Varuna Srinivasan, MBBS, MPH, National Center for Health Research, May 24 2019
In 2015, the FDA approved the drug Addyi for women with low sexual desire disorder that is not due to a medical or mental health problem, medicines, drug use or relationship problems.[1] Addyi is a pill that must be taken daily, not just when a woman wants to “get in the mood.” Patients are told to take it at bedtime to be less affected by side effects.
Whereas Viagra works by increasing blood flow in the penis, Addyi works on the brain somewhat like an antidepressant. Many medical experts have pointed out that it is not clear whether Addyi works any better than placebo, and yet it has risks and is very expensive. A 2016 research review and meta-analysis of 5 published and 3 unpublished studies included almost 6000 women. This analysis found just less than one half of one more sexually satisfying encounters per month for women taking Addyi compared to placebo. However, they also found women taking Addyi had a 400% increase in the number of negative side effects such as dizziness, excessive daytime sleepiness, and nausea compared to women taking placebo, and twice as many events of fatigue. The researchers concluded that the risks outweighed the benefits and that Addyi has no meaningful benefit compared to placebo.[2] The authors recommended that women be cautious and that women with low libido are best treated with an integrative approach that emphasizes on psycho-social interventions.
So, how did this drug get on the market, and why are women paying $100- $400/month to try it?[3]
Addyi was first submitted to the FDA for approval in 2010 by the pharmaceutical company Boehringer Ingelheim.1 The drug was not approved because it failed to significantly increase daily sexual desire. Sexual desire was reported by patients using a daily electronic diary that included information on sexual activity, sexual encounters, orgasms, and desires. The second measure of effectiveness was a scale called Satisfactory Sexual Encounters (SSE) of a test called Female Sexual Function Index. On this scale, patients reported a tiny (0.8-point) increase 4 weeks after starting Addyi compared to placebo. However, the study results showed many side effects, such as low blood pressure, fatigue, dizziness and difficulty falling or staying asleep. Scientists noted that these risks increased when the drug was taken in the morning because patients were awake to experience them. 2
In order to be considered for approval, the FDA requested the company study interaction with alcohol, since the other side effects could be worsened by alcohol. Instead of doing more research, however, the original pharmaceutic company sold the patent to Sprout Pharmaceuticals in 2011. Their studies also had shortcomings. A safety study examining the effect of consuming alcohol while taking Addyi conducted by the company included only 2 women out of 25 participants, all of whom took the medication in the morning. Additionally it was also noted that the alcoholic beverages were consumed quickly (within 10 minutes). The study did not record the amount of alcohol consumed and some participants in the study required medical assistance when they took Addyi with two 5oz glasses of wine, because they experienced severe low blood pressure, with a drop in systolic BP of 28 to 54 mm Hg and a diastolic drop of 24 to 46 mm Hg. The final phase 3 clinical trials reported approximately 1 in 200 women losing consciousness (0.4%) in the Addyi group, which was twice as many as it was among those taking placebo (0.2%).1
After these additional studies, the FDA again rejected Addyi in 2013 because of safety issues. In response, Sprout Pharmaceuticals filed a dispute arguing that their data were sufficient for approval. FDA proposed that the company submit more efficacy studies to help establish a favorable risk-benefit ratio.
While resubmitting drug approval to the FDA for the third time in 2015, Sprout pharmaceuticals simultaneously started a major PR campaign called ‘Even The Score.’ The campaign prompted a wave of gender bias allegations against the FDA. Feminist groups with messages of “female empowerment” and “sexual freedom for women” put pressure on the FDA to approve the drug for women. [4]
The pressure was effective, and the FDA eventually approved the drug in 2015 based on the three efficacy trials showing a small but statistically significant 0.5-point increase per month in sexually satisfying encounters, compared to placebo. However, this was based on a 30-day electronic diary rather than a daily one; critics questioned whether a 30-day diary was as accurate as a daily one. However, FDA’s major concern was safety rather than whether the drug actually works. As a condition of approval, the company was required to have a mandatory risk evaluation & mitigation strategy (REMS) program in place to reduce risks, and to include a black box warning (FDA’s strongest warning) not to drink alcohol if a woman is taking Addyi.
Based on more recent research, FDA decided in April 2019 that women who Addyi no longer need to avoid alcohol. However, the new studies only include women drinking one or two drinks on some days but not others. The FDA still has concerns about interactions with alcohol, warning women ‘to discontinue drinking alcohol at least two hours before taking Addyi at bedtime or to skip the Addyi dose that evening.’ Women are also warned ‘to not consume alcohol at least until the morning after taking Addyi at bedtime.’ [5]
Alternatives to Addyi
In light of the questionable benefits and clear risks, what are the other options? Two non-medical options are cognitive behavioral therapy (CBT) and mindfulness meditation training. The International Consultation on Sexual Medicine published their recommendations based on a meta-analysis of 20 controlled studies looking at cognitive behavioral therapy, and strongly recommended that physicians consider CBT for women with low sexual arousal (recommendation = Grade A). They also gave a B grade recommendation for the use of mindfulness meditation training.
Other experts in the field recommend that physicians use several types of treatment when possible, after discussing options with women and their partners. [6]
Bottom line: There is no clear evidence that Addyi is effective. It is not worth the risk of serious side effects such as dizziness, loss of conscious and low blood pressure for only (on average) one more sexual satisfying event over two months! Other options are more effective.
[1] Joffe HV, Chang C, Sewell C, Easley O, Nguyen C, Dunn S, et al. FDA approval of flibanserin – treating hypoactive sexual desire disorder. N Engl J Med. 2016;374(2):101–4.
[2] Jaspers L, Feys F, Bramer WM, Franco OH, Leusink P, Laan ETM. Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women: A Systematic Review and Meta-analysis. JAMA Intern Med. 2016;176(4):453–462. doi:10.1001/jamainternmed.2015.8565
[3] The Hastings Center, Addyi Rises Again, www.thehastingscenter.org, https://www.thehastingscenter.org/addyi-rises-again/, July 11 2018.
[4] Baid, R., & Agarwal, R. (2018). Flibanserin: A controversial drug for female hypoactive sexual desire disorder. Industrial psychiatry journal, 27(1), 154–157. doi:10.4103/ipj.ipj_20_16
[5] Food and Drug Administration, FDA orders important safety labeling changes for Addyi, www.fda.gov, https://www.fda.gov/news-events/press-announcements/fda-orders-important-safety-labeling-changes-addyi, Aprill 11 2019
[6] Lori Brotto, Sandrine Atallah, Crista Johnson-Agbakwu, Talli Rosenbaum, Carmita Abdo, E. Sandra Byers, Cynthia Graham, Pedro Nobre, Kevan Wylie, Psychological and Interpersonal Dimensions of Sexual Function and Dysfunction, The Journal of Sexual Medicine, Volume 13, Issue 4, 2016, Pages 538-571, (http://www.sciencedirect.com/science/article/pii/S1743609516003052)