By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first drug for the treatment of hypoactive sexual desire disorder in women. Flibanserin, referred to as “the pink pill” is marketed by Sprout Pharmaceuticals as Addyi.
INDICATIONS
Flibanserin is indicated for the treatment of premenopausal women with acquired generalized hypoactive sexual desire disorder (HSDD) as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to co-existing medical or psychiatric conditions, medication or drug substance, or problems within the relationship.1 Acquired generalized HSDD is defined as developing in women who previously had no problem with sexual desire and regardless of the type of stimulation, situation, or partner.
DOSAGE
The recommended dose is 100 mg taken once at bedtime.1 Treatment should be discontinued after 8 weeks if there is no improvement. The drug should not be taken during waking hours as this increases the risk of hypotension and syncope. Flibanserin is available in 100 mg tablets.
POTENTIAL ADVANTAGES
Flibanserin is the first drug approved for this indication.
POTENTIAL DISADVANTAGES
Alcohol is contraindicated with flibanserin, as this combination increases the risk of severe hypotension and syncope.1 The drug is also contraindicated in combination with strong or moderate CYP3A4 inhibitors and in patients with hepatic impairment and is not recommended with a CYP3A4 inducer. Coadministration of CNS depressants besides alcohol, weak CYP3A4 inhibitors, and strong CYP2C19 inhibitors should be done with caution. Flibanserin is not indicated to enhance sexual performance or for the treatment of HSDD in postmenopausal women or men.1 A dose-related (3 to 10 times the clinical dose) increase in the incidence of mammary tumors have been observed in female mice.1 The incidence of appendicitis in Phase 3 studies was 0.13% for flibanserin compared to 0% for placebo. Most frequently reported adverse events (vs placebo) were dizziness (11.4% vs 2.2%), somnolence (11.2% vs 2.9%), nausea (10.4% vs 3.9%), fatigue (9.2% vs 5.5%), and insomnia (4.9% vs 2.8%).
COMMENTS
The mechanism of action of flibanserin is not known. Pharmacologically, it is mainly an agonist of serotonin 1A receptor subtype (5-HT1A) and antagonist of the 2A receptor subtype (5-HT2A).1 Efficacy was shown in three 24-week, randomized, double-blind, placebo-controlled studies in women with acquired, generalized HSDD.1 The co-primary endpoints were the number of satisfying sexual events and assessment of sexual desire. These were determined by responses to questions such as, “Did you have a sexual event?” and “Was the sex satisfying for you?” For sexual desire, response was based on questions such as, “Indicate your most intense level of sexual desire,“ or “Over the past 4 weeks, how often did you feel sexual desire or interest? and “Over the past 4 weeks, how would you rate your level of sexual desire or interest?” Secondary endpoint was distress related to sexual desire based on, “how often did you feel bothered by low sexual desire?” and the desire domain of the Female Sexual Function Index (FSFI). The results showed that statistical differences from placebo were modest. Across the three studies, the number of satisfying sexual events showed a median treatment difference from placebo of 0.5 to 1 per 28 days from a baseline of 2.5 to 3. There was a difference in daily desire in only one of three studies but there was improvement on the secondary endpoint (distress related to desire) and desire domain of the FSFI.1,2 The third study used FSFI as a co-primary endpoint, a less optimal endpoint.2 The mean improvement on the distress score was 0.3 to 0.4 over placebo (on a scale of 0-4 and a mean baseline of 3.2-3.4).2 The results of a driving test, requested by the FDA to assess next-day impairment, suggested no adverse effects.2 The wholesale cost for flibanserin is $800 for a 30-day supply.
CLINICAL IMPLICATIONS
Flibanserin is the first drug approved for HSDD. The clinical benefit seems modest with potential adverse events (hypotension, syncope) and drug to drug interactions, including contraindication with any alcohol use. The FDA rejected this drug in 2010 and 2013 due to small treatment difference that did not clearly outweigh the risks. In August 2015, the FDA, with additional data, in response to the FDA Response letter, concluded the drug had a positive benefit/risk assessment with consideration that there are currently no approved drugs for HSDD. The FDA estimated that about 10% more women treated with flibanserin will achieve clinically meaningful benefit compared to placebo. The FDA is requiring several post-market studies to address risk of hypotension, syncope, fatal outcomes, appendicitis, adverse pregnancy outcomes associated with flibanserin use, and drug-alcohol interaction in females. Flibanserin is approved with a risk evaluation and mitigation strategy (REMS) and will be available only through certified healthcare professionals and certified pharmacies.
REFERENCES
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Addyi Prescribing Information. Sprout Pharmaceuticals, August 2015.
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http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist. Accessed Oct. 1, 2015.
