The
NEW ENGLA ND JOURNAL
of
MEDICINE
Perspective FDA Approval of Flibanserin — Treating Hypoactive Sexual Desire Disorder Hylton V. Joffe, M.D., M.M.Sc., Christina Chang, M.D., M.P.H, Catherine Sewell, M.D., M.P.H, Olivia Easley, M.D., Christine Nguyen, M.D., Somya Dunn, M.D., Kimberly Lehrfeld, Pharm.D., LaiMing Lee, Ph.D., Myong-Jin Kim, Pharm.D., Ashley F. Slagle, Ph.D., and Julie Beitz, M.D.
W
as the Food and Drug Administration (FDA) approval of flibanserin (Addyi) for treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women long overdue? Or was it an error? In the face of divergent views, we at the FDA think it’s important to clarify why flibanserin was approved after being rejected twice. HSDD is characterized by reduced sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty and is not accounted for by coexisting conditions, use of medications, or relationship problems. At a 2014 meeting, the FDA heard from some women about the condition’s effects on their sense of identity, emotional well-being, and relationships.1 Although nonpharmacologic approaches to HSDD are important, we recognized that some women could benefit from drug
therapy. Such treatments must meet the statutory standard for demonstration of effectiveness (substantial evidence from adequate, well-controlled trials) and have favorable benefit–risk profiles. Assessing flibanserin has proven challenging; the drug has been reviewed three times by the FDA and discussed twice at public advisory committee meetings. The first advisory committee, convened in 2010, unanimously recommended against approval.2 In the two phase 3 trials, one primary end point, satisfying sexual events, was achieved, but the other, daily sexual desire, was not. Although the trials showed an effect on sexual desire over the
previous 4 weeks as recalled by participants — assessed with the Female Sexual Function Index (FSFI) — the committee believed that an effect on daily recall of sexual desire was preferable and thought that results on the FSFI, a secondary end point, should not override the failure to achieve a primary end point. The committee also expressed concern about adverse effects such as somnolence and drug interactions. The FDA rejected the application and requested additional studies, including a new phase 3 trial, an alcohol-interaction study, and drug–drug interaction studies. Boehringer Ingelheim, the original applicant, completed a new phase 3 trial with the primary end points of satisfying sexual events and sexual desire as assessed by the FSFI; a secondary end point was reduction of distress related to low sexual
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1
PERS PE C T IV E
FDA Approval of Flibanserin
desire. All three were achieved, and results were consistent with previous findings. However, treatment effects in all three phase 3 trials were small (see Table 1). Major safety concerns regarding flibanserin include risks of hypotension, syncope, and central nervous system (CNS) depression (e.g., somnolence). These risks increase when the drug is taken during the day, with concomitant use of any of the numerous moderate or strong cytochrome P-450 3A4 (CYP3A4) inhibitors such as some of the antiretroviral drugs, antihypertensive drugs, antibiotics, and fluconazole (which increase systemic exposure to flibanserin by a factor of 4.5 to 7), and with alcohol use. In the alcohol-interaction study, some participants had hypotension or syncope requiring intervention, such as being placed supine or in Trendelenburg position, when they took flibanserin with the equivalent of as little as two alcoholic drinks for someone weighing 70 kg (e.g., two 5-oz glasses of wine containing 12% alcohol). These participants had systolic and diastolic blood-pressure reductions of 28 to 54 mm Hg and 24 to 46 mm Hg, respectively. The study did not definitively delineate the risk in premenopausal women who take flibanserin at bedtime because 23 of the 25 participants were men, flibanserin was administered in the morning, and alcohol was consumed rapidly (within 10 minutes). In the phase 3 trials, in which alcohol consumption was not restricted and flibanserin was taken at bedtime, the incidence of syncope was 0.4% with flibanserin and 0.2% with placebo. Although these data appear more reassuring, the extent of alcohol use during these trials was not recorded. 2
Table 1. Efficacy of Flibanserin in Three Phase 3 Trials.* End Point
Mean Baseline
Improvement over Placebo*
Satisfying sexual events
2–3/mo
0.5–1.0/mo (median)
FSFI desire (range, 1.2–6.0)
1.8–1.9
0.3–0.4
Daily desire (range, 0–84)
10–12
1.7–2.3
Distress (range, 0–4)
3.2–3.4
0.3–0.4
* Improvement data represent least-square means, unless otherwise noted. The improvement in daily desire was not statistically significant. FSFI denotes Female Sexual Function Index. For the FSFI and daily desire scales, the higher the number, the greater the sexual desire. For the distress scale, the higher the number, the greater the distress.
Because of residual concerns about the benefit–risk profile, the FDA rejected flibanserin again and requested additional data, including a study to ensure that CNS depression would not affect next-day driving performance. This rejection prompted allegations of gender bias at the FDA, based on erroneous claims that it had approved more than 20 drugs for male sexual dysfunction and none for women. (Those making such assertions included Even the Score, an advocacy campaign partly funded by Sprout Pharmaceuticals, flibanserin’s sponsor after Boehringer Ingelheim sold the rights to the drug.) The FDA rejected these claims and clarified what products had been approved (see Table 2). After completing the additional studies, Sprout submitted fliban serin for a third review. The FDA convened another advisory committee to obtain advice on the benefit–risk profile, given the new data. By a vote of 18 to 6, the committee recommended approval, though some members said it was a difficult decision. In general, those recommending approval acknowledged the small treatment effects and substantial safety concerns but considered the unmet medical need. All votes for ap-
proval were contingent on the inclusion of risk-mitigation strategies beyond labeling. After the advisory committee meeting, the FDA received requests to reject flibanserin again, citing insufficient alcohol-interaction data in women, the infeasibility of abstaining indefinitely from alcohol, drug–drug interactions, the importance of nonpharmacologic approaches to HSDD, concerns about “medicalizing” low sexual desire, and the change from HSDD to “female sexual interest/arousal disorder” (FSIAD) in the newest edition of the Diagnostic and Statistical Manual of Mental Disorders. Patients with HSDD generally meet the criteria for FSIAD if they’ve had symptoms for at least 6 months and are typically unreceptive to a partner’s attempts to initiate sexual activity, but whereas HSDD requires distress caused by low sexual desire, the definition of FSIAD includes distress caused by low sexual desire, low sexual arousal, or both. The clinical trials, and therefore the FDA, evaluated flibanserin only for treatment of HSDD. After careful consideration, the FDA followed the second advisory committee’s recommendations, concluding that efficacy had been established; although
n engl j med nejm.org
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PE R S PE C T IV E
FDA Approval of Flibanserin
Table 2. Medications for Sexual Dysfunction Approved by the FDA Prior to Flibanserin.* Disorder Dyspareunia
Women
Men
Estrogen agonist/antagonist: ospemifene
None
Estrogens: conjugated estrogens vaginal cream, synthetic conjugated B estrogens Peyronie’s disease
Not applicable
Collagenase: collagenase clostridium histolyticum
Erectile dysfunction
Not applicable
Phosphodiesterase type 5 inhibitors: silden afil citrate, tadalafil, vardenafil hydrochloride, avanafil Prostaglandin E1: alprostadil urethral suppository, alprostadil for injection
Other sexual arousal disorders
None
None
Orgasmic disorders
None
None
Sexual desire disorders
None
None
* The list excludes testosterone drugs, which are approved only for replacement therapy in men with deficient testosterone due to specific conditions, not for treatment of sexual dysfunction.3 Vardenafil hydrochloride is available as Levitra (an oral tablet) and Staxyn (an orally disintegrating tablet); alprostadil for injection is available as edex, CaverJect, and CaverJect Impulse.
the average treatment effects were small, about 10% more flibanserin-treated patients than placebo-treated patients reported clinically meaningful improvement. Assuming that the effects of the alcohol interaction in women are at least as severe as those observed in men, the FDA required a boxed warning and an alcohol contraindication. In addition, taking into account the widespread use of alcohol in the United States,4 the agency required a risk evaluation and mitigation strategy (REMS) with “elements to assure safe use” to ensure that the benefits outweigh the increased risk of hypotension and syncope with alcohol. This requirement means that only certified prescribers and pharmacies that have enrolled in the REMS program and completed training can prescribe or dispense flibanserin; prescribers must counsel patients to abstain from alcohol, using a patient–provider agreement form that both parties sign; and certified pharmacies must dispense flibanserin only to patients
with a prescription from a certified prescriber and must counsel the patient to abstain from alcohol before dispensing each prescription. As with other medications that can cause CNS depression, that risk will be managed with labeling, including a warning and a medication guide instructing patients to take flibanserin at bedtime and not to engage in activities requiring full alertness, such as driving, until at least 6 hours after taking the drug and until they know how they’re affected by it. As with other medications that have dangerous drug interactions, that risk will also be managed with labeling, including a boxed warning and a contraindication for moderate and strong CYP3A4 inhibitors, and by using existing software to screen for drug–drug interactions before flibanserin is dispensed. Not all members of the review team recommended the same regulatory action for flibanserin. Some concluded that its benefit– risk profile was unfavorable, even with the safety measures
described here, and recommended against approval.5 In their view, the observed treatment effects were offset by the potentially life-threatening hypotension, syncope, accidental injuries related to CNS depression, and the unclear clinical significance of a drug-related increase in malignant mammary tumors in female mice. They also questioned the generalizability of the phase 3 safety data to all premenopausal women likely to use flibanserin, given the trials’ extensive exclusion criteria. At a minimum, they recommended a preapproval alcohol-interaction study in women. Transparent, robust scientific discussions among FDA staff are encouraged, so that all internal viewpoints can be considered before decisions are finalized. The FDA also considered the recommendations from advisory committee members and the public, including letters both favoring and opposing approval. The agency’s approach aims to ensure that patients and prescribers know about the risks so
n engl j med nejm.org
The New England Journal of Medicine Downloaded from nejm.org on December 14, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
3
PERS PE C T IV E
FDA Approval of Flibanserin
they can make informed decisions about using flibanserin. Because HSDD is symptomatic, patients can directly assess whether any improvements they experience are worth the risks. Flibanserin should be discontinued if HSDD symptoms do not improve after 8 weeks of treatment. It’s impossible to know any drug’s full safety profile at the time of approval. Beyond the safety measures noted above, the FDA is requiring three postapproval trials to further elucidate the alcohol interaction in women, plus enhanced pharmacovigilance for hypotension, syncope, accidental injury, and death. The agency will be able to take regulatory
4
action as needed on the basis of the resulting data. We believe this is a reasonable approach that balances safety and access. Although the FDA does not regulate off-label use, we encourage responsible prescribing and emphasize that the approval is only for the population that was studied — premenopausal women with HSDD. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Food and Drug Administration, Silver Spring, MD. This article was published on December 9, 2015, at NEJM.org. 1. Food and Drug Administration. Patientfocused drug development public meeting and scientific workshop on female sexual
dysfunction, 2014 (http://www.fda.gov/Drugs/ NewsEvents/ucm401167.htm). 2. Transcript for the June 18, 2010, meeting of the Advisory Committee for Reproductive Health Drugs (http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeeting Materials/Drugs/ReproductiveHealthDrugs AdvisoryCommittee/UCM248753.pdf). 3. Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and “age-related hypogonadism” — FDA concerns. N Engl J Med 2015;373:689-91. 4. Results from the 2013 National Survey on Drug Use and Health: summary of national findings. Rockville, MD: Substance Abuse and Mental Health Administration, 2014 (http://www.samhsa.gov/data/sites/ default/files/NSDUHresultsPDFWHTML2013/ Web/NSDUHresults2013.pdf). 5. Food and Drug Administration. Addyi tablets (FDA staff reviews, REMS, labels and action letters). 2015 (http://www.accessdata .fda.gov/drugsatfda_docs/nda/2015/ 022526Orig1s000TOC.cfm). DOI: 10.1056/NEJMp1513686 Copyright © 2015 Massachusetts Medical Society.
n engl j med nejm.org
The New England Journal of Medicine Downloaded from nejm.org on December 14, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
NEW ENGLA ND JOURNAL
of
MEDICINE
Perspective FDA Approval of Flibanserin — Treating Hypoactive Sexual Desire Disorder Hylton V. Joffe, M.D., M.M.Sc., Christina Chang, M.D., M.P.H, Catherine Sewell, M.D., M.P.H, Olivia Easley, M.D., Christine Nguyen, M.D., Somya Dunn, M.D., Kimberly Lehrfeld, Pharm.D., LaiMing Lee, Ph.D., Myong-Jin Kim, Pharm.D., Ashley F. Slagle, Ph.D., and Julie Beitz, M.D.
W
as the Food and Drug Administration (FDA) approval of flibanserin (Addyi) for treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women long overdue? Or was it an error? In the face of divergent views, we at the FDA think it’s important to clarify why flibanserin was approved after being rejected twice. HSDD is characterized by reduced sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty and is not accounted for by coexisting conditions, use of medications, or relationship problems. At a 2014 meeting, the FDA heard from some women about the condition’s effects on their sense of identity, emotional well-being, and relationships.1 Although nonpharmacologic approaches to HSDD are important, we recognized that some women could benefit from drug
therapy. Such treatments must meet the statutory standard for demonstration of effectiveness (substantial evidence from adequate, well-controlled trials) and have favorable benefit–risk profiles. Assessing flibanserin has proven challenging; the drug has been reviewed three times by the FDA and discussed twice at public advisory committee meetings. The first advisory committee, convened in 2010, unanimously recommended against approval.2 In the two phase 3 trials, one primary end point, satisfying sexual events, was achieved, but the other, daily sexual desire, was not. Although the trials showed an effect on sexual desire over the
previous 4 weeks as recalled by participants — assessed with the Female Sexual Function Index (FSFI) — the committee believed that an effect on daily recall of sexual desire was preferable and thought that results on the FSFI, a secondary end point, should not override the failure to achieve a primary end point. The committee also expressed concern about adverse effects such as somnolence and drug interactions. The FDA rejected the application and requested additional studies, including a new phase 3 trial, an alcohol-interaction study, and drug–drug interaction studies. Boehringer Ingelheim, the original applicant, completed a new phase 3 trial with the primary end points of satisfying sexual events and sexual desire as assessed by the FSFI; a secondary end point was reduction of distress related to low sexual
n engl j med nejm.org
The New England Journal of Medicine Downloaded from nejm.org on December 14, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1
PERS PE C T IV E
FDA Approval of Flibanserin
desire. All three were achieved, and results were consistent with previous findings. However, treatment effects in all three phase 3 trials were small (see Table 1). Major safety concerns regarding flibanserin include risks of hypotension, syncope, and central nervous system (CNS) depression (e.g., somnolence). These risks increase when the drug is taken during the day, with concomitant use of any of the numerous moderate or strong cytochrome P-450 3A4 (CYP3A4) inhibitors such as some of the antiretroviral drugs, antihypertensive drugs, antibiotics, and fluconazole (which increase systemic exposure to flibanserin by a factor of 4.5 to 7), and with alcohol use. In the alcohol-interaction study, some participants had hypotension or syncope requiring intervention, such as being placed supine or in Trendelenburg position, when they took flibanserin with the equivalent of as little as two alcoholic drinks for someone weighing 70 kg (e.g., two 5-oz glasses of wine containing 12% alcohol). These participants had systolic and diastolic blood-pressure reductions of 28 to 54 mm Hg and 24 to 46 mm Hg, respectively. The study did not definitively delineate the risk in premenopausal women who take flibanserin at bedtime because 23 of the 25 participants were men, flibanserin was administered in the morning, and alcohol was consumed rapidly (within 10 minutes). In the phase 3 trials, in which alcohol consumption was not restricted and flibanserin was taken at bedtime, the incidence of syncope was 0.4% with flibanserin and 0.2% with placebo. Although these data appear more reassuring, the extent of alcohol use during these trials was not recorded. 2
Table 1. Efficacy of Flibanserin in Three Phase 3 Trials.* End Point
Mean Baseline
Improvement over Placebo*
Satisfying sexual events
2–3/mo
0.5–1.0/mo (median)
FSFI desire (range, 1.2–6.0)
1.8–1.9
0.3–0.4
Daily desire (range, 0–84)
10–12
1.7–2.3
Distress (range, 0–4)
3.2–3.4
0.3–0.4
* Improvement data represent least-square means, unless otherwise noted. The improvement in daily desire was not statistically significant. FSFI denotes Female Sexual Function Index. For the FSFI and daily desire scales, the higher the number, the greater the sexual desire. For the distress scale, the higher the number, the greater the distress.
Because of residual concerns about the benefit–risk profile, the FDA rejected flibanserin again and requested additional data, including a study to ensure that CNS depression would not affect next-day driving performance. This rejection prompted allegations of gender bias at the FDA, based on erroneous claims that it had approved more than 20 drugs for male sexual dysfunction and none for women. (Those making such assertions included Even the Score, an advocacy campaign partly funded by Sprout Pharmaceuticals, flibanserin’s sponsor after Boehringer Ingelheim sold the rights to the drug.) The FDA rejected these claims and clarified what products had been approved (see Table 2). After completing the additional studies, Sprout submitted fliban serin for a third review. The FDA convened another advisory committee to obtain advice on the benefit–risk profile, given the new data. By a vote of 18 to 6, the committee recommended approval, though some members said it was a difficult decision. In general, those recommending approval acknowledged the small treatment effects and substantial safety concerns but considered the unmet medical need. All votes for ap-
proval were contingent on the inclusion of risk-mitigation strategies beyond labeling. After the advisory committee meeting, the FDA received requests to reject flibanserin again, citing insufficient alcohol-interaction data in women, the infeasibility of abstaining indefinitely from alcohol, drug–drug interactions, the importance of nonpharmacologic approaches to HSDD, concerns about “medicalizing” low sexual desire, and the change from HSDD to “female sexual interest/arousal disorder” (FSIAD) in the newest edition of the Diagnostic and Statistical Manual of Mental Disorders. Patients with HSDD generally meet the criteria for FSIAD if they’ve had symptoms for at least 6 months and are typically unreceptive to a partner’s attempts to initiate sexual activity, but whereas HSDD requires distress caused by low sexual desire, the definition of FSIAD includes distress caused by low sexual desire, low sexual arousal, or both. The clinical trials, and therefore the FDA, evaluated flibanserin only for treatment of HSDD. After careful consideration, the FDA followed the second advisory committee’s recommendations, concluding that efficacy had been established; although
n engl j med nejm.org
The New England Journal of Medicine Downloaded from nejm.org on December 14, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
FDA Approval of Flibanserin
Table 2. Medications for Sexual Dysfunction Approved by the FDA Prior to Flibanserin.* Disorder Dyspareunia
Women
Men
Estrogen agonist/antagonist: ospemifene
None
Estrogens: conjugated estrogens vaginal cream, synthetic conjugated B estrogens Peyronie’s disease
Not applicable
Collagenase: collagenase clostridium histolyticum
Erectile dysfunction
Not applicable
Phosphodiesterase type 5 inhibitors: silden afil citrate, tadalafil, vardenafil hydrochloride, avanafil Prostaglandin E1: alprostadil urethral suppository, alprostadil for injection
Other sexual arousal disorders
None
None
Orgasmic disorders
None
None
Sexual desire disorders
None
None
* The list excludes testosterone drugs, which are approved only for replacement therapy in men with deficient testosterone due to specific conditions, not for treatment of sexual dysfunction.3 Vardenafil hydrochloride is available as Levitra (an oral tablet) and Staxyn (an orally disintegrating tablet); alprostadil for injection is available as edex, CaverJect, and CaverJect Impulse.
the average treatment effects were small, about 10% more flibanserin-treated patients than placebo-treated patients reported clinically meaningful improvement. Assuming that the effects of the alcohol interaction in women are at least as severe as those observed in men, the FDA required a boxed warning and an alcohol contraindication. In addition, taking into account the widespread use of alcohol in the United States,4 the agency required a risk evaluation and mitigation strategy (REMS) with “elements to assure safe use” to ensure that the benefits outweigh the increased risk of hypotension and syncope with alcohol. This requirement means that only certified prescribers and pharmacies that have enrolled in the REMS program and completed training can prescribe or dispense flibanserin; prescribers must counsel patients to abstain from alcohol, using a patient–provider agreement form that both parties sign; and certified pharmacies must dispense flibanserin only to patients
with a prescription from a certified prescriber and must counsel the patient to abstain from alcohol before dispensing each prescription. As with other medications that can cause CNS depression, that risk will be managed with labeling, including a warning and a medication guide instructing patients to take flibanserin at bedtime and not to engage in activities requiring full alertness, such as driving, until at least 6 hours after taking the drug and until they know how they’re affected by it. As with other medications that have dangerous drug interactions, that risk will also be managed with labeling, including a boxed warning and a contraindication for moderate and strong CYP3A4 inhibitors, and by using existing software to screen for drug–drug interactions before flibanserin is dispensed. Not all members of the review team recommended the same regulatory action for flibanserin. Some concluded that its benefit– risk profile was unfavorable, even with the safety measures
described here, and recommended against approval.5 In their view, the observed treatment effects were offset by the potentially life-threatening hypotension, syncope, accidental injuries related to CNS depression, and the unclear clinical significance of a drug-related increase in malignant mammary tumors in female mice. They also questioned the generalizability of the phase 3 safety data to all premenopausal women likely to use flibanserin, given the trials’ extensive exclusion criteria. At a minimum, they recommended a preapproval alcohol-interaction study in women. Transparent, robust scientific discussions among FDA staff are encouraged, so that all internal viewpoints can be considered before decisions are finalized. The FDA also considered the recommendations from advisory committee members and the public, including letters both favoring and opposing approval. The agency’s approach aims to ensure that patients and prescribers know about the risks so
n engl j med nejm.org
The New England Journal of Medicine Downloaded from nejm.org on December 14, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
3
PERS PE C T IV E
FDA Approval of Flibanserin
they can make informed decisions about using flibanserin. Because HSDD is symptomatic, patients can directly assess whether any improvements they experience are worth the risks. Flibanserin should be discontinued if HSDD symptoms do not improve after 8 weeks of treatment. It’s impossible to know any drug’s full safety profile at the time of approval. Beyond the safety measures noted above, the FDA is requiring three postapproval trials to further elucidate the alcohol interaction in women, plus enhanced pharmacovigilance for hypotension, syncope, accidental injury, and death. The agency will be able to take regulatory
4
action as needed on the basis of the resulting data. We believe this is a reasonable approach that balances safety and access. Although the FDA does not regulate off-label use, we encourage responsible prescribing and emphasize that the approval is only for the population that was studied — premenopausal women with HSDD. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Food and Drug Administration, Silver Spring, MD. This article was published on December 9, 2015, at NEJM.org. 1. Food and Drug Administration. Patientfocused drug development public meeting and scientific workshop on female sexual
dysfunction, 2014 (http://www.fda.gov/Drugs/ NewsEvents/ucm401167.htm). 2. Transcript for the June 18, 2010, meeting of the Advisory Committee for Reproductive Health Drugs (http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeeting Materials/Drugs/ReproductiveHealthDrugs AdvisoryCommittee/UCM248753.pdf). 3. Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and “age-related hypogonadism” — FDA concerns. N Engl J Med 2015;373:689-91. 4. Results from the 2013 National Survey on Drug Use and Health: summary of national findings. Rockville, MD: Substance Abuse and Mental Health Administration, 2014 (http://www.samhsa.gov/data/sites/ default/files/NSDUHresultsPDFWHTML2013/ Web/NSDUHresults2013.pdf). 5. Food and Drug Administration. Addyi tablets (FDA staff reviews, REMS, labels and action letters). 2015 (http://www.accessdata .fda.gov/drugsatfda_docs/nda/2015/ 022526Orig1s000TOC.cfm). DOI: 10.1056/NEJMp1513686 Copyright © 2015 Massachusetts Medical Society.
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