Aaron: There's been a lot in the news recently about Flibanserin, or what they're calling 'female Viagra'.  That and regular, or male Viagra, were both originally investigated as treatments for conditions other than sexual dysfunction.  Viagra came out of studies on hypertension, and female Viagra for depression, but that's where most of the similarities end. 

How so?  With the help of our intern and pharm-D student, Rachel Hoffman, let's discuss Flibanserin, sometimes called female Viagra, is the topic of this week's Healthcare Triage.

(HT Intro)

Flibanserin was in the news recently because an advisory panel recommended it for conditional approval by the FDA.  Some people don't think that should have happened.  Others think it's ridiculous that male Viagra gets approved and female Viagra might not.  So how do these drugs differ and what do the data say about Flibanserin's efficacy in improving sexual desire in women?

Viagra, or sildenafil and drugs like it are used to treat erectile dysfunction in men.  Erectile dysfunction is often a sign of declining cardiovascular health.  Clogged arteries can impede blood flow, and if there's one thing an erection needs, it's blood flow.  Erectile dysfunction occurs when a sufficient amount of blood to achieve an erection is unable to reach the corpus cavernosa, a pair of spongy tissues that span the length of the penis.  How?  Let's discuss the magic of erections.

When a man without erectile dysfunction becomes sexually aroused, nitric oxide is released into the corpus cavernosa.  The nitric oxide then activates the enzyme guanylate cyclase, resulting in an increase of cyclic guanosine monophosphate or CGMP.  The CGMP then stimulates smooth muscle relaxation in the blood vessels of the corpus cavernosa.  This relaxation of muscles allows the vessels to dilate, the corpus cavernosa then engorges with blood, and voila, an erection is born.

Viagra works by inhibiting phosphodiesterase type 5  or PDE5, an enzyme that breaks down CGMP, indirectly increasing the effect of the nitric oxide release that occurs with sexual stimulation.  Remember how Viagra came out of studies looking at hypertension?  Well, when you dilate blood vessels, blood pressure goes down.  Turns out that it also makes it easier to get an erection, so win!  Now, Viagra will have no effect if a man is not aroused.  It's important to understand that taking Viagra will not cause a spontaneous erection.  A man in question has to be in the mood to reap the benefits of the drug.  It doesn't make you want to have sex more, it just helps you with the physical erection when you do.

Flibanserin is completely different.  It's thought that it works in the brain, not the groin, to increase sexual desire.  Indviduals with little or no feelings of sexual desire may have an imbalance of excitatory and inhibitory neurotransmitters, or chemicals that regulate neural activity.  Flibanserin works by stimulating certain serotonin receptors while inhibiting others.  Specifically, it is a serotonin 1a agonist, or stimulates those, and a serotonin 2a antagonist and blocks those.  In doing so, it promotes an increase in dopamine and norepinephrine, neurotransmitters thought to stimulate sexual desire, and it causes an overall decrease in serotonin, which can inhibit sexual desire.

But as with many drugs affecting the brain, the precise mechanism of action is unknown.  There are lots of drugs we take for mental health that we're pretty much guessing what they do.  But, to recap, Viagra affects blood flow to the penis and requires preexisting feelings of sexual desire to actually work.  Flibanserin affects the brain to increase feelings of sexual desire.  So, please, stop calling Flibanserin, 'female Viagra'.  It makes pharmacology nerds very, very unhappy when you do that.  The two drugs aren't even close to the same thing. 

Another way that the drugs differ is that Viagra is taken on an as-needed basis for erectile dysfunction, meaning you can take it when you want to.  A dose of Viagra starts working within an hour and the man taking it should have an easier time achieving an erection anytime within the next 2-4 hours, should the mood strike him.  Flibanserin, however, needs to be taken every day to see an effect, and what is this effect exactly?  To the research!

Three important clinical trials examine Flibanserin's efficacy using two co-primary endpoints, the first is the female sexual function index, which asks a woman to rank her level of sexual desire on a scale of one to five over the past four weeks.  The second is a measure of satisfying sexual events, which measures the number of such events experienced within a standardized 28 day time frame.

Across the three trials, 3,548 women were randomized in placebo and control groups, with 2,310 receiving Flibanserin, and 1,238 receiving placebo.  Women in the control group took 100mg of Flibanserin every night at bedtime.  After 24 weeks, patients taking Flibanserin had a median increase of a half to one more sexually satisfying event over a 28 day period.  Scores on the Female Sexual Function Index were also statistically significantly different between groups, with women taking Flibanserin reporting an improved mean score of 0.3 to 0.4.  It's not totally clear what that means.

In comparison, a recent meta-analysis of Viagra-type drugs found that the effectiveness can vary, but the absolute differences are impressive.  Men taking placebos achieved erections somewhere between 27 and 35% of the time, compared to 67% to 89% in men taking drugs for erectile dysfunction.  The chance of achieving successful sexual intercourse went from 35% to 69%.  Those are numbers you can get your head around.  That's like an NNT of three. 

And we should also consider that, as with all drugs, Flibanserin is not without its side effects.  It's been shown to cause marked sedation, somnolence, and fatigue.  Those effects can be made worse in those who consume alcohol or take prescription medicines that may inhibit the metabolism of Flibanserin.  These include many drugs for other mental health issues, which also might be associated with decreased sexual interest. 

The first time around, in 2010, the drug was unanimously rejected by the FDA panels.  The second time, in 2013, they were told new studies would still have to be done to show the benefits outweigh the risks.  So they did more studies and added in a new and different outcome, the Female Sexual Function Index.  This time around, the results were significant, whether that's because it was a better outcome or 'cause they designed a new scale to make the study work, isn't clear. 

People have a lot of strong feelings about this drug.  Many advocacy groups believe that it's about time that a drug was approved for women to help with sexual activity.  Others feel that this is just a marketing move by a pharmaceutical company, and that the very minimal benefits might not outweigh the significant and real harms. 

I don't know the answer, but even the FDA panel didn't vote 18 to 6 like many news pieces reported.  They voted 0-18-6.  The 0 was for recommending outright approval, which no one voted for.  What was voted for was suggested approval, with steps taken to limit risks like requiring doctors to be certified to prescribe the drug, making sure that women truly fit the profile, and making sure they understood the significant side effects.  A decision may come as early as August, I don't know what it will be, or even what it should be, but I know we have to start talking about this in a way other than calling it 'female Viagra'. 

Healthcare Triage is supported in part by viewers like you, through Patreon.com, a service that allows you to support the show through a monthly donation.  We'd especially like to thank our honorary research associates, Cameron Alexander and Qadeem Salehmohamed.  Thanks, Cameron and Qadeem.  Healthcare Triage will always be free to watch and share, but your support helps make it bigger and better.