Flibanserin for Hypoactive Sexual Desire Disorder in Premenopausal Women

Out of the Pipeline

Flibanserin for hypoactive sexual desire disorder in premenopausal women

Richard Balon, MD

Flibanserin has libanserin, FDA-approved in August Table 1 shown moderate 2015, is the first medication approved Fast facts about flibanserin to treat acquired, generalized hypoac- efficacy in F Brand name: Addyi tive sexual desire disorder (HSDD) in pre- improving low Indication: Hypoactive sexual desire disorder menopausal women (Table 1). In clinical sexual desire, Approval date: August 2015 trials,1-4 the drug has shown modest effi- Availability date: October 2015 however, it is cacy in improving symptoms of low sexual contraindicated desire (number of satisfying sexual events Manufacturer: Sprout Pharmaceuticals with alcohol use [SSEs], sexual desire, and overall sexual Dosing forms: 100 mg tablets function). Flibanserin is not indicated to Recommended dosage: 100 mg at bedtime enhance sexual performance, for HSDD in postmenopausal women, or in men. tee hearings—mainly because of safety Clinical implications issues but also because of concerns about Flibanserin could help premenopausal efficacy. For example, during the 2013 FDA women who have distressing low sex- hearing, the results presented showed sta- ual desire, which must be acquired and tistically significant, but numerically small, generalized: treatment differences at 24 weeks compared • “Acquired low sexual desire” means with placebo. In an FDA responder analysis that a patient had an adequate sexual desire of the Phase-III trials, after accounting for that decreased or ceased for an unknown the placebo effect, approximately 8% to 13% reason. women were at least “much improved” on • “Generalized low sexual desire” means at least 1 of the primary outcomes.5 that lack of sexual desire occurs all the time Flibanserin is not indicated for women and in all situations, not only with a certain whose low sexual desire is due to (1) coex- partner or in some situations. isting medical or psychiatric condition, (2) Women taking flibanserin could expe- effects of medication or substance abuse, or rience gradually increased sexual desire, (3) a relationship problem. It is unknown increase in SSEs, and decrease of sexual whether supplemental treatment would help distress. Flibanserin is indicated for long- these patients; however, it seems reasonable Discuss this article at term use; however, it should be discontin- that combining flibanserin with psychosocial www.facebook.com/ ued after 8 weeks if the patient does not CurrentPsychiatry report any improvement in symptoms. Dr. Balon is Professor, Departments of Psychiatry and Behavioral The number needed to treat with fliban- Neurosciences and Anesthesiology, Wayne State University School of Medicine, Detroit, Michigan. He is a member of the Current Psychiatry serin likely would be rather large, but it is Editorial Board. not available because of complex outcome Disclosure measures in clinical trials. Flibanserin was The author reports no financial relationships with any company Current Psychiatry whose products are mentioned in this article or with manufacturers 60 March 2016 not approved at 2 previous FDA commit- of competing products. Out of the Pipeline

treatment, such as sex therapy or individual tration of flibanserin. This could lead to therapy, could be beneficial because it may severe hypotension and syncope; there- be difficult to disentangle sexual dysfunction fore, co-administering flibanserin with and relationship issues—2 problems that a strong CYP3A4 inhibitor is contrain- often are interwoven. dicated. Grapefruit juice is a moderate inhibitor of CYP3A4, and in a study of How it works 26 healthy females, 240 mL of grapefruit Flibanserin is a serotonin 1A receptor ago- juice increased flibanserin concentration nist and serotonin 2A receptor antagonist. In 1.4-fold. Flibanserin is excreted though vitro, flibanserin demonstrated high affinity urine and feces. Flibanserin should be taken for the following 5-HT receptors: once a day at bedtime because of sedation, • agonist activity at 5-HT1A somnolence, and possible syncope. • antagonist activity at 5-HT2A, mostly Clinical Point in the prefrontal cortex. Efficacy Flibanserin Flibanserin also has moderate antago- The efficacy of flibanserin for treating HSDD nist activities at the 5-HT2B, 5-HT2C, was established in three 24-week, random- is primarily and dopamine D4 receptors. Flibanserin ized, double-blind, placebo-controlled stud- metabolized in presumably acts centrally in the CNS; it ies (Table 2, page 62). The target population the liver by CYP3A4 has been suggested that flibanserin could in these studies was premenopausal women and to a lesser extent rebalance neural circuitry involved in pro- (mean age 36; range, 19 to 55) with acquired by CYP2C19 cessing sexual desire by reducing serotonin HSDD lasting at least 6 months (mean dura- activity and enhancing dopamine and epi- tion, approximately 5 years). The 3 studies nephrine activity. The exact mechanism of included 1,187 women who received fliban- how flibanserin improves sexual desire in serin, 100 mg at bedtime, and 1,188 women women is unknown. who received placebo. Participants were mostly white (88.6%), and included black Pharmacokinetics (9.6%) and Asian (1.5%) women. The com- Flibanserin has a mean termination pletion rates were 69% for flibanserin and half-life of approximately 11 hours. It is 78% for placebo. Some of the trials included administered once a day (50 to 100 mg) at arms with a lower dosage of flibanserin bedtime. Steady state in healthy women (25 mg and 50 mg), which are not included was achieved after 3 days. Based on clini- in this analysis. cal observations, onset of action seems to As noted in the package insert, these be gradual and reaches maximum efficacy trials each had 2 co-primary efficacy end- in approximately 8 weeks. Patients should points, SSEs and sexual desire: discontinue the drug if no improvement • change from baseline to Week 24 in the is reported after 8 weeks. Flibanserin is number of monthly SSEs (ie, sexual inter- readily absorbed from the gastrointesti- course, oral sex, masturbation, or genital nal tract; however, food slows its absorp- stimulation by the partner) tion. The drug is 98% protein (mostly • change in sexual desire from baseline albumin)-bound. to 24-week endpoint. Flibanserin is primarily metabolized in the liver by cytochrome P450 (CYP) In Study 1 and 2, change in sexual desire 3A4 and to a lesser extent by CYP2C19. from baseline to Week 24 was measured Co-administration of moderate (diltiazem, daily by using an electronic diary. Every day, erythromycin, fluconazole, fosamprenavir, patients rated their sexual desire level by verapamil) or strong (eg, ketoconazole, answering the question, “Indicate your most clarithromycin, nefazodone, ritonavir) intense level of sexual desire” from 0 (no Current Psychiatry CYP3A4 inhibitors increases the concen- desire) to 3 (strong desire). These responses Vol. 15, No. 3 61 Out of the Pipeline

Table 2 Results of clinical trials evaluating efficacy of flibanserin Study 1 Study 2 Study 3 Flibanserin Placebo Flibanserin Placebo Flibanserin Placebo (n = 280) (n = 290) (n = 365) (n = 372) (n = 532) (n = 536) Number of satisfying sexual events (per 28 days) Baseline (mean) 3.0 2.7 2.6 2.7 2.5 2.7 Change from 1.6 0.8 1.8 1.1 2.5 1.5 baseline (mean) Treatment 0.9 0.6 1.0 difference (0.3-1.4) (−0.03-1.2) (0.4-1.5) (95% CI) Clinical Point Electronic diary sexual desire Baseline (mean) 12.9 11.8 12.1 10.2 Not used Not used Flibanserin is Change from 9.1 6.9 8.3 6.7 baseline at week contraindicated 24 (mean) in patients using Treatment 2.3 1.7 difference (−0.1-4.7) (−0.5-4.0) alcohol because of (95% CI) an increased risk of FSFI Desire domain hypotension and Baseline (Mean) 1.9 1.9 1.8 1.8 1.9 1.9 syncope Change from 0.9 0.5 0.9 0.5 1.0 0.7 baseline at Week 24 (mean) Treatment 0.4 0.3 0.3 difference (0.2-0.5) (0.2-0.5) (0.2-0.4) (95% CI) FSFI: Female Sexual Function Index Source: Addyi [package insert]. Raleigh, NC: Sprout Pharmaceuticals; 2015

were totaled over a 28-day period to yield the improvement in change in monthly SSEs monthly sexual desire score, which ranged from baseline to Week 24 compared with from 0 to 84. These 2 studies also used the placebo. In Study 1 and 2, there were no Female Sexual Function Index (FSFI) Desire statistically significant differences between domain as a secondary endpoint. flibanserin and placebo for the electronic diary sexual desire endpoint. In the third Study 3 used the FSFI Desire domain, com- study, there was statistically significant prising 2 questions, as the sexual desire co- improvement in the change in sexual desire primary endpoint: using the FSFI Desire domain with flibanse- • “Over the past 4 weeks, how often rin compared with placebo. The FSFI Desire did you feel sexual desire or interest?” domain findings were consistent across all Responses ranged from 1 (almost never or 3 trials. Flibanserin was associated with a never) to 5 (almost always or always). decrease in sexual distress compared with • “Over the past 4 weeks, how would placebo in all 3 studies. you rate your level (degree) of sexual desire or interest?” Responses ranged from 1 (very Tolerability low or none at all) to 5 (very high). Flibanserin was well tolerated in the 3 clini- In all 3 trials, flibanserin was associated cal trials. As the FDA noted, clinical trials Current Psychiatry 62 March 2016 with a small, yet statistically significant, are conducted under widely varying condi- Out of the Pipeline

tions and therefore adverse reaction rates additional safety data, such as research observed in trials of flibanserin cannot be suggesting the absence of next-day driv- directly compared with those reported in ing impairment and data related to alco- clinical trials of another drug and might not hol use (the study confirming hypotension reflect rates observed in clinical practice. associated with alcohol abuse used a small The discontinuation rate due to adverse sample, and only 2 of 25 participants were reactions was 13% among patients treated women). with flibanserin, 100 mg at bedtime, and 6% among those taking placebo. The most Contraindications common side effects were somnolence, diz- Flibanserin is contraindicated in patients ziness, fatigue, nausea, insomnia, and dry using alcohol because of an increased risk mouth, which appear dose-dependent. of hypotension and syncope. A patient’s Onset of most of these adverse events was alcohol use should be evaluated before Clinical Point within 14 days after the start of treatment. administering flibanserin, and patients Flibanserin was Although hypotension and syncope should be counseled about the importance rarely were seen with flibanserin alone in of abstaining from alcohol. associated with clinical trials, these adverse events occurred Similarly, concomitant use of flibanse- a small, yet more frequently in the morning and when rin with a moderate or strong inhibitor of statistically significant, taken with alcohol and with some drugs CYP3A4 increases the concentration of improvement in (moderate or strong CYP3A4 inhibitors), flibanserin and raises the risk of hypoten- monthly satisfying and in patients with hepatic impairment. sion and syncope. Therefore, the use of a Therefore, women who drink alcohol or moderate or strong inhibitor of CYP3A4 sexual events take a moderate or strong inhibitor of in patients taking flibanserin is contraindi- CYP3A4—both of which are contraindicated. Similarly, patients with liver impair- cated—and those with hepatic impairment ment should not take this drug. should not take flibanserin. Strong CYP2C19 inhibitors (proton-pump Flibanserin should be taken at bedtime, inhibitors, selective serotonin reuptake because the risk of hypotension and syn- inhibitors, benzodiazepines, antifungals) cope is higher when flibanserin is taken could increase flibanserin exposure, which in the morning and because of associated may increase risk of hypotension, syncope, sedation and somnolence. and CNS depression. Discuss these risks with your patients; doing so is particularly Unique clinical issues important when treating women of Chinese Flibanserin is the first FDA-approved medi- heritage and some other Asian women, cation for treating HSDD. It is important to because 20% of these populations are geno- note that the drug originally was developed typic CYP2C19 poor metabolizers. as an antidepressant, but failed to show effi- Because of the increased risk of hypoten- cacy. Researchers noted that the drug was sion and syncope with alcohol use, fliban- more effective than placebo when patients serin is available only through a restricted were asked, “How strong is your sexual program under a Risk Evaluation and desire?” The focus of development then Mitigation Strategy (REMS) called the shifted to a potential treatment of HSDD. Addyi REMS Program. Flibanserin can be Flibanserin was not approved at 2 pre- prescribed or dispensed only by physicians vious FDA hearings, mainly because of and pharmacists who watch this program’s safety concerns. For the second hearing, online slide presentation and pass a compre- the manufacturer, Boehringer Ingelheim, hension test.a which sold the rights to the drug to Sprout aInformation about Addyi REMS and a list of qualified Pharmaceuticals in 2011,6 did not pres- pharmacies are available at www.AddyiREMS.com or by Current Psychiatry ent any new efficacy data, but provided calling 844-746-5745. Vol. 15, No. 3 63 continued Out of the Pipeline

Pregnant women should not take flibanserin because the effect on the fetus Related Resources • Levine SB. Flibanserin. Arch Sex Behav. 2015;44(8):2107- is unknown. Also, because the interac- 2109. tion with some oral contraceptives is • Stahl SM. Mechanism of action of flibanserin, a unknown, patients should be cautioned multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder. CNS Spectr. 2015; about unwanted pregnancy. Women who 20(1):1-6. are breastfeeding also should avoid using Drug Brand Names flibanserin because it is not known whether Cimetidine • Tagamet Fosamprenavir • Lexiva the drug is excreted in breast milk. Clarithromycin • Biaxin Ketoconazole • Nizoral Women taking flibanserin also should Diltiazem • Cardizem Nefazodone • Serzone Erythromycin • E-Mycin Ritonavir • Norvir avoid grapefruit juice, which increases fliban- Flibanserin • Addyi Verapamil • Isoptin serin levels, and avoid using herbal products, Fluconazole • Diflucan Clinical Point resveratrol, and some over-the-counter drugs Length of treatment such as cimetidine. Women who have a has not been depressive disorder also should avoid using flibanserin because their low sexual desire is References 1. Goldfisher ER, Breaux J, Katz M, et al. Continued efficacy determined, but more likely due to depression, which is not a and safety of flibanserin in premenopausal women with Hypoactive Sexual desire Disorder (HSDD): results from a patients should stop therapeutic target for the drug. randomized withdrawal trial. J Sex Med. 2011;8(11):3160- flibanserin if they do 3172. Dosing 2. Thorp J, Simon J, Dattani D, et al; DAISY trial investigators. not experience any Treatment of hypoactive sexual desire disorder in Flibanserin is provided in 100-mg film- premenopausal women: efficacy of flibanserin in the DAISY study. J Sex Med. 2012;9(3):793-804. benefit after 8 weeks coated tablets. It should be taken once a day 3. Derogatis LR, Komer L, Katz M, et al; VIOLET Trial at bedtime; titration is unnecessary. Length Investigators. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in of treatment has not been determined, but the VIOLET study. J Sex Med. 2012;9(4):1074-1085. it is recommended that patients stop fliban- 4. Katz M, DeRogatis LR, Ackerman R, et al; BEGONIA trial investigators. Efficacy of flibanserin in women serin if they do not experience any benefit with hypoactive sexual desire disorder: results from the after 8 weeks. Although there is no guidance BEGONIA trial. J Sex Med. 2013;10(7):1807-1815. in the prescribing information, the medica- 5. Gellad WF, Flynn KE, Alexander GC. Evaluation of flibanserin: science and advocacy at the FDA. JAMA. tion probably could be stopped without 2015;314(9):869-870. tapering because withdrawal effects have 6. Joffe HV, Chang C, Sewell C, et al. FDA approval of flibanserin—treating hypoactive sexual desire disorder. not been observed. N Engl J Med. 2016;374(2):101-104.

Bottom Line Flibanserin is FDA-approved for treating generalized, acquired hypoactive sexual desire disorder in premenopausal women. In clinical trials, the drug increased the number of satisfying sexual events and sexual desire, as measured by a diary and rating scales. Alcohol use and use of any moderate or strong inhibitor of cytochrome P450 3A4 are contraindicated in patients taking flibanserin because of an increased Current Psychiatry 64 March 2016 risk of hypotension and syncope.