The Case:
A 4-year-old boy born with no past medical history presents in cardiac arrest. As resuscitation measures are underway, you obtain collateral from EMS and parents. The patient’s sibling had recently been diagnosed with a viral upper respiratory infection and was prescribed a cough suppressant. Unfortunately, the medication had been left within reach of the child and an unknown number of capsules were ingested. Time of ingestion is approximated to be 1 hour prior to arrival. The parents describe the medication as having a candy-like appearance. After realizing the patient had ingested this medication, they noticed the patient becoming progressively more somnolent and subsequently seizing prompting their call to emergency services. Upon EMS arrival, the patient was in cardiac arrest. EMS shows you the prescription bottle with a handful of capsules remaining.
History:
Benzonatate was introduced as a non-narcotic, peripherally-acting antitussive medication in 1958. Decades later, the opioid epidemic would cause devastation throughout the country leading to a shift away from opioid prescribing. During this timeframe, a rapid increase in prescriptions for non-opioid antitussives such as benzonatate would be seen. From 2004 to 2009, prescriptions in the US increased by 50%. The market share of benzonatate amount antitussives increased from 6.3% to 13%. Additionally, the estimated number of children under age of 10 years receiving benzonatate increased from 10,000 to 19,000.
With this rapid rise in prescriptions of benzonatate emerged more case reports of toxicity, especially in children. This subsequently led the FDA to issue a Black Box Warning in 2010 which warned that the capsules resemble candy and may be visually appealing to young children. Alarmingly, toxicity from benzonatate in children less than 2 years of age has been reported following accidental ingestion of as few as 1 or 2 capsules.
Chemical Structure and Mechanism of Action:
Figure 2: Benzonatate vs. Tetracaine
Benzonatate is structurally related to the ester group of local anesthetics which results in similarities in mechanism of action and toxicity through sodium channel blocking properties. It is a potent voltage-gated sodium channel inhibitor and acts by anesthetizing the pulmonary stretch receptors in the respiratory tract to suppress the cough reflex. The onset of action ranges from 15 to 20 minutes and the duration of actions varies from 3 to 8 hours.
Toxicity:
The safety margin of benzonatate is reportedly narrow and signs and symptoms of overdose can occur rapidly after ingestion. Deaths in children have been reported within hours of accidental ingestion. Overdose results in neurologic and cardiovascular toxicity and collapse related to sodium channel blockade properties. Signs and symptoms of toxicity include alerted mental status, seizures, CNS depression, apnea, respiratory failure, hypotension, ventricular dysrhythmias, and cardiac arrest. If a therapeutic dose is chewed, it can lead to bronchospasm, laryngospasm, seizures, and cardiovascular collapse which further reinforces the danger to children.
Treatment:
The mainstay of treatment is supportive care. Seizures should be treated with benzodiazepines. Cardiac dysrhythmias should be treated in the standard fashion. If a wide complex rhythm is present on ECG, sodium bicarbonate boluses (to overcome sodium channel blockade) should be administered. GI decontamination may be contraindicated as the rapid onset of toxicity may result in the patient presenting altered and unstable upon arrival. Lipid emulsion therapy carries a theoretical benefit given similar structure and toxicity to local anesthetic agents, however, there have not yet been reports on the use of lipid emulsion therapy for benzonatate toxicity. If the patient does not respond to resuscitative measures, cardiopulmonary bypass and extracorporeal membrane oxygenation may be considered. Early consultation with the poison center is prudent.
Authored by Sumeet Sandhu, DO
Faculty reviewer: Jenny Lu, MD
References:
Sandra C. Bishop-Freeman, Erin M. Shonsey, Laura W. Friederich, Michael C. Beuhler, Ruth E. Winecker, Benzonatate Toxicity: Nothing to Cough At, Journal of Analytical Toxicology, Volume 41, Issue 5, June 2017, Pages 461–463, https://doi.org/10.1093/jat/bkx021
McLawhorn MW, Goulding MR, Gill RK, Michele TM. Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration. Pharmacotherapy. 2013 Jan;33(1):38-43. doi: 10.1002/phar.1153. PMID: 23307543.
M. Steven Evans, G. Benton Maglinger, Anita M. Fletcher, Stephen R. Johnson, Benzonatate inhibition of voltage-gated sodium currents, Neuropharmacology, Volume 101,2016,Pages 179-187,ISSN 0028-3908, https://doi.org/10.101 6/j.neuropharm.2015.09.020.
"FDA Drug Safety Communication: Death resulting from overdose after accidental ingestion of Tessalon (benzonatate) by children under 10 years of age". U.S. Food and Drug Administration (FDA). 28 June 2019. Retrieved 22 April 2020.
Thimann DA, Huang CJ, Goto CS, Feng SY. Benzonatate toxicity in a teenager resulting in coma, seizures, and severe metabolic acidosis. J Pediatr Pharmacol Ther. 2012;17(3):270-273. doi:10.5863/1551-6776-17.3.270
Jin C, Zahid E, Sherazi A, Majumder MR, Bedi P. Cardiac Arrest Due to Benzonatate Overdose. Am J Case Rep. 2019;20:640-642. Published 2019 May 3. doi:10.12659/AJCR.915151
Important drugs for cough in advanced cancer. Homsi J, Walsh D, Nelson KA. Support Care Cancer. 2001 Nov; 9(8):565-74.