The U.S. Food and Drug Administration (FDA) approved three medications this summer that represent medical breakthroughs in the treatment of heart disease and sexual desire. Alirocumab and evolocumab are the first in an entirely new class of injectable cholesterol lowering medications known as PCSK9 inhibitors while flibanserin—also known as “Addyi”—is the first FDA approved treatment for sexual desire disorders.
A “pink pill” to enhance female sexual desire
The FDA’s approval of flibanserin two weeks ago marks the world’s first authorization of a prescription drug to treat sexual desire disorders. Addyi or the “pink pill” by Sprout Pharmaceuticals is a once-daily, non-hormonal medication authorized for the treatment of “hypoactive sexual desire disorder” in premenopausal women. While some are considering the drug’s approval the biggest breakthrough for women’s sexual health since female oral contraception, others criticize flibanserin as a “mediocre aphrodisiac” who’s adverse side effects, anticipated costs, and controversial media campaign make “it more trouble than it’s worth” (Pollack, Schulte).
Hypoactive sexual desire disorder or HSDD is estimated to affect 10% of women in the United States. It is characterized by low libido not caused by pre-existing conditions or medication side-effects. According to Dr. Leah Millheiser, director of the Female Sexual Medicine Program at Stanford, “These are women who want to have sex with their partner; they’re attracted to their partner and used to love having sex. It’s as if someone turned off the lightbulb” (Colliver).
Unlike Viagra, which increases blood flow to the genitalia to treat male erectile dysfunction, flibanserin alters levels of neurotransmitters in the brain such as dopamine and serotonin. The drug was originally developed in 2006 as an anti-depressant yet reports of increased sexual desire in women lead to its development as a treatment for HSDD (Gellad).
FDA approval with limitations
In Phase 3 clinical trials conducted by Sprout Pharmaceuticals and reviewed by the FDA, premenopausal women diagnosed with HSDD who took flibanserin daily for 24 weeks reported a 10% improvement in overall sexual satisfaction. The most commonly observed side-effects were dizziness, sleepiness, and fatigue yet severe low blood pressure (hypotension) and loss of consciousness (syncope) were also recorded. The risk of hypotension and syncope increased substantially in conjunction with alcohol use and medications classified as CYP3A4 inhibitors. Sprout also advises against patients taking Addyi in combination with certain oral contraceptives as these may increase the risk of adverse effects.
The FDA rejected flibanserin’s approval in 2010 and 2013 due to its severe side effects and limited efficacy, but indicated in their decision this year that the benefits of flibanserin as demonstrated by Sprout merited approval with appropriate monitoring. An advisory committee of external experts voted 18 to 6 in favor of acceptance on June 4, 2015, and the FDA formalized their approval on August 18, 2015.
“The FDA strives to protect and advance the health of women, and we are committed to supporting the development of safe and effective treatments for female sexual dysfunction,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER) in an August 18th FDA press release. “Because of a potentially serious interaction with alcohol, treatment with Addyi will only be available through certified health care professionals and certified pharmacies. Patients and prescribers should fully understand the risks associated with the use of Addyi before considering treatment.” Addyi will be sold to consumers with a Boxed Warning highlighting the risk of low blood pressure and fainting while physicians and pharmacists are required to complete a training course before prescribing or selling the drug. Women are also advised to discontinue the medication if they observe no effect after eight weeks.
Risks vs. Rewards
Sprout CEO Cindy Whitehead believes Addyi’s approval is a “milestone moment to celebrate.”
“There hasn’t been a whole lot of innovation in this category of women’s health since the birth control pill [in 1960],” she said in an interview with The Washington Post. “This is game-changing for women.”
Dr. Millheiser agrees, stating “This is something my patients and I have been waiting on for years” (Colliver).
Yet critics warn that Addyi’s dangerous side-effects compounded by lifestyle complications far outweigh its benefits. Many are concerned that its counter-indications with alcohol, oral contraceptives, and commonly used CYP3A4 inhibitors such as gingko herbal supplements will make it difficult for women to use the drug appropriately.
“The marginal efficacy over a substantial placebo response was too small, in my opinion, to justify the risks that were observed in this trial,” said Dr. Emilia Bagiella, a statistician who served on the FDA advisory committee and voted against Addyi’s approval. “It would be very difficult in a chronic population to ask women to stop drinking for the rest of their lives, to stop taking some drugs that they might need for the rest of their lives, to maybe not become pregnant because they want to have sex and they can’t do the two things together.”
Addyi must also be taken daily to achieve its effects, increasing the risk for potential complications and generating concerns about a prohibitive cost. Sprout indicates that they will sell Addyi at a comparable cost to erectile dysfunction drugs; about $400 per month. John LaMattina, former head of research and development at Pfizer, questions whether patients or insurance companies will be willing to foot the bill for a drug with “an annual cost close to $5,000 per patient.”
“It’s really a stretch to think that this drug will have the impact both medically and commercially that the PDE-5 inhibitors like Pfizer’s Viagra and Lily’s Cialis had,” he said in a Forbes opinion column. “Physicians will have to be convinced to prescribe Addyi [while] Insurance companies may not be willing to reimburse patients this amount of money for a drug that provides a modest benefit to the majority who take it.”
Pink vs. Blue. How Addyi compares to Viagra. Addyi photo: compraviagraitalia.ne. Viagra photo: Wikimedia.org.
Physicians and research scientists also expressed concern that the drug may be prescribed to patients beyond the target pre-menopausal group. Such usage, though controversial, is legal and doctors have already expressed interest in offering Addyi to men, post-menopausal women as well as HSDD patients that are “casual drinkers” (Pollack).
“The product, as with others, is all but certain to be used off-label among a broader population of women than has been studied…many of whom may have conditions or concomitant medication use that increases the risk of adverse events” stated Dr. Wallid Gellad in an opinion published in the Journal of the American Medical Association. Gellad also noted that the “FDA regulates drug approval and marketing, not the practice of medicine.”
Sprout Pharmaceuticals says they will delay actively marketing Addyi for 18 months to allay concerns about over-prescription (Pollack).
Is HSDD real?
Critics also question whether low libido should be considered an actual medical condition.
“Many people believe that this is just a ploy by the pharmaceutical companies to cash in on a problem that is widespread, and cannot be treated pharmacologically,” said Dr. Tami Rowen, gynecologist and clinical instructor at the University of California, San Francisco, in an interview sponsored by the University of California, Berkeley School for Public Health.
Sex researchers in the Netherlands and Belgium expressed similar concerns in a letter to the FDA that Addyi’s approval would “be based on the mistaken notion that lack of spontaneous sexual desire, absent stimuli, was abnormal” (Pollack).
Sally Greenberg, executive director of the National Consumers League and member of the Even the Score advocacy campaign, praised the FDA’s decision to approve flibanserin.
“It acknowledges that as a condition, HSDD is not simply a psychological problem or a reflection of cultural pressure on women but a biological condition that can be treated with an effective medication,” she said (Schulte).
Addyi’s approval process: marketing masquerade or quest for equality
Even the Score’s high-profile lobbying campaign is another source of controversy surrounding Addyi. After flibanserin’s second rejection by the FDA in 2013, the group, consisting of non-profit organizations including the National Consumers League and led by a Sprout consultant who formerly directed the FDA’s Office of Women’s Health, was formed with funding from Sprout Pharmaceuticals (Gellad). Even the Score advocated for flibanserin as a necessary equalizer for women’s “sexual health equity,” and “ran TV ads, lined up several members of Congress, and gathered more than 60,000 signatures to press” FDA approval of the drug (Schulte). They also accused the FDA of “gender bias” in its approval of male sexual dysfunction drugs but none for women.
While the FDA rejected the claims of gender bias, citing the difference between male sexual dysfunction and low sexual desire (for which there are no approved male treatments), former advisory committee members acknowledge that Even the Score’s advocacy efforts provided a “politically charged atmosphere” in which the FDA had to make its decision (Gellad).
The JAMA opinion letter also notes that Sprout did not present any additional efficacy or clinical trial data at the June committee meeting. In addition, the original trial data provided by the company represented a shift from the use of a daily diary rating to rank flibanserin’s affect on sexual desire to a “4-week recall of the frequency and intensity of desire” that rendered the results more statistically significant.
Adriane Fugh-Berman, a pharmacology professor at Georgetown University and director of Pharmed Out, believes Even the Score and Sprout may have unduly influenced the FDA’s approval. Pharmed Out, a program encouraging evidence-based prescribing, submitted a letter to the FDA with more than 100 signatures opposing Addyi’s approval in light of “an unprecedented and unwarranted manufacturer-funded public relations campaign” (Schulte).
“The FDA turned down this drug twice because the risks outweighed the benefits,” Berman said in an interview with The Washington Post. “The only thing that’s different is a clever, aggressive public relations campaign that Sprout Pharmaceuticals waged successfully. This opens the way for drug companies to pressure the FDA through public relations campaigns to approve more bad drugs: its bad news for rational drug approval.”
Marianne Brandon, a clinical psychologist and sex therapist in Annapolis who served on the FDA committee, disagrees. She voted for the drugs approval with a risk management strategy, stating that the benefits to patients outweighed the manageable and not uncommon risks.
“I can very confidently say to you that…clinically, these differences are extraordinarily meaningful,” she stated in comments to the advisory committee. “My patients would jump at the chance to have one other sexual event a month [and] my understanding is that the alcohol-drug interaction that we see here is fairly common with medications already on the market.” As a condition of FDA approval, Sprout Pharmaceuticals must complete three additional clinical trials to investigate Addyi’s interaction with alcohol.
Regardless of the controversy, Addyi’s approval opens the door for frank discussions about female sexual desire.
“I think this is going to change the conversation that’s taking place in medical offices across the country,” said Dr. Lauren Streicher, an associate professor of clinical obstetrics and gynecology at Northwestern University (Pollack). Dr. Millheiser agrees (Colliver).
“As a result of Viagra [approved in 1998], there was an explosion in research and understanding into what sexual dysfunction is and how we treat it,” she said. “It took 17 years to…get to this day.”
Whitehead says Addyi will be available for prescription on October 17, 2015. Palatin Technologies is also developing a female sexual desire medication with anticipated FDA submission in 2017.
References
Colliver, V. (2015, August 19). “1st ‘Viagra’ for women gains FDA approval.” San Francisco Chronicle. Retrieved from http://www.sfgate.com/nation/article/FDA-approves-first-Viagra-for-women-6451793.php
Gellad W.F. (2015). “Evaluation of Flibanserin: Science and Advocacy at the FDA.” JAMA. Retrieved from
http://jama.jamanetwork.com/article.aspx?articleid=2389384
Pollack, A. (2015, August 18). “F.D.A. approves Addyi, a libido pill for women.” The New York Times. Retrieved from http://www.nytimes.com/2015/08/19/business/fda-approval-addyi-female-viagra.html?_r=1
Schulte, B and Dennis, B. (2015, August 18). “FDA approves controversial drug for women with low sex drives.” The Washington Post. Retrieved from
http://www.washingtonpost.com/national/health-science/fda-approves-controversial-female-viagra-drug/2015/08/18/68d34eca-45f6-11e5-8e7d-9c033e6745d8_story.html
Sprout Pharmaceuticals. (2015, August 18). Sprout Pharmaceuticals Receives FDA Approval of ADDYI™ (Flibanserin 100 MG) [Press release]. Retrieved from
http://www.sproutpharma.com/sprout-pharmaceuticals-receives-fda-approval-addyi-flibanserin-100-mg/
U.S. Food and Drug Administration. (2015, August 18). FDA approves first treatment for sexual desire disorder. Retrieved from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm
Title image courtesy http://compraviagraitalia.net/notizie/index.php
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