In the Journals

Addyi has limited benefit, higher risk for adverse events

A review assessing trials of Addyi found that the treatment increased the number of satisfying sexual events by less than one each month, according to findings published in JAMA Internal Medicine.

Loes Jaspers, MD, department of epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues also reported that Addyi (flibanserin, Sprout Pharmaceuticals) significantly increased the risk for various adverse events, including dizziness and nausea.

"In August 2015, the [FDA] approved flibanserin as a medical treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women," Jaspers and colleagues wrote. "Flibanserin, a 5-HT1A agonist, a 5-HT2A antagonist, and a very weak partial agonist on dopamine D4 receptors, increases levels of dopamine and norepinephrine and decreases serotonin in animal brain areas. Therefore, since dopamine and norepinephrine are thought to promote and serotonin is thought to inhibit sexual desire and arousal, it was suggested that flibanserin enhances sexual desire in HSDD."

The researchers conducted a systematic review and meta-analysis of randomized clinical trials to assess safety and efficacy. After a search of trial registries and databases, Jaspers and colleagues included eight studies in their qualitative assessment and four to seven studies in their quantitative assessment. Collectively, 5,914 women completed the trials. All of the studies were randomized, double-masked and placebo-controlled. Five had been published and three were unpublished.

Results showed that, between participants who received 100 mg flibanserin and placebo, the pooled mean difference for change in mean satisfying sexual events from baseline was 0.49 (95% CI, 0.32-0.67). In addition, the mean difference for eDiary desire score was 1.63 (95% CI, 0.45-2.82) and the mean difference for Female Sexual Function Index desire was 0.27 (95% CI, 0.17-0.38).

The researchers reported that the risk for study discontinuation due to adverse events was 2.19 (95% CI, 1.5-3.2) times higher for participants who received flibanserin compared with patients who received the placebo, including dizziness (4; 95% CI, 2.56-6.27), somnolence (3.97; 95% CI, 3.01-5.24), nausea (2.35; 95% CI, 1.85-2.98) and fatigue (1.64; 95% CI, 1.27-2.13).

Jaspers and colleagues noted that 90% of physicians in the United States indicated that they would prescribe an approved HSDD drug over currently available nonpharmacological treatments.

"The need for sound evidence on the efficacy and safety profile of flibanserin is evident," they wrote. "The findings of this review suggest that the benefits of flibanserin treatment are marginal, particularly when taking into account the concurrent occurrence of [adverse events]. It has been suggested that women with HSDD would benefit most from an integrative approach, including medical, psychiatric, psychological, couple-relationship, and sociocultural domains: the biopsychosocial model."

They also stated that future studies should include more types of participants, including diverse populations of women and women with histories of somatic and psychological comorbidities, before flibanserin is recommended in clinical practice.

In an accompanying editorial, Steven Woloshin, MD, MS, and Lisa M. Schwartz, MD, MS, both with the Center for Medicine at Media at Dartmouth Institute for Health Policy and Clinical Practice in New Hampshire, discussed the results.

"According to the FDA, about 10% more premenopausal women taking the approved dose (100 mg) of flibanserin had a meaningful benefit (ie, were "much" or "very much" improved), but flibanserin increased somnolence, sedation, or fatigue compared with placebo: 21% vs 8%.," they wrote. "Perhaps most importantly, combining flibanserin with alcohol (and other common drugs) can cause dangerous hypotension and syncope — problems so serious that the FDA put a black box warning, its most serious safety alert, on the label."

Woloshin and Schwartz said that, while it is uncertain how politics affected the FDA's certain, it is "clear that the science was weak."

"The flibanserin saga is unsatisfying," they wrote. "The FDA approved a marginally effective drug for a non–life-threatening condition in the face of substantial — and unnecessary — uncertainty about its dangers. Women with distressing sexual desire problems need good treatments. We all need a drug approval process that delivers good decisions based on adequate evidence." – by Chelsea Frajerman Pardes

Disclosures: Jaspers works in ErasmusAGE, a center for aging research funded by Nestlé Nutrition (Nestec Ltd) and Metagenics Inc. Woloshin and Schwarts are cofounders of Informulary Inc., a company that provides data about the benefits, harms, and uncertainties of prescription drugs. Please see the full studies for a complete list of all other authors' relevant financial disclosures.

A review assessing trials of Addyi found that the treatment increased the number of satisfying sexual events by less than one each month, according to findings published in JAMA Internal Medicine.

Loes Jaspers, MD, department of epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues also reported that Addyi (flibanserin, Sprout Pharmaceuticals) significantly increased the risk for various adverse events, including dizziness and nausea.

"In August 2015, the [FDA] approved flibanserin as a medical treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women," Jaspers and colleagues wrote. "Flibanserin, a 5-HT1A agonist, a 5-HT2A antagonist, and a very weak partial agonist on dopamine D4 receptors, increases levels of dopamine and norepinephrine and decreases serotonin in animal brain areas. Therefore, since dopamine and norepinephrine are thought to promote and serotonin is thought to inhibit sexual desire and arousal, it was suggested that flibanserin enhances sexual desire in HSDD."

The researchers conducted a systematic review and meta-analysis of randomized clinical trials to assess safety and efficacy. After a search of trial registries and databases, Jaspers and colleagues included eight studies in their qualitative assessment and four to seven studies in their quantitative assessment. Collectively, 5,914 women completed the trials. All of the studies were randomized, double-masked and placebo-controlled. Five had been published and three were unpublished.

Results showed that, between participants who received 100 mg flibanserin and placebo, the pooled mean difference for change in mean satisfying sexual events from baseline was 0.49 (95% CI, 0.32-0.67). In addition, the mean difference for eDiary desire score was 1.63 (95% CI, 0.45-2.82) and the mean difference for Female Sexual Function Index desire was 0.27 (95% CI, 0.17-0.38).

The researchers reported that the risk for study discontinuation due to adverse events was 2.19 (95% CI, 1.5-3.2) times higher for participants who received flibanserin compared with patients who received the placebo, including dizziness (4; 95% CI, 2.56-6.27), somnolence (3.97; 95% CI, 3.01-5.24), nausea (2.35; 95% CI, 1.85-2.98) and fatigue (1.64; 95% CI, 1.27-2.13).

Jaspers and colleagues noted that 90% of physicians in the United States indicated that they would prescribe an approved HSDD drug over currently available nonpharmacological treatments.

"The need for sound evidence on the efficacy and safety profile of flibanserin is evident," they wrote. "The findings of this review suggest that the benefits of flibanserin treatment are marginal, particularly when taking into account the concurrent occurrence of [adverse events]. It has been suggested that women with HSDD would benefit most from an integrative approach, including medical, psychiatric, psychological, couple-relationship, and sociocultural domains: the biopsychosocial model."

They also stated that future studies should include more types of participants, including diverse populations of women and women with histories of somatic and psychological comorbidities, before flibanserin is recommended in clinical practice.

In an accompanying editorial, Steven Woloshin, MD, MS, and Lisa M. Schwartz, MD, MS, both with the Center for Medicine at Media at Dartmouth Institute for Health Policy and Clinical Practice in New Hampshire, discussed the results.

"According to the FDA, about 10% more premenopausal women taking the approved dose (100 mg) of flibanserin had a meaningful benefit (ie, were "much" or "very much" improved), but flibanserin increased somnolence, sedation, or fatigue compared with placebo: 21% vs 8%.," they wrote. "Perhaps most importantly, combining flibanserin with alcohol (and other common drugs) can cause dangerous hypotension and syncope — problems so serious that the FDA put a black box warning, its most serious safety alert, on the label."

Woloshin and Schwartz said that, while it is uncertain how politics affected the FDA's certain, it is "clear that the science was weak."

"The flibanserin saga is unsatisfying," they wrote. "The FDA approved a marginally effective drug for a non–life-threatening condition in the face of substantial — and unnecessary — uncertainty about its dangers. Women with distressing sexual desire problems need good treatments. We all need a drug approval process that delivers good decisions based on adequate evidence." – by Chelsea Frajerman Pardes

Disclosures: Jaspers works in ErasmusAGE, a center for aging research funded by Nestlé Nutrition (Nestec Ltd) and Metagenics Inc. Woloshin and Schwarts are cofounders of Informulary Inc., a company that provides data about the benefits, harms, and uncertainties of prescription drugs. Please see the full studies for a complete list of all other authors' relevant financial disclosures.