FDA rejects flibanserin for low libido in women

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).

A novel agent shown in clinical trials to improve sex drive in women has been turned down by the Food and Drug Administration, leaving clinicians with no approved treatment options for a commonly reported disorder unless a manufacturer appeal proves successful.

Flibanserin, a drug originally investigated in the 1990s as an antidepressant, was later studied as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women.

HSDD is characterized by a stress-inducing loss of sex drive without an identifiable physical or psychological cause. Flibanserin works by increasing dopamine and norepinephrine, both associated with sexual excitement, and by decreasing serotonin, which is associated with sexual inhibition. In studies, 100 mg of flibanserin daily was associated with statistically significant improvements in the number of satisfying sexual episodes per month as well as improvements in reported sexual desire over placebo, and reduction in stress associated with sexual dysfunction.

Sheryl Kingsberg, Ph.D., chief of behavioral medicine at University Hospitals Case Medical Center in Cleveland, and an investigator on some of the flibanserin research submitted to the FDA, said in an interview that there remains a "huge vacuum" in options for women with HSDD.

"For women for whom the primary loss of sexual desire is drive, which is the biological component to desire, there is nothing," she said. "For postmenopausal women for whom drive is related to declining testosterone, testosterone is an option – but off-label. There are no FDA-approved testosterone options for women."

The FDA cited concerns about flibanserin’s risks compared with its "modest" effect size, according to Sprout Pharmaceuticals, which has already moved to appeal the agency’s decision. In one manufacturer-sponsored randomized controlled trial published this year (n = 1,087), the results of which were submitted to the FDA, flibanserin was seen increasing satisfying sexual events per month by an average of 2.5, compared with 1.5 for placebo (J. Sex. Med. 2013;10:1807-15 [doi: 10.1111/jsm.12189]).

"I know the data very well, and I was convinced that it hit every endpoint," Dr. Kingsberg said. "FDA says they’re concerned about the modest efficacy in light of a risk profile not different from an SSRI [selective serotonin reuptake inhibitor], or even an antihistamine. How much more can women be expected to have in terms of number of events? Any more would push them to be having sex more than women without sexual desire problems."

To Dr. Kingsberg, the FDA’s reluctance to approve flibanserin harks back to 2004, when the FDA said it was unconvinced by the evidence in support of Intrinsa, a transdermal testosterone patch also shown to significantly increase satisfying sexual episodes per month in surgically menopausal women. Then, too, the FDA cited concerns about a modest effect size in light of risk.

In trials, the most frequently reported adverse events associated with flibanserin were somnolence, dizziness, and nausea.

Dr. James A. Simon, clinical professor of obstetrics and gynecology at George Washington University in Washington, said in an interview that he was concerned about what he considered a "double standard for men and women in the regulatory process."

Both flibanserin and the testosterone patch were shown to work in women, he noted, yet both met regulatory obstacles. Meanwhile, dozens of treatments have been approved in the past 20 years for male sexual dysfunction.

HSDD "is a common problem; it’s not a made-up issue," Dr. Simon said. "But right now all we have to try and treat it with are testosterone, some antidepressants that work on dopamine, and some drugs for restless legs syndrome. None of them is approved for this indication."

Dr. Kingsberg disclosed a consulting relationship with Sprout Pharmaceuticals. Dr. Simon disclosed he was a coauthor on several studies of flibanserin, and a former consultant for Sprout.

Dr. Jan Shifren, director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston, said that she found the FDA’s position understandable, but agreed that there appeared to be higher hurdles for women’s sexual health interventions. Dr. Shifren was an investigator in manufacturer-sponsored trials of flibanserin in postmenopausal women but does not have a consulting relationship with the company.

Testosterone replacement treatments for men received fast approval and are in widespread use, she noted, despite lingering safety concerns.

Dr. Shifren said that she was uncertain as to why flibanserin’s manufacturer would aim first to approve the drug for premenopausal women, when studies have found that women in midlife are more likely to report distress related to sexual dysfunction.

In Dr. Shifren and colleagues’ 2008 survey study (Obstet. Gynecol. 2008;112:970-8) in which they evaluated responses from more than 30,000 women, they learned that distress related to low sex drive is more commonly reported by women aged 45-64 years (14.8%) than by younger women (10.8%).