flibanserin

Flibanserin: More Than Just a “Pink Viagra”

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Attention spans are shorter than ever, so maybe it was to be expected that the media would try to tell the entire story of the FDA’s approval of Sprout Pharmaceuticals’ flibanserin on August 18, 2015, for generalized, acquired hypoactive sexual desire disorder (HSDD), with 2 words: “Pink Viagra.”1 Unfortunately, while one of those words is technically correct—the pill is pink—put together they don’t tell the story at all. Flibanserin, to be marketed beginning October 17, 2015, as Addyi, is nothing like sildenafil (Viagra). Flibanserin’s goal is different. Its administration is different. And its mechanism of action is different. Not only is the phrase misleading, but it does a disservice to our understanding of HSDD, to the newly approved treatment for it, and to the potentially millions of women across the country whose lives have been disrupted by the condition.
HSDD has been in the scientific literature since 1977.2 And while it affects 6% to 10% of US women, it still has not received the sort of attention from the scientific community as erectile dysfunction (ED) treatment, which began with the FDA approval of sildenafil 17 years ago and today includes 3 other phosphodiesterase-5 (PDE-5) inhibitors.3-5

HSDD is essentially distressing low sexual desire—distressing being the operative word.6 In the women I see, this is usually an acquired condition. That is, they had what they considered an adequate level of desire, and for some reason unknown to them, it is now diminished or completely absent. As a result, they feel significant distress. They don’t feel like themselves as a sexual being, they’re concerned about the impact of the loss of desire on their relationship, and they’re frustrated with this loss. For these women, increasing the number of “date nights” with their partners, romantic weekend getaways, or other such “cures” are useless. HSDD is biological—it is a daily state of being, is consistent, and persists for years.

There are 2 primary ways that HSDD affects a woman. First, she feels bad about herself, which can carry over into every aspect of her life—in her relationship with her partner, of course, but also in her relationship with her children, her friends, and her colleagues, because it changes her view of herself. Second, her behaviors change. Because she’s not interested in sex, she avoids her partner, so she doesn’t have to make a decision about whether to participate in sex if approached. Some women will say yes, usually out of obligation, every time their partner tries to initiate sex; others decline their partner routinely. Loss of sexual desire changes their relationship, as these women avoid the circumstances in which their partners might approach them. And their partners often respond by blaming themselves or believing she is no longer in love with or attracted to them.

Unlike PDE-5 inhibitors—ED treatments that enhance performance by increasing blood flow to the penis—flibanserin acts to correct the imbalance in the function of neurotransmitters in the brain that affect sexual desire.7,8 While the exact mechanism of action for flibanserin remains unclear, flibanserin has been found to stimulate postsynaptic 5-HT1A receptors and block postsynaptic 5-HT2A receptors in the prefrontal cortex.9 This decreases serotonin activity, which is responsible for sexual inhibition, and indirectly increases the availability of dopamine and norepinephrine, which are responsible for sexual excitement.8 In other words, flibanserin seems to reduce inhibitory effects at the same time as it enhances excitatory effects in reward circuits, leading to the generation of sexual desire. Because of these effects, flibanserin is administered as 100 mg daily at bedtime, with a gradual effect over 2 to 8 weeks.

As the first-ever FDA-approved treatment for HSDD, flibanserin is a breakthrough. It’s going to make a real difference for women because it has the potential to affect them on a daily basis. And it’s going to change my practice, as well as those of many others, since we’ve been using off-label treatments, reassurance, and other unproven interventions—the truth is, these treatments have not been effective. We will finally be able to talk to women with HSDD about a treatment that has FDA approval.

Approval from the FDA also means that patients will be bringing up the topic of their sexuality, and providers will need to understand HSDD and this new treatment option. While flibanserin is not appropriate for all patients, approval opens the door to a bigger discussion between every woman and her health care provider about sexuality and sexual health.

FDA approval also means that an accurate diagnosis of HSDD is more important than ever. More physicians will become familiar with the Decreased Sexual Desire Screener (DSDS), a highly reliable tool that was developed to provide clinicians with easy-to-use screening for the diagnosis of HSDD in women. The DSDS comprises 4 simple yes/no questions:

1. In the past, was your level of sexual desire or interest good and satisfying to you?

2. Has there been a decrease in your level of sexual desire or interest?

3. Are you bothered by your decreased level of sexual desire or interest?

4. Would you like your level of sexual desire or interest to increase?

A fifth question asks about potential factors that might be contributing to the loss of desire, such as medications, recent childbirth, a partner’s sexual problems, or dissatisfaction with one’s relationship.

Diagnostic assessment by a non–sexual medicine expert using the DSDS versus administration of a standard diagnostic interview by a sexual medicine expert demonstrated agreement in 85.2% of cases, with sensitivity of 83.6% and specificity of 87.8%.10 Providers will also need to complete online training about the risks and prescribing of flibanserin before their prescriptions will be filled by certified pharmacies, which is not currently required for use of medications to treat ED despite similar drug interactions.

Flibanserin can improve a woman’s sexual desire so that she becomes interested in sex again—50% of women who received flibanserin responded to treatment during clinical trials. Specifically, the studies showed a 53% improvement in women’s desire for sex as measured by the Female Sexual Function Index-Desire subscale; flibanserin may even restore a woman’s desire to her previously satisfying level.

Avoidant behaviors also change. The woman feels better about herself as a woman and as a sexual being, and her distress decreases (29% decrease in distress evaluated with the Female Sexual Distress Scale); she might even start initiating sexual activity again. And responders report more and better sex as measured by satisfying sexual events, which doubled with flibanserin. On every endpoint, flibanserin was statistically superior to placebo. And those changes matter: 60% of women in the clinical trials indicated the improvement they experienced was clinically meaningful to them.

The power of an established diagnosis, and of having an approved treatment, is that it empowers a woman to decide what’s right for her. She makes the decision whether her distress is high enough to take a medication, and she’s the one who decides through her own experience whether the medication has been effective for her in a way that has changed her life. While we know flibanserin has been shown to be effective in half the women who take it, not all who take it will, in the end, decide it’s right for them.11

What are the adverse effects with flibanserin? As with most CNS drugs, there are adverse effects such as nausea, dizziness, and sedation. These adverse effects are generally mitigated by the bedtime dosing of flibanserin; fewer than 13% of women who took flibanserin in the 6-month registration trials discontinued use due to adverse effects.12

Ultimately, FDA approval of flibanserin not only will help women living with HSDD in the short run, but over the long term it will open up opportunities for a deeper, richer dialogue between physicians and patients (and perhaps on a societal/cultural level). It is a first step that can lead to more research and new drugs to address this very real, very distressing condition experienced by so many women.

Dr Clayton is David C. Wilson Professor and Interim Chair of the department of psychiatry and neurobehavioral sciences at the University of Virginia Health Systems in Charlottesville, VA. She reports that she has received grants from Auspex Pharmaceuticals, Forest Research Institute, Inc, and Palatin Technologies; she is on the Advisory Board/a consultant for Forest Labs, Lundbeck, Naurex, Otsuka, Palatin Technologies, Roche, S1 Biopharmaceuticals, and Sprout Pharmaceuticals; she receives royalties/holds copyright from Ballantine Books/Random House, Changes in Sexual Function Questionnaire, and Guilford Publications; she has shares/restricted stock units in Euthymics and S1 Biopharmaceuticals, Inc. She does not stand to benefit from the approval of any drug under consideration by the FDA; and she has no promotional relationships to declare.

REFERENCES

1. US Food and Drug Administration. FDA approves first treatment for sexual desire disorder. August 18, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm. Accessed September 15, 2015.

2. Jutel A. Framing disease: the example of female hypoactive sexual desire disorder. Soc Sci Med. 2010;70:1084-1090.

3. Shifren JL, Monz BU, Russo PA, et al. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008;112:970-978.

4. Johannes CB, Clayton, AH, Odom DM, et al. Distressing sexual problems in United States women revisited: prevalence after accounting for depression. J Clin Psychiatry. 2009;70:1698-1706.

5. Caplan A. Ethical implications of drugs for erectile dysfunction. Virt Ment. 2014;16:928-931.

6. Brotto LA. The DSM diagnostic criteria for hypoactive sexual desire disorder in women. Arch Sex Behav. 2010;39:221-239.

7. Pfizer. How does VIAGRA® (sildenafil citrate) work? Accessed September 15, 2015.

8. Reviriego C. Flibanserin for female sexual dysfunction. Drugs Today. 2014;50:549.

9. Stahl S. Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder. CNS Spectr. 2015;20:1-6.

10. Clayton AH, Goldfischer ER, Goldstein I, et al. Validation of the decreased sexual desire screener (DSDS): a brief diagnostic instrument for generalized acquired female hypoactive sexual desire disorder (HSDD). J Sex Med. 2009;6:730-738.

11. Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Premenopausal Women Advisory Committee Briefing Document; 2015. Accessed September 17, 2015.

12. Addyi [package insert]. Raleigh, NC: Sprout Pharmaceuticals; 2015.

– See more at: http://www.psychiatrictimes.com/sexual-disorders/flibanserin-more-just-pink-viagra#sthash.zL5ySm0z.dpuf

‘Viagra for Women’ Wins FDA Panel Support | Medpage Today

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Mixed but strong support for so-called ‘Viagra for women’

An FDA advisory committee voted 18-6 Thursday to recommend approval for flibanserin, a drug meant to treat sexual dysfunction and loss of sexual desire in women.

The “yes” vote at the joint meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee included a requirement for “certain risk management options beyond labeling,” such as provider certification and postmarketing studies.

Flibanserin, a product of Sprout Pharmaceuticals, is proposed for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The suggested dose is a 100-mg tablet taken in the evening before bed.

Sprout Pharmaceuticals describes HSDD on its website as “a persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty.” It clarifies that diagnosis is not related to “a medical, substance-related, psychiatric (e.g., depression), or other sexual condition.”

Walid Gellad MD, MPH, of the University of Pittsburgh, voted to recommend approval of the drug, but tempered his support saying he saw its benefits as “modest” or “less than modest.” “But I think that puts it in good company with other approved drugs.”

Gellad supported a risk evaluation and management strategy (REMS) and also supported provider certification.

Michele Orza, ScD, the panel’s acting consumer representative and a senior adviser at the Patient-Centered Outcomes Research Institute, in Washington, voted against approving the drug. Orza called the treatment effect “minimal” or “marginal at best” and said she worried that as the FDA considers future products it will find that the standard is “too low and problematic.”

If You Drink, Don’t

The majority of the committee recommended a REMS strategy as well as other postmarketing studies specifically focused on use of the drug with alcohol, long-term studies to assess the drugs effects on fertility, harm to a fetus, cancer risks, and accidental injury.

In his opening statement, Hylton Joffe, MD, director of the Division of Bone, Reproductive and Urologic Products (DBRUP) acknowledged that there is an unmet need for a drug to treat HSDD. He agreed that the sponsor had met its primary endpoints in three phase III clinical trials.

Missing the Endpoint

All three trials showed “statistically significant improvement” in the number of orgasms and other satisfying sexual events (SSE) and a reduction in sex-related distress in participants taking flibanserin compared with control participants, according to FDA reviewers. The sponsor drug showed a median placebo-corrected increase of approximately 0.5-1.0 SSEs per month, from the median baseline of two to three events per month.

Neither of the first two trials demonstrated a statistically significant improvement in the secondary endpoint of sexual desire, when rated in a daily electronic diary. However, both showed a statistically significant improvement when such desire was rated using the Female Sexual Function Index (FSFI). A third trial, which used the FSFI as a co-primary endpoint for sexual desire, found the endpoint statistically significant:

“From a mean baseline of about 1.8-1.9 on the FSFI desire score, flibanserin resulted in a placebo-corrected mean increase of 0.3-0.4 (the FSFI desire score range is 1.2-6.0).”

“From a mean baseline of 3.2-3.4 on the distress score, flibanserin resulted in a placebo-corrected mean improvement of 0.3-0.4 (on a scale of 0-4).”

But the sponsor and FDA are “not in full agreement that the FSFI is optimized for assessing sexual desire,” the staff review noted. At the meeting, Ashley Slagle, MS, PhD, endpoints reviewer for FDA, said the FSFI “specifically includes multi-barrel instruction, making it unclear what components might be driving any score change, so … if one component [like fantasizing] improves but other components might not improve; it’s unclear whether a change in one single element represents meaningful change.”

Safety Concerns

Joffe also highlighted the drug’s major safety concerns: hypotension, syncope, and central nervous depression and its “sizable placebo effect.”

Some of the panel’s safety concerns centered on alcohol use while on flibanserin. The committee noted the data on alcohol use was particularly unhelpful as Sprout’s pivotal alcohol study included only two women.

Speakers for the meeting’s public hearing portion were divided on the drugs’ approval.

Lisa Larkin, MD, a women’s health internist who practices in Cincinnati, told the committee “day after day” she sees patients distressed by their sexual health concerns.

“I take real issue with those who suggest that low libido in women is always the result of relationship or situational issues, anxiety, depression, something that can always be addressed in psychotherapy or that pharma has somehow created this disorder as a niche for a drug.” She urged those who ascribe to those view to spend a day in her practice.

Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group, in Washington, D.C., questioned whether there was any new information on the drug now compared with 5 years ago, “when an FDA advisory committee voted 11-0 that the benefits did not outweigh the risks … I have concerns about exclusions in the trials and [the drug’s] minimal level of effectiveness.”

Wolfe noted that hypotension and syncope are not trivial and can result in serious, irreversible, or life-threatening injuries. “If there were clear evidence of a clinically meaningful benefit, accompanied by manageable risk, approval might be appropriate, but neither of these two is the case. I would urge the FDA to reject the drug; it isn’t ready for prime time.”