Flibanserin (Addyi) was approved by the U.S. Food and Drug Administration in August 2015 as a once-daily, non-hormonal medication for treating hypoactive sexual desire disorder (HSDD) in premenopausal women. Some clinicians criticize the diagnostic term HSDD for being hopelessly vague and turning individual variations of human sexual response into a pathological condition.
HSDD is no longer listed as a specific diagnosis in the current edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5), but the term still refers to a lack of or significantly reduced sexual interest that persists for at least six months, causes distress, and is not attributable to a medical condition or medication effect.
Sales of Addyi have not been brisk, and little data are available about post-marketing experience with adverse effects and toxicity. A recently published case report, however, describing a flibanserin overdose in a toddler prompted me to review some key facts about the drug.
A 2-year-old boy was brought to the hospital after exhibiting decreased mental status and muscle tone, along with possible seizure activity. (Clin Toxicol [Phila] 2017 Aug 17; doi: 10.1080/15563650.2017.1355465.) History revealed that he had ingested up to six of his mother's 100 mg flibanserin tablets.
On arrival, the child did not respond to pain. His vital signs were unremarkable, and his serum glucose level was 90 mg/dL. Significant findings on physical exam included dilated pupils and facial twitching but no clonus or hyperreflexia. The seizure-like activity stopped after he was given 1.5 mg lorazepam IV. Subsequently, he appeared to be postictal. A comprehensive urine drug screen revealed the presence of 1-(3-trifluoromethylphenyl)-piperazine (TFMPP) and caffeine. The child was admitted to the pediatric intensive care unit where he gradually improved overnight. He was discharged home the next day.
Here are the top four things to know about flibanserin.
Fact 1: Flibanserin does not work like sildenafil (Viagra). Sildenafil is a phosphodiesterase inhibitor that relaxes smooth muscle and increases blood flow to the penis. The purported mechanism for the action of flibanserin involves the modulation of neurotransmitters. The drug increases levels of dopamine and norepinephrine, and selectively decreases levels of serotonin in specific regions of the brain (such as the prefrontal cortex) involved in sexuality. This rebalancing may enhance the chemicals that increase sexual desire (dopamine and norepinephrine) while inhibiting the one that decreases desire (serotonin).
Fact 2: The active metabolite of flibanserin is actually a common street drug. Flibanserin is converted by the hepatic enzyme CYP3A4 into the metabolite TFMPP. As the authors of this case report pointed out, “TFMPP is used recreationally as a stimulant and hallucinogen often in combination with an analogue benzylpiperazine (BZP).” (Clin Toxicol [Phila] 2017 Aug 17.) The BZP/TFMPP combo is sometimes labeled “Liquid X” or (misleadingly) as “Legal Molly,” and is said to have effects similar to those of ecstasy (MDMA).
Fact 3: Flibanserin has a potentially dangerous interaction with alcohol. While the drug was being developed, an ethanol challenge study found that some volunteers given the standard 100 mg dose of flibanserin along with the equivalent of two or four alcoholic drinks developed orthostatic hypotension or syncope, sometimes requiring treatment with ammonia smelling salts or leg raising. Notably, this study used only 25 subjects, 23 of whom were men.
Addyi carries a black box warning alerting clinicians and patients to this interaction because of these findings. An elaborate risk evaluation and mitigation strategy (REMS) system has been set up requiring that prescribers and dispensing pharmacies be certified in using the drug. It is mandatory that patients be warned not to use any alcohol at all. The pharmaceutical manufacturer Valeant told me that post-marketing data on this interaction have been submitted to the FDA and are now being reviewed.
Fact 4: Flibanserin is contraindicated in patients taking strong or moderate CYP3A4 inhibitors. Flibanserin is metabolized primarily by this specific portion of the hepatic cytochrome P450 system, so CYP3A4 inhibitors can significantly increase levels of the drug and its half-life, risking severe hypotension and syncope. (Table.) The drug is contraindicated in women with hepatic impairment for similar reasons.
Caffeine was detected in the child's urine in this case report, but the amount was not quantified and it was not clear what the source was. I talked with Matthew Valento, MD, one of the study's authors, who said the consulting toxicologists did not think the presentation was due to caffeine toxicity because there was no vomiting, tachycardia, or hypokalemia (serum potassium was 5.0 mEq/L). Flibanserin can also increase serotonin levels in certain parts of the body, but the absence of clonus or hyperreflexia did not suggest serotonin syndrome. The child developed a transient fever up to 101.1°F during his overnight stay in the PICU. No infectious etiology was identified, and it was not clear whether the fever was drug-induced or attributable to some other cause.