Accidental Flibanserin Ingestion in Children Causing Acute Respiratory and Central Nervous System Depression

Abstract

This commentary serves to raise awareness for health care professionals about the potential risks of accidental ingestion of flibanserin tablets by children. Flibanserin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acquired generalized hypoactive sexual desire disorder in premenopausal women. Since its approval in 2015, the FDA has identified five reports of serious accidental ingestion by toddlers. All five children, boys with ages ranging from 18 months to 2 years, presented with central nervous system and respiratory depression, and two of them required intubation. A combination of hypertension, hyperthermia, and seizure-like activity was also seen in four of the five children. The clinical manifestation resembles serotonin syndrome (eg, tachycardia, hypertension, and muscle stiffness). As flibanserin use increases, greater awareness by health care professionals regarding the risk of accidental pediatric ingestion is needed to facilitate preventative counseling for patients with young children.

Addyi (flibanserin) was approved by the U.S. Food and Drug Administration (FDA) in August 2015 for the treatment of acquired generalized hypoactive sexual desire disorder in premenopausal women.¹ Hypoactive sexual desire disorder is described as low sexual desire that causes marked distress or interpersonal difficulty that is not due to a coexisting medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance.

Flibanserin modulates serotonin receptors and stimulates release of norepinephrine and dopamine in the prefrontal cortex.² Flibanserin binds to several serotonin (5-hydroxytryptamine or 5-HT) receptors; it has agonist activity at 5-HT1A and antagonist activities at 5-HT2A, 5-HT2B, and 5-HT2C. After oral ingestion in adults, the time to achieve peak plasma flibanserin concentration is 45–60 minutes (range 0.75–4.0 hours); its half-life is approximately 11 hours. Flibanserin is primarily metabolized in the liver by the cytochrome P450 enzyme system.³ When taken daily as prescribed by premenopausal women, flibanserin 100 mg (one tablet) is known to cause central nervous system (CNS) depression (eg, somnolence, sedation, fatigue). In the clinical trials conducted before approval, CNS depression occurred at an incidence of 21% in flibanserin-treated patients compared with 8% in the placebo group.⁴ Other reported side effects of single doses of flibanserin are hypotension, syncope, dizziness, nausea, fatigue, insomnia, and dry mouth.

It is important to note that flibanserin has a narrow safety margin; during clinical development, doses higher than 250 mg of flibanserin could not be tolerated by adults.⁴ Because of the known narrow safety margin in adults and the inherent differences in pharmacokinetic absorption, metabolism, and elimination between adults and young children, any dose of flibanserin could be more dangerous in the pediatric population, let alone doses that could not be tolerated in adults (ie, the 400–1,500 mg taken in the cases described below). Currently, there is no known specific antidote for the accidental ingestion of flibanserin or for cases of overdose (see Prescribing Information).

In 2019, flibanserin labeling and its risk message were updated to remove the contraindication for taking flibanserin and drinking alcohol at the same time (see Prescribing Information).⁵ Therefore, the use of flibanserin is expected to increase. Despite the anticipated blockbuster status for flibanserin at the time of approval, the market uptake of flibanserin thus far has been slow, possibly for the following reasons: 1) a Risk Evaluation and Mitigation Strategy, whereby prescribing and dispensing of the drug were initially limited to health care professionals and pharmacies that were certified by the Risk Evaluation and Mitigation Strategy; 2) the increased risk of severe hypotension and syncope when flibanserin is taken with alcohol, which is highlighted in a Boxed Warning, and the previous contraindication of the co-administration of flibanserin and any alcohol; and 3) the small average treatment effects demonstrated in clinical trials (an increase of one or fewer satisfying sexual events per month, and about 10% more flibanserin-treated patients than placebo-treated patients reported clinically meaningful improvement).¹ In October 2019, additional postmarketing safety data allowed for modification of the Risk Evaluation and Mitigation Strategy to remove the prescriber and pharmacy certification requirements. The current drug label also removes the contraindication for alcohol use while taking flibanserin. Instead, the label warns that use of flibanserin and alcohol close together increases the risk of severe hypotension and syncope. Specifically, patients should wait at least 2 hours after consuming one or two standard alcohol drinks before taking flibanserin or skip flibanserin if they have consumed three or more standard drinks. Given the removal of the contraindication for alcohol use along with the removal of the certification requirements for prescribers and pharmacies, the use of flibanserin is expected to increase.

POSTMARKETING CASES

During the FDA’s routine monitoring of postmarketing adverse events reported with flibanserin use, cases of accidental ingestion in toddlers were identified. These cases included serious CNS and respiratory depression necessitating hospitalization and ventilatory support in select cases.

The FDA queried the FDA Adverse Event Reporting System database and the American Association of Poison Control Centers’ National Poison Data System through June 30, 2021, for cases of flibanserin ingestion by pediatric patients from both domestic and foreign sources. Brand or trademarked names were not derived from the cases obtained from the National Poison Data System. Cases identified in the National Poison Data System were limited to single-substance exposures in which a medical outcome of either a moderate or major effect was documented by the American Association of Poison Control Centers clinician. A total of five unique cases, all domestic, were identified across both data sources from 2016 to 2020; three cases were identified from the FDA Adverse Event Reporting System, and two cases were identified from the National Poison Data System. All three cases identified from the FDA Adverse Event Reporting System were also published in the medical literature (Willenbring B, Lintner C, Bangh S, Cole J. Accidental flibanserin poisoning in a child resulting in CNS depression and intubation for airway protection [abstract]. J Med Toxicol 2017;13:20. doi: 10.1007/s13181-017-0599-3).^6,7 A separate query of the published medical literature was also completed, and no additional cases were identified. A brief summary with the pertinent information from all five cases is provided below:

• A 2-year-old boy ingested up to 700 mg of flibanserin (seven flibanserin tablets) approximately 2 hours before emergency department (ED) arrival. The mother reported the child as being ataxic and somnolent postingestion. In the ED, notable symptoms included ataxia, fever, mild hypertension, lethargy, and myoclonus. Evidence of aspiration pneumonia was also noted. The child was ultimately intubated secondary to worsening mental status (Glasgow Coma Scale score of 6) before transfer to a tertiary care center. On hospital day 3, the child was extubated and discharged home without sequelae.

• A 2-year-old boy ingested up to 600 mg of flibanserin (six flibanserin tablets) approximately 2 hours before ED arrival. The mother reported that the child initially displayed decreased responsiveness (not coming or turning when his name was called) 30 minutes after a sibling witnessed him playing with pill bottles, then he became limp and his eyes rolled back. In the ED, notable symptoms included mild hypertension, lack of blinking, mydriasis, unresponsiveness to painful stimuli, transient facial twitching, and the absence of both clonus and hyperreflexia. A benzodiazepine was administered to treat suspected seizure-like activity, which was then noted to resolve (facial twitching stopped, and he became responsive to painful stimuli; postictal state was suspected). An intravenous fluid bolus was also administered. The child was transferred to a children’s hospital about 4 hours after ED arrival. Although some of his symptoms improved (ie, continued absence of clonus, purposeful extremity movement, spontaneous eye opening), he continued to exhibit dysmetria, hypotonia, and mydriasis. Notable substances identified through a urine drug screen by gas chromatography and mass spectrometry included caffeine, a caffeine metabolite, and 1-(3-trifluoromethylphenyl)-piperazine. During his overnight stay in the pediatric intensive care unit (PICU), he developed fever without any associated symptoms. Mild speech slurring and mild unsteadiness on his feet were noted the next morning but resolved throughout the day. After improvement in his neurologic examination, he was transitioned from the PICU and discharged home, approximately 24 hours after his initial ingestion of flibanserin.

• A 23-month-old boy ingested up to 1,000 mg of flibanserin (10 flibanserin tablets) approximately 1 hour before ED arrival. The father reported putting the child down for a nap, and 30 minutes later the child was noted to be unarousable; an empty flibanserin bottle was found nearby. In the ED, notable symptoms included hypertension, lethargy, and tachycardia; the child became unresponsive shortly thereafter. Before PICU transfer, intravenous fluids were initiated, two doses of a benzodiazepine were administered for a seizure and upper extremity spasms, respectively, and oxygen was started. On PICU arrival, decorticate posturing, slight rigidity of the lower extremities, and possible twitching in the upper extremity were documented; however, by the evening, the child was noted to be more awake with less tachycardia. The next morning, although a fever was noted, the child was behaving appropriately for his age, with no further rigidity, and was reactive to stimuli. Approximately 24 hours after ED arrival, he was alert, mobile, and cleared for oral intake.

• A 22-month-old boy ingested up to 400 mg of flibanserin (four flibanserin tablets) approximately 30–40 minutes before ED arrival. The father reported finding the child unresponsive on the floor (behind a curtain with an open medication bottle and pills on the floor) with some foaming at the mouth and his eyes rolled back. In the ED, notable symptoms included ongoing oral foaming and vomiting. The child was then intubated owing to decreased mental status and poor respiratory effort before PICU transfer (sedation was achieved with a benzodiazepine and an opioid infusion). Posturing of the upper extremities, but no limb jerking, was noted on examination during transport to the PICU. On PICU arrival, spontaneous movement of all extremities was observed as his sedation was decreased. A brain magnetic resonance imaging scan and overnight electroencephalographic monitoring did not identify trauma or seizures. Given his fever, there was concern for aspiration (because mucus plugs were removed during intubation), resulting in the initiation of antibiotics. Sedation was stopped the next morning, and the child was extubated. On hospital day 2, he was transferred from the PICU to the pediatric floor, followed by discharge to his home on hospital day 3.

• An 18-month-old boy ingested up to 1,500 mg of flibanserin (15 flibanserin tablets) at an unknown amount of time before ED arrival. The child was found unresponsive by his family. In the ED, he was noted to be asleep but arousable with good oxygen saturation and stable vital signs; however, it was determined that an overnight PICU admission was warranted for observation. On PICU transfer, oxygen was started because he was desaturating, and tachycardia and significant sedation were documented. The next morning, he was more alert (but not at baseline) and had been weaned off the oxygen. Continued improvement in mentation and oxygenation were noted throughout the day.

These five cases describe unwitnessed and accidental ingestion of flibanserin tablets by male toddlers ranging in age from 18 months to 2 years. The presumed number of flibanserin tablets ingested ranged from 4 to 15 tablets and was calculated by the estimated number of missing tablets. These case reports detail CNS depression in the toddlers, including unresponsiveness, decreased responsiveness to voice and pain, somnolence, lethargy, “eyes rolled back in head,” and mydriasis, occurring as early as 30 minutes from the time of ingestion. Respiratory depression requiring intubation was reported in two cases; in two other cases, oxygen desaturation or treatment with supplemental oxygen as a precaution was reported. Effects on motor function, which included ataxia, spontaneous myoclonic or tonic-clonic movements, muscle twitching, and foaming at the mouth, were reported in four of the five cases, with the latter events suggesting seizure-like activity. One toddler was thought to be in a postictal state, but no bowel or bladder incontinence was reported. Tachycardia and hypertension were also reported, with hyperthermia observed in four cases. No electrolyte disorders were found. Abnormal creatine kinase levels were not reported. Although treatment was mostly supportive, benzodiazepines were administered in three cases. All of the toddlers recovered and were discharged after a period of observation, which included time in the PICU (approximately 24–72 hours, if reported).

DISCUSSION

The clinical presentation after the accidental ingestion of flibanserin in these toddlers had some, but not all, of the features of serotonin hyperactivity with release of monoamine catecholamines (dopamine and norepinephrine), specifically hypertension, hyperthermia, tachycardia, fever, muscle rigidity, and tonic-clonic movements suggestive of seizure-like activity. If solely due to serotonin modulation, the clinical picture would more closely mimic pure serotonin syndrome, a potentially life-threatening condition. It is unclear how flibanserin’s mixed activity at the serotonin receptors could change the manifestations of accidental ingestion or overdose.

Another relevant contributing source of serotonin excess is the finding of a minor flibanserin metabolite, 1-(3-trifluoromethylphenyl)-piperazine, on toxicologic screen in one of the reported cases. 1-(3-trifluoromethylphenyl)-piperazine, in combination with other piperazines, has been used as a substitute for the recreational drug referred to as “Ecstasy,” “Molly,” or “Legal X.” Ecstasy and other similar compounds are sympathomimetic amphetamines and are structurally similar to serotonin.^8–10 1-(3-trifluoromethylphenyl)-piperazine causes the release of norepinephrine and dopamine while blocking their reuptake into presynaptic vesicles, leading to serotonin syndrome. As with other serotonin agonists, Ecstasy-related drugs cause CNS stimulation rather than depression (as reported in the cases above), with known effects of agitation, hyperactivity, anxiety, and even delirium. Hypertension, tachycardia, hyperthermia, muscle rigidity, brain edema, hallucinations, and nausea as well as seizures are also known to occur.^11,12 The effect of 1-(3-trifluoromethylphenyl)-piperazine was evaluated during the preapproval process for flibanserin, and the clinical risk was considered low because it comprised 5% of flibanserin exposure.³ However, some of the features of the cases of accidental flibanserin ingestion could be a function of the 1-(3-trifluoromethylphenyl)-piperazine and its piperazine effects and unrelated to flibanserin-associated serotonergic activity, especially given the large doses of flibanserin that were thought to have been ingested.⁶

It is unclear whether the motor symptoms reported in these cases—spontaneous myoclonic or tonic-clonic movements, muscle twitching, and oral foaming—represent seizure activity. Some combinations of these events were reported in four of the five cases. One case documented resolution of the abnormal movements after benzodiazepines were administered and mentioned the presence of a “postictal state”; however, additional details were not provided.

Currently, flibanserin is dispensed in 30-count square white bottles with a child-resistant container closure. The label on the bottle is also white, with single pink strips on either side. The oblong-shaped flibanserin tablet is marketed as the “little pink pill” whose hue resembles bubble gum. In appearance, the pink color and shape of the tablet could be confused for a piece of candy by a child. Other potential factors, such as child-resistant container malfunction, user error with possibly incomplete closure of the bottle, repackaging into a different container for ease of use, or lack of supervision, could all play a role in accidental ingestion. Flibanserin is approved for use in premenopausal women, who are likely to have young children in the home, making the potential for accidental ingestion more likely.

It is not surprising that toddlers are at increased risk of accidental drug exposure and ingestion, because toddlers are curious by nature and inclined to explore their environment.^13,14 Although accidental ingestion by toddlers is not a problem unique to flibanserin, the narrow safety range of flibanserin dosing in adults highlights a relatively greater concern with accidental ingestion of this drug. Further, no pharmacokinetic data are available in children or adolescents. In addition to the known narrow safety range in adults, the inherent differences in drug metabolism between adults and children may explain the severity of the clinical presentation observed in these toddler cases, which included profound CNS and respiratory depression, both of which are serious and potentially life-threatening. These considerations elevate the concern for accidental pediatric ingestion of flibanserin.

We believe that health care professionals should be aware of the potential life-threatening risks to children after accidental flibanserin ingestion. This is especially important given the expected increase in flibanserin prescribing and usage, potentially elevating the risk for accidental ingestion by a child. These risks include unresponsiveness, respiratory failure, hypertension, tachycardia, hyperthermia, and seizure-like activity, as well as potential exposure to 1-(3-trifluoromethylphenyl)-piperazine, an Ecstasy-like flibanserin metabolite. Those who prescribe flibanserin should counsel patients with young children to keep the medication out of reach of children, to keep pills stored in child-resistant containers, to make sure the top of the container is properly closed after each use, and to seek medical attention immediately if accidental ingestion is suspected.