Flibanserin and Female Sexual Desire

Rx Photo Pixland / thinkstockphotos.com E Editor s note: The Rx column is intended to objectively inform and report on new developments in pharmacologic treatments and medical devices. Because in many cases the products being reported on have not been on the market for an extended period, the literature cited is likely to include trials sponsored by the pharmaceutical manufacturer(s). Flibanserin and Female Sexual Desire Heidi Collins Fantasia According to the World Health Organization, sexual health is a multifaceted state of physical, emotional, mental, and social well-being in relation to sexuality, and it includes not only the absence of dysfunction but also having pleasurable sexual experiences (2015). Sexual health Abstract Female hypoactive sexual desire disorder (HSDD) is one type of sexual problem that can affect women. It is characterized by low or absent sexual desire that cannot be attributed to another cause and results in difficulty in interpersonal relationships. HSDD is not well understood, and women may not report symptoms of difficulties to their health care providers. In August 2015, the U.S. Food and Drug Administration approved flibanserin, a nonhormonal oral medication for the treatment of HSDD in premenopausal women. Flibanserin is the only currently available pharmacologic treatment for HSDD. This article will provide an overview of flibanserin, including potential adverse reactions, special considerations for use, and implications for nursing practice. http://dx.doi.org/10.1016/j.nwh.2016.03.002 Keywords female hypoactive sexual desire disorder female sexual interest/arousal disorder flibanserin nwhjournal.org 2016, AWHONN 309

Rx Heidi Collins Fantasia, PhD, RN, WHNP-BC, is an assistant professor in the College of Health Sciences, School of Nursing at the University of Massachusetts Lowell in Lowell, MA, and a nurse practitioner at Health Quarters in Beverly, MA. The author reports no conflicts of interest or relevant financial relationships. Address correspondence to: heidi_fantasia@uml.edu. disorders, including disorders of low desire, have complex etiologies that have been difficult to accurately define and treat (Nappi, 2015). Researchers have estimated that approximately 12% of women will experience some type of self-reported sexual problem in their lifetime, including problems with sexual desire (Shifren, Monz, Russo, Segreti, & Johannes, 2008). Hypoactive sexual desire disorder (HSDD) is one type of sexual problem reported by women, although the exact incidence is difficult to estimate because of lack of validated measurement Sexual health is a multifaceted state of physical, emotional, mental, and social well-being in relation to sexuality, and it includes not only the absence of dysfunction but also having pleasurable sexual experiences tools, lack of clinical experts, and reluctance of women to discuss sexual concerns with their health care providers (DeRogatis et al., 2011). Female HSDD is characterized by low or absent interest in sex that results in personal distress and difficulty within intimate relationships (American Psychiatric Association, 2013; Kingsberg & Woodard, 2015). Until recently there have been no approved pharmacologic therapies to treat HSDD in women. In August 2015, the U.S. Food and Drug Administration (FDA) approved flibanserin (Addyi, Valeant Pharmaceuticals, Laval, Quebec, Canada) as the first medication to treat HSDD in premenopausal women (FDA, 2015). This column will review flibanserin s mechanism of action and adverse effects, special considerations for use, and implication for nurses who work with women experiencing HSDD. (Note: Recent revisions to the Diagnostic and Statistical Manual of Mental Disorders [American Psychiatric Association, 2013] changed the diagnosis of HSDD to female sexual interest/ arousal disorder [Joffe et al., 2016], but for this column the term HSDD is used.) Controversy Surrounding FDA Approval The approval of the first pharmacologic treatment for HSDD in women has not been without controversy (Joffe et al., 2016). First, the prevalence of HSDD has been questioned. The prevalence of any female sexual problem has been reported at more than 40% by some researchers, although this figure is from a study that was published more than 16 years ago; the researchers did not specifically examine HSDD but instead included it among many other sexual complaints (Laumann, Paik, & Rosen, 1999). In addition to questions about the prevalence of HSDD, some health care providers have questioned whether this disorder has been created merely to sell a product and increase pharmaceutical profits (Meixel, Yanchar, & Fugh-Berman, 2015). Because there is no established norm for sexual desire, others have questioned whether HSDD is a condition that needs treatment or is a normal variant on a continuum of sexual expression and interest (Quigley, 2015). These views conflict with those of clinicians and researchers who believe that women s sexual health has been long overlooked and recognize HSDD as a prevalent condition that has not received enough attention (Kingsberg & Woodard, 2015; Nappi, 2015). An additional concern that has been raised is the possibility of off-label use in populations of women with a broader range of health conditions than were initially included in clinical trials (Gellad, Flynn, & Alexander, 2015). Women who participated in the clinical trials were excluded if they were taking multiple different medications or had pre-existing medical conditions. Therefore, to meet the criteria for HSDD and treatment with flibanserin, a woman must be experiencing symptoms of HSDD that are not caused by a pre-existing medical or psychiatric condition, medication/substance use, or difficulty within her relationship (Sprout Pharmaceuticals, Inc., 2015). Because no postmenopausal women were included in clinical trials, the FDA has approved flibanserin for use in only premenopausal women (Sprout Pharmaceuticals, Inc., 2015), thus excluding a large population of women who may be experiencing low sexual desire. When all of these criteria are considered, the population of women who are considered appropriate candidates according to the FDA approval decision becomes narrower. This increases the chance that health care providers might choose to prescribe this medication for a broader population of women than was 310 Nursing for Women s Health Volume 20 Issue 3

Photo Zeljko Bozic / thinkstockphotos.com initially intended, which may increase the risk of adverse reactions (Gellad et al., 2015). Overview of Flibanserin The exact mechanism of flibanserin in the treatment of HSDD among premenopausal women is not completely known. Flibanserin acts on serotonin and dopamine neurotransmitter systems that are involved in the sexual response system of the brain (Basson, Driscoll, & Correia, 2015; Stahl, Sommer, & Allers, 2011; Uphouse, 2014). Flibanserin initially underwent trials as an antidepressant but failed to receive FDA approval because of lack of efficacy. However, during the antidepressant drug trials it was noted that flibanserin had prosexual effects. This backward translation of side effects led to a new FDA application with the indication of flibanserin for low sexual desire (Basson et al., 2015; Gellad et al., 2015). Dosage and Administration Flibanserin is supplied as a pink oval tablet for oral use. The recommended dose of flibanserin is 100 mg at bedtime. It is recommended for bedtime use only because of risks of hypotension, syncope, somnolence, and sedation. Taking the medication during waking hours could increase the risk of injury if central nervous system symptoms were to occur during typical activities during awake-time hours such as driving, work, exercise, or other activities for which concentration and alertness are necessary. Missed doses should not be doubled or taken when the woman remembers. Instead, the next dose should be taken on the next day at bedtime (Sprout Pharmaceuticals, Adverse Reactions There are possible adverse reactions that are important to consider. The FDA has required flibanserin to carry a black box warning to highlight the most significant of these potential reactions. Hypotension, possibly resulting in syncope, has occurred. Specifically, if flibanserin is taken with alcohol, the risk of severe hypotension and syncope increases; therefore; women who are taking flibanserin must not drink any alcohol for the duration of treatment. Additional central nervous system effects may include dizziness, fatigue, and sedation (Gellard et al., 2015; Jaspers et al., 2016). During clinical trials, female mice developed malignant mammary tumors when exposed to dosages up to 10 times the recommended dosage; however, the clinical significance of this in humans is unknown (Sprout Pharmaceuticals, Drug Interactions Flibanserin interacts with medications that are classified as weak moderate CYP3A4 inhibitors and strong CYP2C19 inhibitors. Both classes of medication affect the metabolism of flibanserin and increase bioavailability, resulting in greater flibanserin levels and potentially an increase in adverse reactions, specifically hypotension and syncope. Examples of strong CYP2C19 inhibitors include protein pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, and antifungals. CYP3A4 inhibitors include oral contraceptives, cimetidine, ranitidine, fluconazole, grapefruit juice, and antibiotics such as ciprofloxacin and erythromycin (Sprout Pharmaceuticals, Contraindications In addition to the contraindications of alcohol and medications that may increase flibanserin levels, flibanserin should not be used by women with any hepatic impairment, even mild. Elevated flibanserin levels have occurred in women with hepatic impairment, and this has the potential to increase the risk of adverse events such as hypotension and syncope (Sprout Pharmaceuticals, Special Populations Flibanserin is approved for use in premenopausal women. There are no human data on safety in pregnancy. In animal studies fetal toxicity occurred during episodes of maternal toxicity from higher-than-recommended dosages. Animal models may not accurately reflect human safety or harm. Flibanserin is not recommended for pediatric or geriatric use and is not indicated for use during and after the menopause transition. Flibanserin is excreted in animal milk, but data are lacking on human milk. Because of the possibility of drug excretion in human milk and potential sedative effects on the infant, flibanserin is not recommended during lactation (Sprout Pharmaceuticals, Rx June July 2016 Nursing for Women s Health 311

Rx Implications for Nurses Diagnosing HSDD is challenging, and nurses must recognize that women may have experienced symptoms of this disorder for years before seeking treatment. Women with HSDD may report a variety of symptoms, including absent or low interest in or desire for sex and/ or inability to respond to sexual stimuli despite describing a healthy relationship with their partner (Kingsberg & Woodard, 2015). Women may feel frustrated and embarrassed and not sure of how to discuss their concerns with their health care provider. It is important to establish a nonjudgmental and supportive environment to facilitate taking a prescription that is dispensed (Sprout Pharmaceuticals, Nurses can help women locate a participating pharmacy and should be aware that it may not be the same pharmacy where a woman s other prescriptions are filled (see Box 1). Education about the risks of using alcohol while taking flibanserin is extremely important. No safe level of alcohol has been established during treatment with flibanserin. It is Education about the risks of using alcohol while taking flibanserin is extremely important complete sexual history and full symptom disclosure (Kingsberg & Woodard, 2015). Because of the potential risk for serious adverse reactions that could result in injury, flibanserin can be prescribed only by health care providers who have participated in pharmaceutical company sponsored training, have completed a knowledge assessment, and have enrolled in the Risk Evaluation and Management Strategy program. The Risk Evaluation and Management Strategy program was a condition necessary for FDA approval of flibanserin (Gellad et al., 2015). Additionally, pharmacies must also complete a similar program, train all pharmacy staff, and counsel women about the risk of alcohol use with each Box 1. Participating Pharmacies important to assess baseline alcohol use and whether abstaining from alcohol for the duration of treatment is possible. A patient provider agreement form has been developed for health care providers and is available at https:// www.addyirems.com/addyiui/rems/pdf/ Flibanserin is available only through a restricted Risk Evaluation and Management Strategy program. Not every pharmacy participates in this program. A list of participating pharmacies can be found at www.addyirems.com or by calling 1-844-746-5745. Photo istock Collection / thinkstockphotos.com 312 Nursing for Women s Health Volume 20 Issue 3

addyiremsprogrampatientprovider- AgreementForm.pdf (Sprout Pharmaceuticals, This form should be signed by the woman and her health care provider. A copy should be placed in the health record and the informational section given to the woman for reference. Even with education, prescribing restrictions, and agreement forms, concern has been raised regarding whether all women taking flibanserin will be able to completely abstain from alcohol during treatment. Because all adverse effects are not currently known, including all the risks that may be associated with combining flibanserin with alcohol, additional postapproval trials will be conducted (Joffe et al., 2016). Nurses caring for women taking flibanserin should evaluate any knowledge deficits; review understanding of alcohol risks; and discuss signs and symptoms of hypotension, including dizziness, lightheadedness, and syncope. To avoid the potential for injury, women who are experiencing these symptoms should be educated to lie down if possible, seek emergency medical help if the symptoms are severe or do not resolve, and always seek help if the symptoms are associated with a loss of consciousness. Additionally, specific instructions on how to take the medication need to be reviewed. Flibanserin must only be taken at bedtime, so that if hypotension occurs the woman is already lying down or sleeping, which may reduce the chance for falls and injury. Any known or suspected adverse events should be reported to the FDA through the adverse event reporting program (see Box 2). Nurses should review all current prescription and nonprescription medications (including herbal medications and supplements) with women who are considering treatment with flibanserin, because multiple medications have the potential to interact with flibanserin and result in increased bioavailability and adverse events. Women who Box 2. Reporting Adverse Events All health care providers are encouraged to report actual or suspected adverse events to www.fda.gov/medwatch or 1-800-FDA-1088. are taking flibanserin should discuss all their medications (prescription, over the counter, supplements) with their health care provider to identify possible drug interactions. Decisions about whether to begin or continue treatment with flibanserin if use will occur concurrently with medications that have known interactions should be made on an individual basis. It is not fully known how flibanserin works to increase sexual desire, and it may not work for all women. Education should be provided regarding overall efficacy and treatment expectations. In clinical trials women who took flibanserin reported 0.5 to 1.0 more satisfying sexual event per month compared with women in the placebo group, which is a relatively small clinical improvement (Basson et al., 2015). A recent review by Jaspers et al. (2016) concluded that treatment with flibanserin resulted in, on average, one half additional satisfying sexual event per month. A therapeutic effect should be seen after 8 weeks of treatment. Women should be aware that if there is no improvement in symptoms after 8 weeks, then the medication will be discontinued. Increasing the dosage is not an option because of the increased risk of adverse events when the dosage of flibanserin Nurses should review all current prescription and nonprescription medications (including herbal medications and supplements) with women who are considering treatment with flibanserin, because multiple medications have the potential to interact with flibanserin and result in increased bioavailability and adverse events exceeds 100 mg/day (Sprout Pharmaceuticals, Women must understand that for a therapeutic effect to occur, flibanserin must be taken every night; it is not an as needed medication or a female equivalent to medication for male erectile dysfunction. Additionally, women should be advised that in addition to pharmacologic treatment, nonpharmacologic therapies for female sexual dysfunction can be considered, including individual counseling, behavioral and couples therapy, diet and lifestyle modifications, and complementary and alternative therapies such as mindfulness, yoga, and acupuncture (Bradway & Boullata, 2014). As with all new medications, flibanserin will most likely become a toptier (i.e., high-copay) medication for women who have prescription coverage as part of their health insurance. Through December 2016 women may be able to reduce copay costs further through a program offered by Sprout Pharmaceuticals. If women already have health insurance with coverage for prescription medication and meet additional eligibility requirements set forth by the manufacturer, they may be able to obtain a 30-day supply of flibanserin for as low as $20 for a limited number June July 2016 Nursing for Women s Health 313

of months. This benefit does not apply to women without commercial health insurance. Out-of-pocket expenses for 30 tablets of flibanserin could be as high as $800 based on early estimates from the manufacturer. Full details of this program and potential costs can be found at www.addyi.com. Conclusion Although the FDA approval of flibanserin represents a new treatment option for premenopausal women who are experiencing low sexual desire, the availability of this recent pharmacologic treatment is not without controversy. Women who are considering treatment with flibanserin will need to weigh a risk/benefit profile that includes the potential for serious adverse events and relatively small treatment efficacy. Nurses will be an integral part of the health care team for women taking flibanserin in the provision of education, support, reassurance, and assistance with obtaining prescriptions. NWH References American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author. Basson, R., Driscoll, M., & Correia, S. (2015). Flibanserin for low sexual desire in women: A molecule from bench to bed? EBioMedicine, 2(8), 772 773. doi:10.1016/j.ebiom.2015.08.009 Bradway, C., & Boullata, J. (2014). Pharmacologic therapy for female sexual dysfunction. The Nurse Practitioner, 39(1), 16 27. doi:10.1097/01. NPR.0000440641.32261.7c DeRogatis, L. R., Clayton, A. H., Goldstein, A., Lewis-D Agostino, D., Wunderlich, G., & Cotton, D. (2011). ediary and Female Sexual Distress Scale in evaluating distress in hypoactive sexual desire disorder (HSDD). The Journal of Sex Research, 48(6), 565 572. doi:10.1080/00224499.2010.524321 Gellad, W. F., Flynn, K. E., Alexander, G. C. (2015). Evaluation of flibanserin: Science and advocacy at the FDA. Journal of the American Medical Association, 314(9), 869 870. doi:10.1001/ jama.2015.8405 Jaspers, L., Feys, F., Bramer, W. M., Franco, O. H., Leusink, P., & Laan, E. T. M. (2016). Efficacy and safety of flibanserin for the treatment of hypoactive sexual desire disorder in women: A systematic review and meta-analysis. JAMA Internal Medicine, 176(4), 453 462. doi:10.1001/ jamainternmed.2015.8565. Joffe, H. V., Chang, C., Sewell, C., Easley, O., Nguyen, C., Dunn, S.,... Beitz, J. (2016). FDA approval of flibanserin Treating hypoactive sexual desire disorder. The New England Journal of Medicine, 374, 101 104. doi:10.1056/ NEJMp1513686 Kingsberg, S. A., & Woodard, T. (2015). Female sexual dysfunction: Focus on low desire. Obstetrics & Gynecology, 125(2), 477 486. doi:10.1097/aog.0000000000000620 Laumann, E. O., Paik, A., & Rosen, R. C. (1999). Sexual dysfunction in the United States: Prevalence and predictors. Journal of the American Medical Association, 281(6), 537 544. doi:10.1001/jama.281.6.537 Meixel, A., Yanchar, E., & Fugh-Berman, A. (2015). Hypoactive sexual desire disorder: Inventing a disease to sell low libido. Journal of Medical Ethics, 41(10), 859 862. doi:10.1136/ medethics-2014-102596 Nappi, R. E. (2015). Why are there no FDA-approved treatments for female sexual dysfunction? Expert Opinion of Pharmacotherapy, 16(12), 1735 1738. doi:10.1517/14656566.2015.1064393 Quigley, M. (2015). Evidence and ethics: Once more into the fray. Journal of Medical Ethics, 41(10), 793 794. doi:10.1136/medethics-2015-103103 Shifren, J. L., Monz, B. U., Russo, P. A., Segreti, A., & Johannes, C. B. (2008). Sexual problems and distress in United States women: Prevalence and correlates. Obstetrics & Gynecology, 112(5), 970 978. doi:10.1097/aog.0b013e3181898cdb Sprout Pharmaceuticals, Inc. (2015). Addyi (flibanserin): Highlights of prescribing information. Raleigh, NC: Author. Retrieved from https://www. addyi.com/files/addyi-pi-9-28-15.pdf Stahl, S. M., Sommer, B., & Allers, K. A. (2011). Multifunctional pharmacology of flibanserin: Possible mechanism of therapeutic action in hypoactive sexual desire disorder. Journal of Sexual Medicine, 8(1), 15 27. doi:10.1111/j.1743-6109-2010.02032.x U.S. Food and Drug Administration. (2015). FDA approves first treatment for sexual desire disorder [press release]. Retrieved from http://www. fda.gov/newsevents/newsroom/ PressAnnouncements/ucm458734.htm Uphouse, L. (2014). Pharmacology of serotonin and sexual behavior. Pharmacology, Biochemistry, and Behavior, 121, 31 42. doi:10.1016/j. pbb.2013.11.008 World Health Organization. (2015). Sexual and reproductive health: Defining sexual health. Geneva, Switzerland: Author. Retrieved from http://www. who.int/reproductivehealth/topics/ sexual_health/sh_definitions/en/ 314 Nursing for Women s Health Volume 20 Issue 3