panel that voted in favor of flibanserin's approval. In an interview, he said he had tried to balance the need for the medication against the very real safety concerns and the relatively modest effect size.
As flibanserin hits the market, he said, "there is no doubt that the adverse events are going to be worse in real life than we saw in the trials."
On the other hand, "biology is important," said Deborah Arrindell, vice president for health policy for the American Sexual Health Association, a supporter of Even the Score, a coalition of groups that includes Sprout Pharmaceuticals and that has pushed for approval of the drug. Having a medical treatment for women with HSDD, she said, represents real progress.
Women who have concerns about their level of sexual desire will be able to work with their providers to determine if flibanserin is a medication that could help them. Approval of flibanserin, Ms. Arrindell said, signals further acknowledgment that "women have a right to sexual pleasure, and that sexual health is part of one's overall health and well-being."
Dr. Patrick J. Woodman, a urogynecologist and clinical professor at Michigan State University College of Osteopathic Medicine in East Lansing, Mich., said he plans to prescribe flibanserin for some of his patients. An increase of about one additional SSE per month doesn't sound like much, he said, but "that increase of one event can be a 100% improvement in what many women are experiencing right now."
Dr. Lisa Larkin, scientific co-chair of Even the Score, and director of the UC Women's Center in Cincinnati, applauded the FDA's decision, saying that she hopes the approval opens the pipeline to research and development for more medications for women's sexual health. Dr. Larkin, an internist with a special interest in women's health, does not receive compensation for her position with Even the Score.
"This is a landmark day," she said. "These are real women suffering from a real medical condition."
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Caption: Flibanserin, marketed as Addyi, is expected to be available by Oct. 17.
Please note: Illustration(s) are not available due to copyright restrictions.
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|Publication:||Clinical Psychiatry News|
|Date:||Sep 1, 2015|
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