Flibanserin Studies Continue: Will It Ever Become The Female Viagra?

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The libido enhancement drug flibanserin (trade name Addyi) took center stage last week after winning long-sought approval from the U.S. Food and Drug Administration (FDA). The coverage from advocates and nonbelievers has run the gamut—advice, caution, and criticism likely to confuse undecided—but curious—onlookers. But exactly how Addyi drums up sex drive is still murky.

The drug has a long backstory. It was originally investigated in 1995 by pharmacologist Franco Borsini and a team of researchers at Boehringer Ingelheim Italia in Milan as an antidepressant because of its ability to regulate neurotransmitters—the brain’s chemical-signaling molecules. In particular, the team suspected that the drug regulated three key neurotransmitters thought to influence mood: serotonin, dopamine, and norepinephrine.

A clinical trial found it did little to alleviate depression, but did seem to have an effect on mood. It just wasn’t the mood the researchers were expecting. These early trials tipped clinicians to flibanserin’s more prominent role in sexual health, as female subjects had higher scores on the Arizona Sexual Experience Scale, a survey that asks participants to rate their satisfaction on a variety of sexual health topics, like how often participants felt sexual desire and how intense that desire was.

A separate group of researchers, also at Boehringer Ingelheim, completed their first clinical trials to explore flibanserin as a libido-enhancer in 2008. They measured levels of desire through a journal-based evaluation in which subjects recorded their levels of sexual drive on a daily basis. But FDA twice concluded that the resulting increases in libido were not statistically significant, and regulators were wary of potentially dangerous side effects like dizziness, sleepiness, nausea, and fainting.

So what turned FDA’s red light green? For one: the parameters of the trials. Clinical investigator on the latest Addyi trials Sheryl Kingsberg explains that the evaluation of sexual desire in the brain is not a particularly clear-cut measurement. As the three clinical trials progressed over the course of about 8 years, so did techniques in determining desire, says Kingsberg, a reproductive biology and psychology researcher at University Hospitals Case Medical Center in Cleveland, Ohio, and consultant to Sprout Pharmaceuticals, which bought flibanserin from Boehringer Ingelheim in 2011, and was in turn purchased last week by Valeant Pharmaceuticals.

The results from the latest trials, in 2014, focused on three endpoints: sexual function index (where women answered questions about sexual experience and rated levels of sexual desire on a scale of one to five over the last 28 days), satisfied sexual events, and distress felt from a low libido. Overall, women reported about one more positive sexual experience per month, and about 10% more of the patients who took Addyi reported meaningful improvements, according to a survey of those three categories, compared with a placebo group. By these measures, FDA approved Addyi as the first drug meant to kindle desire.

Though it’s been nicknamed the “female Viagra,” the two drugs function in very different ways—Viagra aims to enhance performance whereas Addyi aims to balance chemicals in the brain that correlate to desire. Still, researchers have only a rough sense of what the drug does to the brain. Stephen Stahl, a psychologist at University of California, San Diego, and researchers from Boehinger Ingelheim wanted to clarify how it works on a chemical level.

In a 2011 paper in The Journal of Sexual Medicine that reviews previous studies of its mechanisms, they explain it in this way: Serotonin, which is thought to impede sexual interest, has two types of receptors in the brain. 5-HT1A acts like brakes for serotonin production, and 5-HT2A accelerates production.

Flibanserin works by enhancing 5-HT1A (putting on the brakes) and inhibiting 5-HT2A (stopping acceleration). Between the two, serotonin production is heavily downregulated. Additionally, flibanserin’s downregulation of serotonin decreases the firing of certain neurons thought to regulate the release of other neurotransmitters, namely, dopamine and norepinephrine (both thought to enhance sexual interest). The exact mechanism for these transient shifts in neurotransmitter levels, however, is still largely unknown.

Stahl says that these same mechanisms probably elicit the side effects that concern potential users—flibanserin’s effect on a serotonin receptor called 5-HT1A likely causes dizziness and nausea, and its effects on another, 5-HT2A, are likely linked to sleepiness. The clinical trials also showed that combining alcohol and flibanserin exacerbates these effects. Trials after the drug is on the market (slated for October) will take a closer look at how alcohol really interacts with the drug. For now, FDA has cautioned users with a black-box warning.

If you’re a woman experiencing a diminishing libido, you might be waiting anxiously for what men have enjoyed since 1998: your own version of Viagra.

For men, the little blue pill Viagra (or other brands of erectile dysfunction medicine) may be a familiar part of their medical arsenal, but for women, their own pink pill is still just a dream.

One study reports sexual dysfunction being common in women, with “a community prevalence of 30-50%.”Another study from 2002 states that sexual desire can be affected by certain female reproductive life events and experiences, including menstrual cyclehormonal contraceptives, pregnancy (particularly postpartum states and lactation), hysterectomy and both peri- and post-menopause.

And since most of us experience”singly or in combination”one or many of these events, is it any wonder that so many adult women in the United States have female hypoactive sexual desire disorder (also known as HSDD)? Basically, this means that a woman experiences a persistent or recurrent lack of thoughts about sex, sexual fantasies and/or desire for sexual activity.

A lagging libido can impact not just how you feel physically but also emotionally, affecting your quality of life. That’s the key element in diagnosing HSDD. If your lack of interest in sex causes you distress or interpersonal difficulty, then you may have HSDD. If you’re not interested in sex but you’re comfortable with that and it’s not affecting your quality of life, then you don’t have HSDD.

For those who are concerned and want a pill to fix it, where is the female Viagra?

Things were moving right along. Until they weren’t.

Flibanserin was being studied as a nonhormonal treatment for premenopausal women with low sexual desire. But it has had a rough journey—and the voyage is not yet complete.

Developed by the pharmaceutical company Boehringer Ingelheim, flibanserin has been through many vigorous clinical trials. But when the U.S. Food & Drug Administration (FDA) halted approval of the drug in 2010, asking for more research, Boehringer Ingelheim dropped its developmental efforts. Later, the rights to it were transferred to Sprout Pharmaceuticals, which is currently pursuing appeal and approval of the drug.

The drug works by increasing levels of the neurotransmitters dopamine and noradrenaline, while lowering levels of serotonin. It needs to be taken once a day, every day, and can cause side effects like fatigue, sleepiness, dizziness or nausea.

According to an article on , Sprout reported they resubmitted an application in 2013 that included 14 new clinical studies that showed data on more than 3,000 patients. More than 11,000 people have thus far participated in clinical trials for the drug, but the FDA still hasn’t approved it, characterizing the drug as having a modest effect. Sprout plans to resubmit the drug application to the FDA later this year.

Two earlier North American flibanserin studies showed a statistically significant difference between flibanserin and placebo for “satisfying sexual events,” but both of those trials failed to demonstrate a statistically significant improvement in sexual desire. Therefore, neither study proved that flibanserin met the criteria for successfully treating HSDD.

There are currently a few other drugs that are in the works to treat women’s low sexual desire, but none have completed the trials necessary to be considered by the FDA.

A quick search around the Web, shows that there are several medications, plus a whole lot of non-pharmaceutical alternatives, available to treat male sexual dysfunction. Mayo Clinic lists Viagra, Cyalis and Levitra. WebMD lists five, adding Staxyn and Stendra to the list. And then there are testosterone hormones and herbal supplements.

In a Washington Post article, Jan Shifren, director of the Midlife Women’s Health program at Massachusetts General Hospital, says: “The principal problem for men is plumbing. They don’t have low libido.” Women, she says, don’t have a problem with anatomy, but have a much more complex problem. When it comes to women, says Shifren, “I suspect there will never be a simple pill.”

Next week, I’ll bring you some information on women and sexuality from an interesting and informative lecture I attended during my recent visit to the Miraval Resort & Spa in Tucson, Arizona. As hesitant as I was to come in from the lovely warmth and sunshine, the discussion “Let’s Talk About Sex (For Women Only),” led by registered nurse and certified menopause practitioner Sheryl Brooks, gave me a lot to think about on the subject of women and libido.

I’m a 37-year-old married female with two small children, a full-time job, and not enough hours in the day. Putting my career as a journalist aside, you’re darn straight I have a lot of questions about the new female sex drive drug!

Despite being inappropriately and inaccurately hailed as the “female Viagra,” the story behind flibanserin, marketed in the ongoing tradition of bizarre drug names as Addyi, is complex. In fact, it’s about as complex as, well, the female sex drive is. And the answer to whether or not you should get a prescription for it if you’ve been feeling less libido than you’d like? That’s complex too.

Addyi is the first drug approved by the FDA for “hypoactive sexual desire disorder,” defined by the FDA as “characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance.” (I already have questions: does breastfeeding count as a “co-existing medical condition?” Wait, is it safe while breastfeeding? Sigh. Nevermind.)

The rapid post-licensure acquisition of Addyi’s manufacturer, Sprout Pharmaceuticals, by the Canadian company Valeant for $1 billion implies that Addyi is some sort of wonder drug — or, at least, that its hype is more about profit than helping women. And the evidence bears that out a bit. The drug failed to gain FDA approval twice because of questions about its effectiveness and how many women it can actually help, especially given some major side effects.

One of those side effects is a tremendous drawback that some women may not take as seriously as they need to: you cannot drink alcohol while taking Addyi — and it’s designed to be taken daily on a regular basis, not just when you want to want sex. That means total abstinence from alcohol. Since alcohol can be one hell of an effective libido enhancer for many women, how many are going to trade one for the other?

This interaction is so serious – it can cause a drop in blood pressure and fainting – that “health care professionals must assess the likelihood of the patient reliably abstaining from alcohol before prescribing Addyi,” the FDA states. The agency is requiring both doctors and pharmacists to undergo an online certification process before being allowed to prescribe or dispense the drug, and the manufacturer must conduct three additional studies on the interaction of Addyi with alcohol.

To learn more about the background of the drug, how effective it is, who might be eligible to take it and what to expect from it, I had a conversation with Dr. Karen E. Adams, clinical professor of OBGYN and Director of the Midlife Women’s Clinic at Oregon Health and Science University, who has been following the drug’s development closely and who treats many patients with concerns about their libido. [Notes in brackets are my own additions or edits.

Why is flibanserin (Addyi) controversial?

Female sexual complaints are so, so common, and some of the best data we have say that somewhere between 40% and 50% of women across the spectrum have some kind of complaint of sexual dysfunction. It’s hugely common in one form or another, and there has not been much success in drug development for that.

Part of it is that it’s so multi-factorial, and the FDA has been careful, and appropriately so, to look for evidence of safety and effectiveness. This is the third time flibanserin has come to the FDA, and it was with a new pharmaceutical company that partnered with a PR campaign by an organization named “Even the Score,” which brought politics into the whole FDA approval process.

At the hearing for the advisory committee, the Even the Score group brought in 20 women to provide testimony about the degree of suffering and how their sexual dysfunction was really affecting their lives, their relationships and their sense of well-being. The FDA was really sensitive to the charges leveled against them of gender discrimination. But it’s not all that effective, and there are some serious side effects. It was a challenge for the FDA to figure out what to do with this drug.

How serious is female sexual dysfunction and the concerns that women have regarding their libido?

It’s really prevalent across populations. I see mostly peri-menopausal and post-menopausal women but also women in their 20s and 30s as well. [Note: The best study, she said, is a 1999 study in JAMA that found 43% of women and 31% of men complained of some form of sexual dysfunction.] It is very distressful for women, and the FDA has approved the drug specifically for “a lack of sexual desire that causes distress to the woman or in her relationship.” I have a lot of patients who never have sex, and they’re okay with that. The only time it’s a problem is if it’s a problem for the woman or her partner. By definition, it’s a condition that’s causing distress.

What exactly does flibanserin (Addyi) do? How does it act on the body?

That’s what’s really interesting about this. People are hyping this as the female Viagra, but it’s really different from Viagra in a couple of important ways. Number one, Viagra works almost 100% of time for men. But only 1 in 10 women is going to benefit from flibanserin, so it’s much less effective than Viagra. Number two, Viagra works by increasing blood flow to the penis, whereas flibanserin works on neurotransmitters in the brain, almost like antidepressants. [Flibanserin is actually a failed antidepressant whose mechanism on mice was to act on serotonin in a way different than other antidepressants and to increase dopamine.

Number three, with Viagra, men just take it when they want to have sex. Women have to take flibanserin every day, and it takes about four weeks to begin to see an effect. Peak effects aren’t seen until eight weeks. How many women want to take a drug every day that affects their brain to improve their libido?

What are the possible side effects of flibanserin (Addyi)? Can you discuss the interaction with alcohol in particular?

It has pretty significant side effects. The big ones are nausea, dizziness and fainting. [According to the FDA, the “most common adverse reactions associated with the use of Addyi are dizziness, sleepiness, nausea, fatigue, insomnia and dry mouth.”] It’s designed to be taken at night. We have to be very careful not to give it to women who have conditions that could make a problem from the drug worse. Say a woman already has a blood pressure condition. Then you add this drug, and she’s fainting at work or while driving.

The FDA recently approved flibanserin, marketed as Addyi, to treat low sex drive in women.

In addition to those side effects, the risk of fainting is worse if a woman drinks alcohol or is taking a particular drug that is metabolized in the same way as flibanserin. A lot of drugs use the same liver enzyme, and one drug that I think is really relevant is Diflucan (fluconazole), used to treat yeast infections. If women take Diflucan and then take flibanserin, it’s going to interact and increase their risk of fainting.

The side effects are magnified for people who drink alcohol, so women who agree to take this medication have to agree to never drink alcohol. Probably what’s going to happen is women are going to take this drug and, after a few weeks, they’ll say, “Oh, it’s fine, so I’ll have a little glass of wine, and we’ll see.” It’s not too much of a stretch to think of women having fainting episodes in restaurants because they mixed it with alcohol. I know for my own patient population, the majority of my patients who are moderate income women, pretty educated, working and have kids, there are very few of them that don’t have a glass of wine now and then. So I think it could be a problem. It’s a risky drug in that way.

How effective is it really? How well does it work, and how many women could benefit?

That’s the other thing — in the women we think might be candidates for this drug, does it work? In the trials, they found that women at baseline were having 2.7 “sexually satisfying events” per month. Sexually satisfying events were defined as “intercourse, manual sex, oral sex, or masturbation, with or without orgasm.” Women taking the placebo went to 3.7 events per month, and women taking flibanserin went to 4.5 per month. [So, women are getting not quite one whole additional “sexually satisfying event” — potentially without orgasm — than on placebo.

These were well designed trials, and the effect seemed to be real, but it’s small, and it only occurred in about 10% of women. One could argue that what we have here is a minor aphrodisiac with scary side effects. How many women are going to be eligible for the drug and how effective are they going to feel that it is?

How much data do we have about long-term risks of using flibanserin?

We don’t have any long-term data. Any time a new drug is brought to market, it’s on the basis of short-term studies, and it remains to be seen how it’s going to be tolerated over time. Again, this drug is designed to be taken every day like an antidepressant and presumably a person would be maintained on it, so that’s an unanswered question right now.

What’s considered “normal” or typical levels of desire in women?

I spend a fair amount of time talking to my patients about what’s normal. The traditional model of sexual response (research by Masters and Johnson) is that sexual activity starts with desire, goes up through arousal, then plateaus a little bit, there is an orgasm (or several orgasms), and then there’s resolution. This is an up and down model. That actually has turned out not to be the case for most women.

Clinical trials showed flibanserin (Addyi) to be effective for only about 10% of women. Image by Bodog.com via Wikimedia Commons

In the early 2000s, researcher Rosemary Basson proposed what’s now known as the Basson Model, or what she termed “the new model of women’s sexual response.” For most women, sexual response is more of a circle, and the major point in that circle is emotional intimacy. Feeling emotionally safe with her partner makes her responsive to sexual stimuli. At that point she may begin to feel desire or arousal, which may or may not lead to orgasm. If she has a positive experience, it will bring her back around to emotional receptivity, making her more receptive the next time around. A woman can enter that circle from any point.

The reason this makes sense is that most women don’t walk around with a feeling of just free-floating desire whereas, for men, they usually do tend to have a little more of that initial desire. For women, desire will become part of it, but it’s often not the starting point. Explaining what’s normal can also be very helpful because women wonder why they’re not just thinking about sex all the time.

However, there’s an element of eroticism that has to come into it. It’s about intention and putting some energy toward it. You’re not going to get off the couch at 9:30, after work and dealing with your kids and putting them to bed, and feel like the sexiest thing on the planet. I spend time talking to my patients about sex toys, lubricants and other novelties to make sex fun again. We get out of that headspace because we’re so wrapped up in so many of our demands of our daily lives. Sex is adult play, and I think there is a whole lot that can be done for women with low sex drive. It’s so much more than just a pill.

What about women with small children or women who are breastfeeding — should they expect to have decreased libido?

You can see where evolution would favor women who don’t want to have sex while they’re nursing. One could argue that there’s some evolutionary biology at play here for a woman because it’s not going to make sense for her to be pregnant while she’s nursing. [Recall that contraception is extremely new in human history.] It may just be that there are certain times in our lives when we’re not supposed to want to have sex.

So what should a woman who is dissatisfied with her libido do?

There are three things that predict an active healthy sex life for women: one is mental health. There is a high correlation of desire complaints with things like anxiety, depression and mood disorders, so that has to be evaluated and treated. The next is physical health. For a woman who never goes to the gym or feels unattractive or out of shape, having sex can feel like working out or can just be uncomfortable. For a woman who has diabetes or MS or some other type of chronic illness, that can definitely affect her sexual life, her desire and her sexual activity.

The third one is a new relationship. The effect of longevity on sex drive is interesting. At the beginning of a relationship, a woman’s lust equals men’s. At somewhere between one and four years into a relationship, women’s desire tends to decline. It’s that hormone cocktail of romance. That feeling when you are falling in love, where you think of the person all the time and want to be with them all the time, is a phenomenon called limerence. That just doesn’t last, and it’s probably a good thing it doesn’t last. Nobody would fly airplanes or run for president because we’d all be having sex.

Limerence settles down into comfort, security and safety. When I see a woman who says, “I love my partner, but I’m just kind of not into having sex anymore,” that’s something we have to explore. We have to start thinking about effort and intention. What are they doing to prioritize sex in their relationship? A lot of this needs to be addressed in individual or couples psychotherapy. It’s really inappropriate to start with a pill. You have to look at all the potential causes of why a woman might not have a sex drive.

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