A description of the clinical course of severe benzonatate poisonings reported in the literature and to NPDS: A systematic review supplemented with NPDS cases.

BACKGROUND: Benzonatate is a commonly prescribed medication that can be lethal in acute overdose of a small number of capsules. OBJECTIVE: This was a systematic review to describe the course of severe poisoning and deaths from benzonatate supplemented with the National Poison Data System (NPDS) fatalities module. METHODS: The NPDS was queried from 2000 to 2018 for benzonatate fatalities. Pubmed, Cochrane, Embase, and Google Scholar were searched for combinations of benzonatate and "poisoning," "overdose," and "toxicity." References of relevant articles were searched for additional publications. Articles were included if they described the clinical course of at least one patient suffering from benzonatate poisoning and available in English. Dual independent review and extraction were performed. RESULTS: Seventeen cases from NPDS and 19 published reports met the inclusion criteria resulting in 36 cases, mostly (28/36) self-harm ingestions. Most patients were young [17 (11-29), median (IQR)] and female (22). Onset of toxicity was rapid at <5 min (9). Most common symptoms included cardiac arrest (29), seizures (24), and dysrhythmias (24). Treatments included intubation (26), cardiopulmonary resuscitation (28), vasopressors (20) and others. Return of spontaneous circulation was achieved in 23/28 patients, but most had significant neurologic deficits or other end organ damage and 5 survived with a good neurologic outcome. CONCLUSION AND RELEVANCE: Overdose ingestions of benzonatate can cause significant toxicity with a rapid onset. Interventions performed were generally supportive in nature. Duration of directly toxic effects is short, but dramatic with neurologic devastation and resuscitated patients often still have a poor outcome.

N-Ethyl Pentylone (Ephylone) Intoxications: Quantitative Confirmation and Metabolite Identification in Authentic Human Biological Specimens.

N-ethyl pentylone (ephylone) has been identified as the most recent novel stimulant to emerge into the arena of evolving novel psychoactive substances (NPS). Due to its novelty, information regarding case reports with associated quantitative confirmations, biotransformation pathways, and identified unique metabolites will assist the scientific community in understanding the implications of the emergence and risks associated with N-ethyl pentylone use. Authentic blood specimens (n = 26) submitted as part of toxicological death investigations or drugged driving casework tested positive for N-ethyl pentylone, and were quantitatively analyzed by liquid chromatography tandem mass spectrometry (LC-MS-MS). N-ethyl pentylone concentrations ranged from 12 to 1,200 ng/mL, with mean (±standard deviation) and median concentrations of 313 (±366) and 125 ng/mL, respectively, excluding one case measured at 50,000 ng/mL. N-ethyl pentylone was often found in combination with other drugs of abuse and NPS, include a variety of novel opioids including fentanyl analogs. Oral fluid specimens (n = 5), collected from recreational drug users at a dance music festival, were quantitatively analyzed using LC-MS-MS. Concentrations ranged from 12.6 to 1,377 ng/mL. Additional analysis was performed to characterize the metabolic profile of N-ethyl pentylone using human liver microsomes (HLM), followed by confirmation of the presence of the proposed metabolites in a subset of the blood specimens and oral fluid specimens. Metabolomic analysis was performed using a liquid chromatograph quadrupole time-of-flight mass spectrometer (LC-QTOF), followed by data processing using MetabolitePilot™ software. In vivo verification of in vitro HLM-generated metabolites resulted in the confirmation of four metabolites. Reduction of the beta-ketone to an alcohol resulted in the most prominent metabolite found in the authentic specimens, and its uniqueness to N-ethyl pentylone leads to this metabolite being an appropriate biomarker to determine N-ethyl pentylone ingestion. This is the first study to report N-ethyl pentylone concentrations and to characterize the metabolic profile of N-ethyl pentylone.

Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration.

STUDY OBJECTIVE: To augment the December 2010 United States Food and Drug Administration (FDA) Drug Safety Communication on accidental ingestion of benzonatate in children less than 10 years old by summarizing data on emergency department visits, benzonatate exposure, and reports of benzonatate overdoses from several data sources. DESIGN: Retrospective review of adverse-event reports and drug utilization data of benzonatate. DATA SOURCES: The FDA Adverse Event Reporting System (AERS) database (1969-2010), the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project (NEISS-CADES, 2004-2009), and the IMS commercial data vendor (2004-2009). PATIENTS: Any patient who reported an adverse event with benzonatate captured in the AERS or NEISS-CADES database or received a prescription for benzonatate according to the IMS commercial data vendor. MEASUREMENTS AND MAIN RESULTS: Postmarketing adverse events with benzonatate were collected from the AERS database, emergency department visits due to adverse events with benzonatate were collected from the NEISS-CADES database, and outpatient drug utilization data were collected from the IMS commercial data vendor. Of 31 overdose cases involving benzonatate reported in the AERS database, 20 had a fatal outcome, and five of these fatalities occurred from accidental ingestions in children 2 years of age and younger. The NEISS-CADES database captured emergency department visits involving 12 cases of overdose from accidental benzonatate ingestions in children aged 1-3 years. Signs and symptoms of overdose included seizures, cardiac arrest, coma, brain edema or anoxic encephalopathy, apnea, tachycardia, and respiratory arrest and occurred in some patients within 15 minutes of ingestion. Dispensed benzonatate prescriptions increased by approximately 52% from 2004 to 2009. CONCLUSION: Although benzonatate has a long history of safe use, accumulating cases of fatal overdose, especially in children, prompted the FDA to notify health care professionals about the risks of benzonatate overdose. Pharmacists may have a role in preventing benzonatate overdoses by counseling patients on signs and symptoms of benzonatate overdose, the need for immediate medical care, and safe storage and disposal of benzonatate.

Cardiac arrest with residual blindness after overdose of Tessalon® (benzonatate) perles.

BACKGROUND: The extent to which benzonatate (Tessalon®), a structurally similar agent to other local anesthetics including tetracaine and procaine, poses a risk to the public is not fully appreciated as it is still one of the most widely prescribed antitussives available. OBJECTIVES: To report a case of cardiac arrest with residual blindness after Tessalon® overdose, review its clinical manifestations, toxicology and management considerations, and describe the need for rational prescribing. CASE REPORT: A 17-year-old woman with no previous medical history presented to the Emergency Department (ED) status post cardiac arrest. One to two hours prior, the patient had ingested at least 10 200-mg Tessalon® capsules as part of a suicide attempt. The patient was sedated, intubated, and given magnesium as prophylaxis against recurrent dysrhythmias. Emergent gastric lavage was performed and well tolerated. A 24-h hypothermia protocol with 6-h cooling period was initiated. Toxicological studies, chest radiograph, and a computed tomography scan of the head were all unremarkable. The patient was admitted to the Pediatric Intensive Care Unit for further work-up and supportive care. The patient was extubated and able to follow some commands 1 week post-admission. The patient developed blindness and experienced generalized confabulations, which did not resolve. CONCLUSION: Ingestion of Tessalon®, a seemingly innocuous and widely prescribed antitussive, may pose a risk to patients due to its potential for the rapid development of life-threatening adverse events and limited treatment options in the overdose setting. Rational prescribing and patient education is needed.

Benzonatate Ingestion Reported to the National Poison Center Database System (NPDS).

Little has been published on benzonatate ingestion, with the few case reports suggesting significant risk of seizures after poisoning. A 7-year retrospective review of all single substance ingestion of benzonatate reported to the National Poison Center Database System (NPDS) from 2000 to 2006. In this review, there were 2,172 patients, of which 1,280 (58%) were female. Mean age was 20 years, with 676 (30%) <6 years. Serious outcomes occurred in 116 (moderate, n = 81, 4%; major, n = 31, 1%; and death, n = 4, 0.2%). Mean age of those with serious outcome was 21 years, with 41 (35%) in children less than 6 years old. Forty-nine percent (1,084) patients were treated in a healthcare facility (HCF) of which 148 (7%) were admitted for medical care. Clinically significant effects that were documented included tachycardia (n = 31, 1%), agitation (n = 30, 1%), seizure (n = 23, 1%), coma (n = 14, 0.6%), ventricular dysrhythmia (n = 9, 0.4%), cardiac arrest (n = 8, 0.3%), hypotension (n = 7, 0.3%), and asystole (n = 6, 0.2%). Of patients with seizures reported, eight patients (0.4%) had multiple/discrete seizures and two had status epilepticus documented. Dysrhythmias but not seizures occurred in all fatalities in this review. Significant CNS and cardiac effects occurred in a small subset of this study (<1%), while half the patients received direct medical care in an HCF. No correlation between age and severity of medical outcome was detected by statistical analysis. A prospective study to better evaluate potential HCF triage criteria such as dosage, age, or preexisting conditions may be warranted. The fatalities from this study were due to dysrhythmias rather than seizures as previously reported in previous case reports. There were no clinical correlations between severity of outcomes and dose ingested. A median dose of 200 mg or greater suggests a potential for producing serious outcomes in a benzonatate exposure.

Benzonatate overdose associated with seizures and arrhythmias.

BACKGROUND: Benzonatate is an antitussive with a unique chemical structure. It can contain as many as 8 structural analogs. Therefore, laboratory analysis of benzonatate is difficult. We report 2 cases of benzonatate poisoning with seizures and cardiac arrest and an analytical method to identify and quantify benzonatate in human plasma. CASE REPORTS: Case 1: A 12-month-old male presented to the emergency department of a rural hospital following ingestion of an unknown amount of benzonatate. Upon arrival, the child was seizing and in full cardiac arrest. Resuscitative measures were unsuccessful and the child died shortly after arriving at the emergency department. Case 2: A 39-year-old male ingested 36 benzonatate capsules in a suicide attempt. Enroute to the health care facility, the patient experienced a seizure, had a cardiac arrest, and was cardioverted. Upon arrival at the emergency department, the patient was acidotic with a pH of 6.8. Gastric lavage was performed followed by the administration of activated charcoal. Six hours after arrival at the emergency department, the patient was alert, oriented, and hemodynamically stable. The patient was observed for 24 hours and subsequently discharged. Laboratory confirmation of benzonatate in the plasma of the patient was performed using high-pressure liquid chromatography with tandem mass spectrometry (MS/MS). The benzonatate concentration was estimated to be 2.5 micrograms/mL. CONCLUSION: Seizures and cardiac arrest are possible following an acute ingestion. Quantitative analysis of benzonatate is possible using high-pressure liquid chromatography with tandem mass spectrometry. Routine analysis for benzonatate is not common.

An apparent fatal overdose of terodiline.

The results of a forensic toxicological investigation on a young man with an unknown cause of death are reported here. Analysis revealed the presence of a possibly fatal level of terodiline in blood and urine. No other drugs were detected. Terodiline was detected by thin-layer and gas-liquid chromatography and identified by gas chromatography/mass spectrometry. Quantification was carried out by a mass fragmentographic procedure using the m/z 100 from terodiline for selective ion monitoring (SIM). The blood and urine concentrations were found to be greater than 10 mg/L, whereas therapeutic concentrations in serum are usually not more than 1 mg/L. Support and confirmation of the laboratory results was provided at the subsequent inquest. It was revealed that the deceased had died from the inhalation of vomit due to an oral overdose of terodiline. To the best of our knowledge this is the first reported death due to fatal poisoning with terodiline in the United Kingdom.

Two fatalities resulting from Tessalon (benzonatate).

Two fatal cases involving Tessalon (benzonatate) were quantitated by ultraviolet (UV) and high performance liquid chromatography (HPLC). The first case involved an infant found choking; Tessalon perles were found with the child. The second case involved a successful suicide of an 18-year-old that consumed a "handful" of phenytoin and benzonatate and expired within 1 hr of the ingestion. Blood, brain and kidney concentrations are reported. These are believed to be the first two reported cases involving this compound.