The benefits of flibanserin for women's libido are "marginal" considering its side-effects, and its approval by U.S. regulators was based on weak science, doctors say.

Flibanserin (Addyi) was twice rejected by the U.S. Food and Drug Administration as a treatment for low or "hypoactive sexual desire disorder" in premenopausal women before it was given the green light in August 2015.

Now researchers in the Netherlands have combed through five published and three unpublished studies on 5,900 women. The systematic review and meta-analysis of the drug's safety and efficacy is published in Monday's issue of JAMA Internal Medicine.

"Women do experience some sort of benefit, but the benefits are marginal and have to be seen in the light of more side-effects," study author Dr. Loes Jaspers of Erasmus University Medical Centre in Rotterdam, said in an interview.

On average, treatment with flibanserin resulted in one more satisfying sexual event, such as intercourse or masturbation, every two months, compared with those taking a placebo.

"The findings of this suggest that the benefits of flibanserin treatment are marginal," particularly when taking into account adverse events or side-effects that can occurred at the same time in about one in three women, Jaspers said.  

'The FDA approved a marginally effective drug for a non-life-threatening condition in the face of substantial and unnecessary uncertainty about its dangers.' - Dr. Steven Woloshin and Dr. Lisa Schwartz

The most common side-effects of the drug included four times higher risk of dizziness and sleepiness, double the risk of nausea and slightly less than double the risk of fatigue, the reviewers found.

Jaspers said given the current findings, she wouldn't recommend that the drug be approved in the European Union. Rather, she'd like to see more studies on women with chronic diseases and taking different types of medications before it's implemented in clinical guidelines.

"The flibanserin saga is unsatisfying," Dr. Steven Woloshin and Dr. Lisa Schwartz of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, N.H., said in  journal commentary published with the review.

"The FDA approved a marginally effective drug for a non-life-threatening condition in the face of substantial and unnecessary uncertainty about its dangers."

Woloshin said all FDA clinical reviewers, who knew the data the best, voted to reject the drug, but they were overruled by senior administrators who acknowledged the drug's limited efficacy but stressed unmet medical needs for women.

Importantly, combining flibanserin with alcohol and other common drugs can cause dangerous hypotension and syncope or fainting. The FDA required its most serious warnings, known as black box warnings, for these potential adverse events.

Public health issue

But when the FDA asked manufacturer Sprout Pharmaceuticals to submit an alcohol study, the company chose to perform it on 23 men and just two women for a drug meant for women only.

If a women takes flibanserin and alcohol with dinner and passes out driving, then the risk becomes a public health issue, Woloshin said in a journal podcast.

When Sprout resubmitted the drug to the FDA in 2015, the company provided no new data on its benefits, the commentators said.

Instead, the company launched an advocacy group, Even the Score, promoting the drug to journalists, women's groups, Congress and the FDA to push for the drug's approval saying women had no other drugs for low sexual desire.

Woloshin and Schwartz argue companies should be required to follow the FDA's advice on designing key studies, such as the alcohol one. They also want the open questions about its harms to be included front and centre in the prescribing information and advertising, instead of requiring people to seek out the information in the regulator's approval letter. 

Canadian drug company Valeant Pharmaceuticals reached a friendly deal to buy North Carolina-based Sprout Pharmaceuticals last August after the FDA approval.

Valeant's chief medical officer defended the drug option. 

The new meta-analysis confirmed earlier drug trial findings, said Dr. Tage Ramakrishna in an email. He is also the company's president of research and development quality.

"It is crucial that women suffering from [hypoactive sexual desire disorder] are able to speak to their physicians about the full range of options — including medical treatment — to manage this serious and well-established condition," Ramakrishna said.

"Analyses such as the one published in JAMA Internal Medicine, by omitting context and downplaying the importance of increased sexually satisfying events to those with HSDD, makes that conversation more difficult."

Valeant filed a regulatory application with Health Canada for the drug in the fourth quarter of 2015, a company spokeswoman said.