Clozapine Toxicity in Two Young Siblings Due to a Pharmacy Dispensing Error: a Pediatric Case Report

Abstract 

Introduction

Clozapine is an atypical antipsychotic used to treat refractory schizophrenia; in both therapeutic use and overdose, it can cause significant toxicity. We report two young siblings who developed altered mental status after ingesting clozapine due to a pharmacy dispensing error.

Case Report

A 5-year-old girl and her 19-month-old sister presented to the emergency department (ED) with altered mental status after they took their first dose of what was believed to be cimetidine, prescribed to treat molluscum contagiosum. Both children were discharged after a brief period of observation in the ED. Two days later, when the older child continued to be symptomatic, their mother used a web-based pill identifier and discovered that the pills dispensed by the pharmacy were 200 mg clozapine tablets, not the cimetidine that had been prescribed. Ingestion was confirmed with an elevated serum clozapine concentration in the older child of 17 mcg/L at 85 hours post-ingestion (adult therapeutic range: 350–600 mcg/L). Both children had complete resolution of their symptoms 4 days following the ingestion with supportive care alone.

Discussion

We report two cases of pediatric clozapine toxicity due to a pharmacy dispensing error. The error was due, in part, to similarly named medications being stored adjacent to each other on a shelf. Dispensing errors are not rare occurrences and their root causes are multi-factorial. This case demonstrates the importance of reducing such errors, particularly for medications with potential for severe toxicity.

Introduction 

Clozapine, an atypical antipsychotic, is used to treat refractory schizophrenia in adults. Its mechanism of action is multifactorial and involves weak antagonism of D1 and D2 receptors as well as antiserotonergic, antiadrenergic, antimuscarinic, and antihistaminic effects and agonism of the M4 muscarinic receptor [1]. The clinical manifestations of clozapine overdose in adults include hypotension, tachycardia, altered mental status, visual hallucinations, sialorrhea, and dysarthria [1, 2]. There are also several serious adverse effects associated with its use at therapeutic levels including agranulocytosis, myocarditis, and seizures. The data for pediatric clozapine ingestions are limited but suggest that young children have similar clinical manifestations of clozapine overdose to that of adults but have more pronounced toxicity at lower relative doses [2, 3].

Due to adverse effects associated with its use, clozapine is subject to a strict monitoring and dispensing protocol, the Risk Evaluation and Mitigation Strategy (REMS). Providers and pharmacies must be certified in Clozapine REMS to prescribe and dispense this high-risk medication. Additionally, pharmacy dispensing of all medications is a complex process. Errors can occur at multiple steps in the medication dispensing procedure and can be due to many factors. Community pharmacy dispensing errors in the USA occur at an estimated rate of 1.5% of all filled prescriptions [4]. It is crucial to analyze such errors when they arise, in particular when they lead to adverse patient outcomes, in order to determine their root causes and prevent future occurrences. We report two cases of unintentional pediatric clozapine ingestion in a pair of siblings due to a pharmacy dispensing error.

Case Report

A 5-year-old girl (AS) and her 19-month-old sister (RS), both without any significant past medical history, presented to the emergency department (ED) with lethargy and confusion which began approximately 30 min after they both took their first dose of what was believed to be 200 mg of oral cimetidine, prescribed to them to treat molluscum contagiosum. The children’s mother gave AS one entire pill which she chewed and swallowed, and for RS, she crushed one pill and mixed it into water which RS drank. On arrival to the ED, AS’s vital signs were the following: blood pressure, 116/70 mm Hg; heart rate, 120 beats/minute; respiratory rate, 20 breaths/minute; temperature, 36.3 °C; O2 saturation, 99% on room air. RS’s vital signs were the following: blood pressure, 109/73 mm Hg; heart rate, 154 beats/minute; respiratory rate, 28 breaths/minute; temperature, 36.2 °C; O2 saturation, 100% on room air. Both children were lethargic, drooling, and had roving eye movements. AS was confused and agitated at times with abnormal arm movements and had her eyes open when sleeping. The initial presentation was attributed to an adverse reaction to cimetidine. The ED provider contacted the regional Poison Control Center (PCC) regarding the ingestion of cimetidine and per the PCC’s recommendations, both children were observed for 4 hours. Both children were subsequently discharged home without any laboratory or imaging studies performed.

Following ED discharge, the children’s mother did not give them any subsequent doses of the medication as it was believed to be the cause of their altered mental status. RS remained somnolent, but then returned to baseline approximately 24 hours after ingestion. AS was lethargic and confused for the following 2 days. Given the persistence of AS’s symptoms, the mother examined the tablets in the prescribed bottle of cimetidine (off-white oval pills with “4405” printed on one side and “200” on the other) and an online pill identifier identified the tablets as 200 mg clozapine. Two days post-ingestion, the children were evaluated by their pediatrician who reported the clozapine ingestion to the regional PCC. The PCC recommended the pediatrician obtain vital signs, complete blood count, and electrocardiogram and refer the patient AS to the ED if she remained altered. The children were closely monitored by their pediatrician, returning to their pediatrician’s office on day 3 and day 4 post-ingestion, at which point laboratory studies were obtained. An electrocardiogram was never performed. Approximately 85 hours post-ingestion, laboratory evaluation of AS demonstrated a complete blood count, complete metabolic panel, and liver function tests all within normal limits. Serum clozapine concentration was 17 mcg/L (adult therapeutic range: 350–600 mcg/L) and norclozapine (a major metabolite) concentration was 55 mcg/L (Table 1) [5]. AS returned to her baseline normal mental status on day 4 post-ingestion.

Table 1.

Laboratory evaluation of patient AS at 85 h post-ingestion.

Laboratory parameter	Value	Reference range
Complete blood count
Hemoglobin	12.0	11.5–14.0 g/dL
Hematocrit	36.5	34.0–42.0%
White blood cells	6.8	5.0–16.0 thousand/mcL
Platelets	396	140–400 thousand/mcL
Total neutrophils, %	38.2	35–65%
Neutrophils, absolute	2598	1500–8500 cells/mcL
Basic metabolic panel
Sodium	142	135–146 mmol/L
Potassium	4.1	3.8–5.1 mmol/L
Urea nitrogen (BUN)	11	7–20 mg/dL
Creatinine	0.42	0.20–0.73 mg/dL
Chloride	102	98–110 mmol/L
Carbon dioxide	23	20–31 mmol/L
Liver function tests
ALT	16	8–24 U/L
AST	36	30–39 U/L
Alkaline phosphatase	245	96–297 U/L
Bilirubin, direct	0.1	<  = 0.2 mg/dL
Bilirubin, indirect	0.2	0.2–0.8 mg/dL
Albumin	4.6	3.6–5.1 g/dL
Protein, total	7.4	6.3–8.2 g/dL
Xenobiotic concentrations
Norclozapine	55	25–400 mcg/L
Clozapine	17	N/A mcg/L
Lead, blood	< 1	N/A mcg/L

The children’s pediatrician contacted the pharmacy which, in turn, investigated the cause of the dispensing error. The pharmacy determined that cimetidine and clozapine were situated adjacent to one another on the shelf. In order to prevent recurrence of this error, they relocated clozapine to a separate, more secure location.

At a follow-up appointment 3 months post-ingestion, both children remained healthy with no apparent sequelae.

Consent for publication of this case was obtained and provided to the journal in accordance with JMT policy.

Discussion

In this case report, we describe two young siblings with unintentional ingestions of clozapine due to a medication error who developed acute clozapine toxicity characterized by drooling, ataxia, and altered mental status. While the differential diagnosis for altered mental status in young children is broad, the simultaneous and abrupt onset of symptoms consistent with clozapine toxicity occurring in both children 30 min after ingesting the pills, as well as the confirmatory serum clozapine level, makes clozapine toxicity the clear cause of their presentation.

Clozapine is a mainstay of treatment for refractory schizophrenia [6, 7]. However, several serious adverse reactions associated with its therapeutic use, most notably agranulocytosis, myocarditis, seizures, and increased risk of pneumonia, have led to multiple box warnings and strict drug monitoring requirements [8]. While the clinical manifestations of clozapine toxicity in adults are well described in the literature, acute unintentional pediatric ingestion of clozapine is uncommonly reported. Of the reported cases, children have presented with altered mental status, ataxia, respiratory depression, drooling, and slurred speech—toxic effects similar to those in adults but with symptoms that are more pronounced with as little as 50 mg of clozapine and at serum concentrations that are within therapeutic range for adults [2, 3, 9, 10]. While most children have recovered within 48 h of ingestion, there are several reported cases of acute clozapine ingestion leading to critical illness requiring intubation and hemodynamic support, two of which resulted in death [2, 3, 9–12].

Both children in our case report recovered with supportive care. However, it took 4 days for the 5-year-old child to return to baseline after a single 200 mg tablet ingestion. Furthermore, it was not until 2 days after the ingestion that the cause of the children’s altered mental status was discovered by their mother through the use of a pill identifier website. When the medication dispensing error was determined, it was reported to the pharmacy and further investigation was undertaken into the etiology of the error. The pharmacy reported that the bottles of cimetidine and clozapine were placed next to one another on the shelf.

To our knowledge, unintentional pediatric clozapine ingestion due to a pharmacy dispensing error has not been previously reported. There has been insufficient research into the rate of community pharmacy dispensing error in the USA; however, the best estimate based on a systematic review of the existing literature is 1.5% of all dispensed prescriptions have an error which amounts to approximately 94.5 million of the 6.3 billion prescriptions filled in the USA in 2020 [4, 13]. When looking specifically at new prescriptions, the estimated rate is even higher (3.2%) [14]. Beyond this, minimal data exist on the precise incidence of community pharmacy dispensing error in in the pediatric population. Children pose a unique challenge and are more vulnerable to medication errors due to a multitude of factors, including patient-specific weight-based dosing, lack of readily available pediatric formulations, and inadequate training or familiarity with pediatric prescriptions due to their relative rarity [15, 16]. The scope of possible dispensing errors is vast and includes incorrect drug, incorrect strength, incorrect dosage, incorrect quantity, and incorrect instructions [14]. One observational study of 50 community pharmacies in the USA identified computer entry, pulling medication off the shelf, and counting pills as the most common points in the dispensing process for errors to occur [14]. Studies of community pharmacy dispensing error have demonstrated numerous contributing factors including pharmacist workload, similar drug names, inadequate lighting, workplace distractions, and similar packaging [17]. Many strategies have been proposed to combat dispensing error, including avoiding storing similarly named medications next to one another, which may have prevented the error in this case. Another mainstay of error prevention is improving upon accuracy of the inspection process, where all components of the prescription are verified and mistakes can be identified [14]. One technique that has demonstrated efficacy involves the pharmacist keeping a copy of the original prescription at hand throughout all steps of the filling process and also while counseling the patient [14]. Data also supports the use of automated systems and barcode scanning to minimize dispensing errors; however, further research is needed to establish industry-standard best practices [16].

This case report of a pharmacy dispensing error where two drugs with similar names were stored adjacent to one another illustrates one particular area for improvement in medication stocking protocols, and it exemplifies the need for pharmacies to have standardized practices to prevent dispensing errors. These two young children experienced avoidable toxicity from clozapine overdose, and fortunately they recovered without long-term sequelae. This case adds to the existing literature on clozapine toxicity in children and highlights the importance of thoroughly investigating any newly prescribed or recently refilled medications when a patient presents with undifferentiated altered mental status or symptoms that seem inconsistent with an adverse effect of their prescribed medication.

Author Contribution

Hannah St. Francis: conceptualization, investigation, and writing – original draft. Madeline H. Renny: conceptualization, investigation, and writing – reviewing and editing. Rana Biary: supervision and writing – reviewing and editing. Mary Ann Howland: conceptualization and writing – reviewing and editing. Mark K. Su: supervision, conceptualization, and writing – reviewing and editing.

Funding

None.

Declarations

Consent for Publication

Consent for publication of this case was obtained and provided to the journal in accordance with JMT policy.

Conflict of Interest

None.