Flibanserin Approval Not Supported by Data, Review Suggests

Diana Phillips

February 29, 2016

A review of clinical trial data looking at the safety and efficacy of a drug intended to boost female libido shows the US Food and Drug Administration approved "a marginally effective drug for a non-life-threatening condition in the face of substantial — and unnecessary — uncertainty about its dangers," according to Steven Woloshin, MD, and Lisa M. Schwartz, MD, from the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire, in an editorial that accompanies a systematic review and meta-analysis of the available evidence, both published online February 29 in JAMA Internal Medicine.

Flibanserin, also called the "pink pill," was approved by the US Food and Drug Administration last year, amid much controversy, to treat hyposexual desire disorder, or diminished libido, in premenopausal women.

Dr Woloshin and Dr Schwartz join the chorus of scientists and others claiming that the aggressive lobbying campaign by the drug manufacturer, Sprout Pharmaceuticals, overshadowed concerns about flibanserin's safety and effectiveness and contributed to its approval, despite the dearth of adequate evidence.

"While it is unclear how strongly politics influenced the decision, it is clear that the science was weak," the editorialists write, pointing to the findings from the systematic review by Loes Jaspers, MD, from the Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues.

Dr Jaspers and colleagues reviewed data from five published and three unpublished studies that enrolled 5914 women and found minimal meaningful benefit with flibanserin. Specifically, the pooled mean differences for change in satisfying sexual events (SSEs) from baseline between 100 mg flibanserin and placebo were 0.49 (95% confidence interval [CI], 0.32 - 0.67), or one half additional satisfying sexual event per month.

In other words, "women had, on average, 2.5 satisfying sexual events per before entering the study, and flibanserin added one half additional satisfying sexual experience per month," whereas the risks for certain adverse effects, including sleepiness and dizziness, increased fourfold with the drug, study coauthor Ellen T. M. Laan, PhD, from the Department of Sexology and Psychosomatic Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, the Netherlands, said in a recorded interview with JAMA Internal Medicine.

All of the studies included in the analysis were randomized, double-blind, placebo-controlled trials designed to assess the treatment effects of flibanserin in premenopausal and postmenopausal women. Yet, "the overall quality of the evidence for both efficacy and safety outcomes was very low," reflecting study design limitations, indirectness of evidence, and efficacy outcomes that were more favorable in published vs unpublished studies, the authors explain.

In addition to the number of SSEs per month, additional primary outcomes were monthly sexual desire intensity (eDiary measure of daily desire score) and the Female Sexual Function Index desire domain. Safety outcomes included any adverse events, drug-related adverse events, adverse events leading to study withdrawal, the four most common adverse events (dizziness, somnolence, nausea, and fatigue), and severe and serious adverse events.

The mean differences from baseline in eDiary desire score (only measured in studies that included premenopausal women) and Female Sexual Function Index desire were, respectively, 1.63 (95% CI, 0.45 - 2.82) and 0.27 (95% CI, 0.17 - 0.38).

"[T]he perceived minimum important difference for the SSE eDiary in postmenopausal women ranged from 0.16-1.84 per month. Hence, the mean difference for change in SSE per month in this study was also at the lower end of this spectrum," the authors write.

On the adverse event side, the risk ratio for study discontinuation resulting from adverse events was 2.19 (95% CI, 1.50 - 3.20), and the risk ratios for the four most common adverse events for the flibanserin relative to placebo were 4.00 (95% CI, 2.56 - 6.27) for dizziness, 3.97 (95% CI, 3.01 - 5.24) for somnolence, 2.35 (95% CI, 1.85 - 2.98) for nausea, and 1.64 (95% CI, 1.27 - 2.13) for fatigue.

"The absolute number of serious [adverse events] was small, and the risk ratio did not differ between flibanserin and placebo users (1.48 [95% CI, 0.91-2.41])," the authors report, noting that all other safety outcomes "showed a statistically significant difference between 100-mg flibanserin vs placebo (P < .001) in main analyses."

On the basis of their findings, the authors conclude that "the benefits of flibanserin treatment are marginal, particularly when taking into account the concurrent occurrence of [adverse events]."

The most important question, the authors stress, "concerns the clinical relevance of the statistically significant efficacy outcomes, particularly considering [adverse events] that could worsen with concurrent alcohol intake or CYP3A4 inhibitors, including oral contraceptives and fluconazole."

In light of evidence that the majority of American physicians would prescribe an approved hyposexual desire disorder drug over available nonpharmacologic options, additional studies are warranted "[b]efore flibanserin can be recommended in guidelines and clinical practice," the authors write. They note that such studies "should include women from diverse populations, particularly women with (a history of) somatic and psychological comorbidities, medication use, and surgical menopause."

Calling the approval history of flibanserin "unsatisfying," the editorialists call for "a drug approval process that delivers good decisions based on adequate evidence."

Dr Jasper and one coauthor work in ErasmusAGE, funded by Nestlé Nutrition (Nestec Ltd), and Metagenics Inc. Dr Laan was involved in the European Union study as an investigator at the Department of Sexology and Psychosomatic Obstetrics and Gynecology at the Academic Medical Center. Dr Woloshin and Dr Schwartz are cofounders of Informulary Inc.

JAMA Intern Med. Published online February 29, 2016. Article full text, Editorial full text

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