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A peek behind the science curtain

Bethany Brookshire

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With flibanserin approval, a complicated drug takes the spotlight

Whether the “little pink pill” is a boon or a boondoggle depends on who you ask

Addyi (flibanserin)

In August, the Food and Drug Administration approved Addyi (flibanserin) for the treatment of low sexual desire in women. But whether the benefits outweigh the risks depends on who you ask.

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Ever since Viagra was first approved for men, female advocates have been waiting for their “little pink pill.” On August 18, the day arrived: Flibanserin — a failed antidepressant — received approval from the Food and Drug Administration to boost sexual desire in women. Immediately articles and blog posts were published that questioned the new drug. Some noted its low efficacy and interactions with alcohol and with other medications, and cast a leery eye at the strong advocacy associated with the drug’s approval. Supporters and some patients praised the decision, saying it opened the door for other companies to develop alternatives.

Flibanserin, soon to be marketed as Addyi, has been in clinical trials to treat low desire since the mid-2000s. It has been previously rejected by the FDA, once in 2010 over concerns of its efficacy and once again in 2013, when the FDA questioned whether the side effect risks outweighed the benefits. Sprout Pharmaceuticals appealed the decision and after additional safety studies, the drug finally got approval.

But is it beneficial? Or do the potential side effects make flibanserin not worth the risk? The answer depends a lot on who you ask.

Desire is complicated, and so is distress

It all starts with desire. “A woman’s sexual response is dynamic. It’s not amenable to a quick fix,” says Christopher Jayne, an obstetrician and gynecologist in Houston, who led one of the clinical trials of flibanserin, the “SUNFLOWER” study published in 2012 in the Journal of Sexual Medicine. “For men, 80 percent of sexual dysfunction is erectile dysfunction or premature ejaculation. We fix a physiological aspect, the erection, and we can treat erectile dysfunction.” Sexual dysfunction in women, he notes, is not so simple.

And flibanserin is no quick physiological fix. Instead, it acts on chemicals in the brain, primarily receptors for serotonin, a chemical messenger involved in mood, among many other things. While the drug’s full mechanism isn’t known, stimulation of those serotonin receptors may drive serotonin levels in reward-related areas of the brain down. This might in turn send dopamine — a neurochemical associated with feelings of reward — up.  “Dopamine and serotonin, I think of it like one makes you hot and the other makes you cold,” says Judith Volkar, an obstetrician and gynecologist at the University of Pittsburgh Medical Center. So adjusting the balance might help people feel a little, well, hotter.

The drug was approved to treat hypoactive sexual desire disorder, or HSDD. The disorder’s criteria include little to no interest in sex, few sexual thoughts or fantasies and decreased pleasure in sexual relations. Up to 10 percent of women might exhibit HSDD, according to results from a prevalence survey published in 2008, says Anita Clayton, a psychiatrist at the University of Virginia who is a consultant with Sprout and helped develop the surveys used to assess desire in the clinical trials for the drug. In that study, rates of distress over sexual desire were also linked to other factors, including mental illnesses, socio-economic status, education and poor health.

The most important criteria, says Volkar, who has no ties to Sprout or any other drug company, is whether a low libido bothers you. “If you’re going to define HSDD, you have to associate it with distress,” she says. “If someone doesn’t have interest in sex and doesn’t care, it’s not a disorder.”

But Adriane Fugh-Berman, a general practitioner based at Georgetown University in Washington, D.C., and director of PharmedOut, which speaks out against pharmaceutical marketing practices, disputes that HSDD is a valid diagnosis: “I make it a point not to memorize criteria for invented diseases.” She believes that Sprout and advocacy groups have taken symptoms that might indicate disparity between a couple’s libidos or stress from other sources and formed an illness where none really exists, noting that “there’s no scientifically validated level of libido.”

Enter flibanserin

Debates about the condition aside, Boehringer Ingelheim, the company that originally developed flibanserin, and Sprout, which acquired the drug in 2012, tested the drug in clinical trials in which 1,227 women diagnosed with HSDD received the now-approved 100-milligram dose at bedtime. After 24 weeks of treatment, 43 to 60 percent of patients saw an improvement of about nine to 14 percent over placebo, which translated to an additional 0.5 to one satisfying sexual experience per month.  The drug also increased overall ratings of desire and decreases feelings of distress compared with placebo.

But whether that one additional experience is worthwhile depends on who is having it. “That was the great debate at the FDA: Is this one sexually satisfying experience per month worth taking a medicine every day?” says John Thorp, an obstetrician and gynecologist at the University of North Carolina, Chapel Hill, who led the DAISY clinical trial for flibanserin, published in 2012 in the Journal of Sexual Medicine. “Some folks would say if you have none in a year, then once a month is great. Others would take issue. It’s also a very masculine view of sex, this counting.”

And then there are the side effects.

In a study of 1,543 people receiving the 100-mg dose, the most common side effects were dizziness (11 percent of patients), sleepiness (11 percent) and nausea (10 percent), followed closely by fatigue (nine percent). “It appears there are the fewer problems with side effects when you take 100 milligrams at bedtime,” Clayton says. The drug helps you sleep, and then “the other side effects, you’re sleeping through those.”

Side effects like these make others wonder if the benefits are worthwhile. “The benefit is less than one additional [satisfying sexual experience] per month. The drawback is one out of five people who take it have an adverse event,” says Fugh-Berman.

The drug also interacts with many others current on the market for different conditions, and has restrictions. For example, if you want to take flibanserin, don’t drink. The studies (though conducted almost entirely in men) showed that there’s a definite interaction between flibanserin and alcohol, with an increased number of side effects such as dizziness and fainting at moderate and high alcohol doses. There’s also an interaction with various medications that affect the CYP3A4 enzyme in the liver, which can includes some antidepressants (such as Prozac), progesterone-based contraceptives, cannabinoids such as marijuana and, oddly, grapefruit juice.

Because of those interactions, the FDA demanded a series of warnings on the label and risk-evaluation and mitigation strategies for providers, which means a short educational course before they are allowed to prescribe or dispense the drug. Despite these, it will probably sell well. Sprout Pharmaceuticals has expressed confidence that insurers would cover the drug, leaving patients with a co-pay of around $35 to $70 per month. But if not, Sprout has compared the price to “a month’s supply” of Viagra, which can cost close to $400 for 10 tablets without insurance.

Boon or boondoggle?

With a small benefit, potentially serious side effects and some significant drug interactions, should flibanserin have been approved at all?  Clayton says absolutely.I think they approved it based on the science,” she says. “[The FDA] appointed an advisory committee that reviewed these data, they picked people from all kinds of expertise, and their vote was 18-6 for approval.” She maintains that a small group of vocal naysayers are behind the concerns in the media. “I think people downplaying the evidence haven’t looked at the evidence.”

But Thorp, who ran one of the clinical trials for the drug, believes that advocacy groups had far more to do with the final approval than the science itself. “I think the effects are modest,” he says. “I think purely on the science they would lose. I think [the pharmaceutical company] did a brilliant job of mobilizing public opinion.”

“I think I would have reluctantly voted no,” he adds. “But I think many people of good will would have voted yes, in a sort of symbolic fashion. To show they value women’s health, they value markets investing in women’s health, that women’s sexuality is as important as male sexuality. I think it became a symbolic vote.”

But that symbol might not be a good one, cautions Fugh-Berman. “It’s not feminist to accept a lower standard of drug efficacy and safety for women than for men,” she says.

It’s definitely not the most effective drug out there, agrees Volkar. But, she notes, at least now women who are suffering severe distress will have something they can try. “It’s not necessarily a great drug,” she says. “But it’s the first drug that’s at least an option.”

It may not be the only one for long. Buspirone — a drug approved by the FDA for anxiety — has a similar profile to flibanserin. Both have their primary activity at the serotonin 1A receptor, though other receptor activities differ. And in a four-week trial, published in 1999 in the Journal of Clinical Psychopharmacology, investigators noticed that buspirone produced a significant improvement in sexual function. Another study, published in the American Journal of Psychiatry in 2000, showed similar improvements. It even has a similar side effect profile as flibanserin, with some people experiencing dizziness, somnolence and nausea. While it has been approved for anxiety, buspirone is still in phase two clinical trials for HSDD.

From committee to clinic

How popular and effective flibanserin turns out to be will be a matter for doctors and women themselves to work out. “I believe if flibanserin is going to play a role in sexual dysfunction for women, it’s going to be part of a complex approach to addressing the women’s sexual health issues,” Jayne says. “The drug alone is not going to be an answer for the majority of women.” A full treatment approach, he explains, might encompass other types of therapy, including couples counseling. But, he admits, “Realistically? Women are going to come in asking for it, and doctors are going to prescribe it.”

The biggest long-term effect probably won’t be whether flibanserin itself works for women at all. Instead, flibanserin’s approval may encourage other companies to step up and make a drug with more significant effects. Volkar hopes this will be the beginning of more and better drugs for HSDD. “I think the best thing to come out of it is that more companies will be interested,” she says. “Now we have this drug that’s a little bit beneficial, and it has some side effects, let’s see if we can get something better. That’s how we advance medicine.”

If there were any other potential drugs with greater efficacy and fewer side effects, flibanserin might have been left on the shelf entirely. To me, the hope of further investment seems a poor reason to approve a drug with such minor improvements and major expectations. People suffering from sexual disorders deserve options for treatment. And equality in treatment options is important. But if equality is what we’re after, women deserve better than this.  

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