Benzonatate Exposure Trends and Adverse Events

The primary objective of this retrospective analysis was to characterize benzonatate exposure in pediatric patients with a special focus on trends in hospitalizations and deaths from benzonatate misuse. The secondary objective was to compare benzonatate exposures with those of codeine- and hydrocodone-containing antitussive medications (narcotic antitussive medications) and dextromethorphan-containing antitussive medications (nonnarcotic antitussive medications) in pediatric patients.

This study focused on trends in children <17 years old. Where possible, subgroup analyses were performed using pediatric age bands of 0 to 5 years, 6 to 9 years, and 10 to 16 years. Adult benzonatate exposures and AEs were analyzed as needed to provide context.

This study used IQVIA National Sales Perspective⁷  2019 sales distribution data to determine the primary setting of care for benzonatate prescriptions and IQVIA Total Patient Tracker⁸  2012 to 2019 data to estimate the number of unique patients dispensed prescriptions for antitussive medications from US retail pharmacies. Data on the over-the-counter utilization of dextromethorphan- and codeine-containing antitussive medications are not included in the analysis. Trends for benzonatate and comparator antitussive medications derived from National Poison Data System (NPDS) data from 2010 to 2018 reporting exposure cases to US Poison Control Centers (PCC).^9,10  See Supplemental Table 3 for select NPDS terms and definitions. Additionally, data analyses included counts from the National Electronic Injury Surveillance System – Cooperative Adverse Drug Event Surveillance (NEISS-CADES) project for hospital emergency department (ED) visits for adverse drug events (ADEs) involving benzonatate or other antitussive medications from 2004 to 2018.^11,12  A query of the FDA Adverse Event Reporting System (FAERS)¹³  database from May 20, 2010 (data-lock date of FDA’s previous evaluation on benzonatate safety), to December 31, 2019 retrieved case level data for AEs with benzonatate. FAERS cases were included if they described patients <17 years old that reported abuse, misuse, or unintentional exposure to benzonatate. Reports were excluded if they were duplicate or if they were included in FDA’s previous benzonatate safety analysis. For completeness, this study included a search of the PubMed database for literature published between 2011 and 2020 describing cases of AEs with benzonatate that were not already reported in FAERS, NPDS, or the FDA’s previous evaluation of benzonatate safety.³ 

Retail pharmacy sales accounted for ∼90% of United States antitussive medication bottle or package sales based on IQVIA National Sales Perspective sales distribution data in 2019. Consequently, this analysis focused on data from retail pharmacies and excluded data from nonretail settings, such as inpatient hospitals. In 2019, an estimated 3.6 million pediatric patients <17 years old received antitussive medication prescriptions dispensed through retail pharmacies. Of these, 3.3 million patients (90%) received dextromethorphan-containing antitussive medications, 351 000 patients (10%) received benzonatate, 50 000 patients (1%) received codeine-containing antitussive medications, and 14 000 patients (<1%) received hydrocodone-containing antitussive medications.

Pediatric patients who received benzonatate dispensed prescriptions increased by 62% from an estimated 217 000 unique patients in 2012 to 351 000 unique patients in 2019 (Fig 1). The primary driver for increase in total pediatric benzonatate use was increased use in patients 10 to 16 years old. Benzonatate use was negligible in patients 0 to 5 years old. Notably, adult patients ≥17 years old who received benzonatate dispensed prescriptions increased from an estimated 5.1 million patients in 2012 to 11.7 million patients in 2019 (Fig 1). From 2012 to 2019, utilization of codeine-, hydrocodone-, and dextromethorphan-containing antitussive medications in pediatric patients decreased by 94%, 91%, and 10%, respectively.

From 2010 to 2018, there were 4689 benzonatate exposure cases in NPDS for children <17 years old (Table 1).¹⁴  The number of NPDS cases involving benzonatate in children increased during the study period with increases of 3% to 24% annually. Annual numbers of NPDS benzonatate cases increased across all pediatric age groups with greater absolute increases in the 0 to 5 and 10 to 16 year old groups (Table 1). Benzonatate cases represented a small proportion of the total cases in NPDS. In 2018 alone, patients 0 to 5 years old accounted for 44% of the 2.1 million cases for any substance.¹⁵  By contrast, only 468 benzonatate cases were reported to PCCs in 2018 for children 0 to 5 years old (799 benzonatate cases involved patients aged <17 years old) (Table 1).

Most NPDS benzonatate pediatric cases from 2010 to 2018 involved a single substance (3727 cases, 80%). Most of those cases were classified as unintentional exposures (3590 cases, 77%) (Table 1). The number of single-substance unintentional benzonatate exposure cases increased over time in children in all age groups (Fig 2). Most single-substance unintentional benzonatate exposure cases involved children 0 to 5 years old (2718 cases, 83%). Of the unintentional exposure cases in children <17 years old, 79% (1636 cases) had no clinical effect, 2.3% (48 cases) had a moderate clinical effect, 0.4% (8 cases) had a major clinical effect, and 0.1% (3 cases) resulted in death (Table 2). Death cases involved patients aged 9 months to 4 years and reported clinical effects included cardiac arrest, respiratory arrest, seizure, cough or choke, mydriasis, pupil(s) nonreactive, acidosis, hyperglycemia, electrolyte abnormality, excess secretions, bradycardia, and asystole. The annual number of multisubstance unintentional benzonatate exposure cases remained low and stable across all pediatric age groups (Fig 2). Cases involving intentional benzonatate exposure increased among children 10 to 16 years old for both single- and multiple-substance exposures with a more pronounced increase for multiple-substance exposures (Fig 2). Most intentional benzonatate exposure cases involving misuse or abuse were for children 10 to 16 years old (59 cases, 61%), and for single-substance exposures (74 cases, 77%). Among single-substance intentional misuse or abuse benzonatate exposure cases, 66% (31 cases) had no clinical effect, 13% (6 cases) had moderate clinical effects, and no cases had major clinical effects or death (Table 2). Most NPDS intentional suspected suicide cases involving benzonatate were for children 10 to 16 years old (904 cases, 99.8%) and involved multiple substances (602 cases, 66%). Single-substance suspected suicide benzonatate cases were associated with no clinical effect in 48% of cases, moderate clinical effects in 16% of cases, major clinical effects in 5% of cases, and death in 0.8% (Table 2).

Among the total 4689 benzonatate cases in NPDS, 3068 (65.4%) were referred to or treated in a health care facility. Overall, in the subset of NPDS benzonatate cases with related clinical effect, 95% had no serious medical outcome (ie, did not have moderate or major clinical effect, or death) (Table 1). By contrast, NPDS cases involving codeine-, hydrocodone-, and dextromethorphan-containing antitussive medications in children <17 years old decreased over the study period. Most of these cases (≥85%) involved single-substance exposures and were primarily unintentional exposures (Fig 3).

An estimated 2775 ED visits across the United States for ADEs involved benzonatate ingestion in children during the 2004 to 2018 period. National estimates of ED visits for ADEs in children <17 years old were of a similar magnitude for comparator codeine-containing antitussive medications (3742 visits) and hydrocodone-containing antitussive medications (2608 visits). The estimate appears higher for dextromethorphan-containing antitussive medications (12 336 visits). Unintentional ingestion, coded as “accidental drug intake by a child” (ADIC), accounted for nearly all ED visits for benzonatate-related exposures in children aged 0 to 5 years (2205 visits). Similarly, ADIC accounted for most of the ED visits reported for dextromethorphan-containing antitussive products in 0 to 5 year old patients. Although ADIC ED visits in the 0 to 5 year old age group for codeine- or hydrocodone-containing antitussive products were too small for stable national estimates, ADIC contributed to ∼49% of ED visits involving narcotic-containing cough and cold medicines (CCM) in patients in this age group.

From 2010 to 2019, AE reports for benzonatate in FAERS increased over time. The main cause for the increasing trend in FAERS reports was increased reporting in adult patients (Fig 4).

Ten FAERS cases described abuse, misuse, or unintentional exposure to benzonatate in pediatric patients. Six FAERS cases described clinical symptoms including cardiopulmonary arrest, seizures, dysrhythmias, metabolic derangements, vomiting, lethargy, coma, and loss of consciousness. Most of the cases (8 cases) described patients aged 10 to 16 years and the remaining cases (2 cases) described patients aged 0 to 5 years. Both cases in children 0 to 5 years old described unintentional ingestions leading to a fatal outcome. In contrast, all cases for children 10 to 16 years old reported intentional benzonatate ingestion, some specifying intention for suicide or abuse. All 8 of the intentional exposure cases resulted in hospitalizations and of these, 6 cases reported fatal outcomes.

Review of the literature published after 2010 identified 3 new cases of benzonatate overdose. The 3 cases were attributed to intentional overdose. One case involved an adult whose clinical outcome was death.¹⁶  The remaining 2 cases described children aged 13 and 17 years who had nonfatal outcomes of coma, seizures, hypotonia, cardiac dysrhythmias, and apnea.^17,18 

This study provides a comprehensive evaluation of drug utilization data, NPDS, NEISS-CADEs, FAERS, and the medical literature to understand benzonatate exposure and AE trends. The current study demonstrates that benzonatate utilization increased over the 2012 to 2019 period and that increase mirrored an increase in NPDS benzonatate exposure cases from 2010 to 2018. Recent studies evaluating benzonatate and CCM safety reported similar findings,^19–22  but this is the first study that focuses on benzonatate safety in pediatric patients and that concurrently provides the context of individual CCM utilization data.

The rise in benzonatate utilization may be a secondary effect of public health efforts to curb inappropriate narcotic prescription use, as prescriptions for codeine- and hydrocodone-containing antitussive medications simultaneously decreased over the same study period. The rise in benzonatate utilization noted in this study may also reflect patients’ commitment to obtaining pharmacological relief for cough and cold symptoms.^23–26  Approximately 4 million children <2 years old receive antitussive medications and other CCM weekly in the United States.²⁷  Despite broadcast public health concerns over the safety and lack of efficacy of CCM in young children, some studies show that parents continue to seek out CCM for their children,²⁶  sometimes despite warnings in labels.²⁸ 

Benzonatate safety considerations extend beyond the recognition of AEs that occur with appropriate prescribed use. The near negligible quantity of benzonatate prescriptions dispensed to children 0 to 5 years old in this study indicates a general trend for prescribing in accordance with the FDA-approved indication. Yet, the prominence of unintentional and ADIC exposure cases in 0 to 5 year old patients in the NPDS and NEISS-CADES data highlights the inherent risks associated with widespread availability of benzonatate. Accessibility to medical products at home presents a risk for unintentional ingestion in young children^29–31  as oral exploration is a normal part of development in infants, and young children may be enticed to consume objects that resemble candy. Previous studies demonstrated that in older children and adolescents, access to medical drug products in the home may lead to medical drug product misuse, abuse, and use in suicide attempts.^32–36  Consistent with these observations, findings from the NPDS data demonstrated an increase of intentional benzonatate exposure cases mostly for the purpose of suicide attempt in children 10 to 16 years old.

Benzonatate exerts its effects peripherally by desensitizing pulmonary vagal stretch receptors involved in the cough reflex.³⁷  Onset of action occurs 15 to 20 minutes and effects may last for 3 to 8 hours.^1,37  Structurally, benzonatate is related to local anesthetic agents in the para-amino-benzoic acid class (eg, procaine and tetracaine) and acts as a potent voltage-gated sodium channel inhibitor.^1,17,38,39  At supratherapeutic doses, benzonatate may cause neurologic and cardiovascular toxicity related to sodium channel blockade. Clinical manifestations may include restlessness and tremors that can progress to tonic-clonic convulsions, followed by central nervous system (CNS) depression resulting in cardiorespiratory arrest.^1,38  CNS effects may also be related to a prior sensitivity to related agents.^1,38,40,41  Case reports of toxicity with single doses of benzonatate suggest narrow therapeutic margins.^2,5,38,40  Inappropriate benzonatate administration potentiates the risk for toxicity as crushing or chewing benzonatate capsules can produce a local anesthetic effect of the oral mucosa and esophagus leading to choking, bronchospasm, laryngospasm, and cardiorespiratory collapse that mimics the systemic toxicity seen at higher doses.^1,2,5,38  Toxic effects can have rapid-onset and can lead to persistent and devastating neurologic effects.^4,6  Management of benzonatate toxicity involves general supportive measures, but awareness of benzonatate exposure may allow for more targeted treatment with agents that reverse sodium channel blockade or with lipid emulsion therapy.^16,38,42  However, recognition of benzonatate exposure is challenging as symptoms of benzonatate toxicity are nonspecific and routine laboratory screening for benzonatate is uncommon.^38,43 

Findings from this study prompt consideration for rational prescription for benzonatate.⁴⁴  Cough is often a symptom of underlying chemical, inflammatory, or mechanical irritation of the bronchial tree²²  and effective treatments involve evaluation and treatment of underlying conditions.²⁴  Therapies aimed at providing temporary relief from cough symptoms generally do not alter the course of underlying disease and do not demonstrate effectiveness in alleviation of cough symptoms, particularly in children.^45–52  Limited data for benzonatate effectiveness and evidence of hazards associated with increased use and availability may encourage prescription of supportive measures and other remedies, such as honey for the treatment of cough^53,54  in lieu of benzonatate in some cases. When benzonatate is prescribed, patients and caregivers should receive instruction on proper administration. Caregiver counseling should also include guidance on the appropriate storage of benzonatate and other medications in areas that are inaccessible to children.⁵⁵  Further communication about the proper disposal of unused medications may be appropriate as rates of toxic pediatric exposure to medical products remains high, despite the availability of childproof containers and other resources intended to reduce unintended drug exposure.⁵⁶  Additionally, improved provider and caregiver awareness of benzonatate toxic effects may prompt more expedient medical evaluation and treatment.

Although this study offers insight into benzonatate exposure trends and AEs in pediatric patients, it has several limitations. First, there was no confirmation of actual benzonatate exposure across the evaluated sources (FAERS, NPDS, or NEISS CADES). Another major study limitation is that taken at face value, all data sources potentially underestimate AEs for benzonatate and comparator drugs. This is because the data sources rely mostly on voluntary reporting (FAERS), calls to PCCs for advice by the public or healthcare professionals (NPDS), and small sampling and exclusion of cases that resulted in deaths within the ED (NEISS-CADES). Importantly, data sources may provide poor ascertainment of out-of-hospital deaths as drug exposures resulting in unattended or out of hospital death do not reliably result in an evaluation in the ED and are unlikely to generate a call to a PCC. Furthermore, the extent to which information is duplicated across these data sources is unknown. These limited data cannot be used to reliably measure whether there has been an increase in serious outcomes in children in excess of their increasing benzonatate utilization. Additionally, these data do not indicate whether benzonatate has a higher risk of serious outcomes in children than other antitussive medications as it was not possible to accurately quantify the number of exposures to all CCMs that are available by prescription or over-the-counter. More research is necessary to assess how the risk for these serious outcomes with benzonatate compares with that of other antitussive medications.

This analysis shows that although benzonatate prescription utilization represents a small percentage of pediatric antitussive medication use, there has been a rise in its unintentional ingestion in young children and its misuse and abuse in older children. These findings highlight the need for judicious prescription of benzonatate and continued vigilance for benzonatate-associated AEs as downstream effects of increased benzonatate prescribing may result in increased exposure in children for whom the drug was not prescribed. Anticipatory guidance at the time of benzonatate prescribing should include discussions with patients and caregivers about keeping benzonatate out of reach of children to avoid unintentional ingestions in younger children and potential misuse and use for suicide attempts by older children. Additionally, providers should educate themselves, patients, and caregivers on benzonatate’s safety profile at the time of prescribing to improve recognition of symptoms of toxicity (eg, restlessness, tremors, convulsions, or coma).

ADE

adverse drug event

ADIC

accidental drug intake by a child

AE

adverse event

CCM

cough and cold medicine

ED

emergency department

FAERS

FDA Adverse Event Reporting System

FDA

Food and Drug Administration

NEISS-CADES

National Electronic Injury Surveillance System – Cooperative Adverse Drug Event Surveillance

NPDS

National Poison Data System

PCC

poison control center