Benzonatate Toxicity: Nothing to Cough At
Acute cough caused by a viral upper respiratory infection (URI) and other etiologies is a common diagnosis made by health care providers. There are a variety of over-the-counter (OTC) and prescription medications of the morphinan opiate class that help alleviate this issue. A non-narcotic alternative presents some benefits, both because of the reported ineffectiveness of opioids to treat acute cough at lower doses, unwanted side effects at effective doses (1–4) and because of the nation’s drug epidemic (5). Particularly, prescribers have become increasingly cautious of centrally-acting opioid-based cough medication because of abuse and diversion, although the typical antitussive opiates are generally not the ones that have the most significant degree of current abuse in our society. Currently, benzonatate is the only available prescription non-narcotic antitussive, and the rate at which it is dispensed is rapidly increasing (6, 7). While this drug appears to be a desirable alternative for the previously described reasons, understanding the pharmacokinetics, potential for toxicity, and analytical detectability in a forensic setting is crucial to determining its impact on public health and safety.
Benzonatate (Tessalon® Perles) was approved in 1958 as a peripherally-acting antitussive for its ability to inhibit cough before its mechanism of action was completely understood. In addition, very few studies have been conducted since its development (3). Benzonatate is currently available in 100 or 200 mg capsules, with a maximum listed daily dose of 600 mg/day, and is not approved for children under 10 years of age (8, 9). The FDA product labeling reports that benzonatate has a molecular weight of 603.7 g/mol with a side chain of nine ethoxy units. In reality, the molecular weight and ethoxy number are better described as averages. Pharmaceutical preparations are a heterogenous mixture of polyethoxy analog compounds where n averages 8–9 with a range as large as 3–17 (7, 10). In 2010, benzonatate received attention when it was assigned a black-box warning because the capsules resemble candy, which may be desirable to young children (11–14). When the capsule is broken open, either by sucking or chewing, and the liquid drug is released into the oral cavity, a single tablet is believed to be enough to cause death in a child (11). McLawhorn et al. describe fatalities in 20 of the 31 overdose cases reported to the FDA Adverse Event Reporting System (AERS), recognizing a rapid onset of symptoms (within 1 h) and a relatively low margin for safety (6).
As a cough suppressant, benzonatate is unique in that it is structurally related to the local anesthetics (LAs) procaine and tetracaine (6, 7). Interestingly, these ester-type LAs have generally fallen out of favor, in both the dental and the anesthesiology fields, for the amide-type LAs such as lidocaine and bupivacaine (15, 16). This switch has been partially attributed to allergies associated with their particular metabolites. Unusual reactions to p-aminobenzoic acid (PABA)-derived ester-based LAs have been associated with these underlying allergies; however, the incidence of true IgE-mediated reactions is unknown and presumed to be rare (15–18). Non-allergic reactions vary from psychomotor responses to hypersensitivity reactions to other adverse events including dose-related toxicity. Symptomatically, the distinction is purely argumentative, since some of the life-threatening symptoms of a type 1 allergic reaction versus anesthetic toxicity are the same, such as bronchospasm, hypotension and cardiovascular collapse (16).
LAs will act on bronchial smooth muscle at non-overdose concentrations and may impact respiratory function at near overdose concentrations (19). Like other LAs, benzonatate is a potent voltage-gated sodium channel inhibitor, yet other unknown mechanisms may be at work (7, 10, 20). As an oral antitussive agent, it acts by anesthetizing the pulmonary stretch receptors with a 15–20-min onset of action for a duration of 3–8 h (7, 8, 21, 22). Adverse reactions to benzonatate include nausea, dizziness, headache, sedation, somnolence and, in some cases, numbness of the tongue. Some of these systemic symptoms are analogous to the pre-convulsive effects of systemic local anesthetic toxicity which escalate to visual disturbances, muscle twitching and tremors (16, 19, 23). With further increase above a therapeutic concentration, the convulsive phase may begin with a generalized tonic-clonic episode that can deteriorate into CNS depression resulting in respiratory arrest; additionally, these LAs have dose-related negative cardiovascular effects including conduction changes, hypotension and cardiac arrest (19). Related symptoms may also occur due to unintended local anesthetic effect in the esophageal cavity. When a therapeutic dose, administered as a single capsule, is chewed or crushed, there is potential for bronchospasm, laryngospasm, seizures and cardiovascular collapse which mimics the systemic toxicity seen at high doses (6, 15, 19, 20).
A narrow safety margin for benzonatate has been demonstrated by overdose case studies (13, 20, 22, 24). In several of the published over-ingestion cases, as well as those observed in our office, only a small handful of pills was enough to cause seizures, a cardiac event and death. Interestingly, the product insert directs one to not double up a missed dose of benzonatate and only take a maximum of 200 mg at a time. Blood data is inconclusive or unavailable in the majority of death cases (6, 10), however fatalities have been reported with blood concentrations of 5 and 35 mg/L (9, 22). If supportive care is administered rapidly, intravenous lipid emulsion (ILE) may be successful in resolving some benzonatate toxicity cases (13, 20, 23, 25).
Benzonatate is analytically problematic and will be underestimated in forensic laboratory reports because of the chemical and pharmacological make-up of this prescription product. Details obtained through investigation by the medical examiner helped to support the possibility of benzonatate over-ingestion in some of our in-house cases. Benzonatate is rapidly hydrolyzed by plasma butyrylcholinesterase (BChE) to the major metabolite 4-(butylamino)benzoic acid (BABA) along with the corresponding polyethylene glycol monomethyl ethers (Figure 1) (7, 9, 21). The series of polyethoxy metabolites (e.g., n = 9 identified by the NIST mass spectral database as 2-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethanol) and BABA (identified by comparison to a USP standard) are detectable in our acidic/neutral screen described in previous publications (26) and a phthalate peak of unknown origin appears in our basic drug extraction (27). Once the metabolic peak pattern became recognizable, the North Carolina Office of the Chief Medical Examiner (N.C. OCME) discovered three benzonatate-related cases over the past year and a total of six potential cases since 2012. It is possible that past benzonatate-related cases were not identified based on our previous lack of knowledge. Figure 1.
Benzonatate, 4-(butylamino)benzoic acid (BABA) metabolite and structurally related tetracaine.
Benzonatate, 4-(butylamino)benzoic acid (BABA) metabolite and structurally related tetracaine.
Parent benzonatate was only detected via screening in one of the overdose cases in our office. It appeared as a late-eluting compound after trazodone in the base screen and was quantitated by a reference laboratory using traditional HPLC methodology. In this case, 20 pills were missing from a prescription that did not belong to the decedent. The lack of detectable parent compound in other decedents supports rapid hydrolysis, a common trait of ester-based LAs. The reference laboratory did not detect benzonatate in a suicidal overdose with a note and several empty bottles of medication found at the scene, including benzonatate, using their traditional methodology; however, the remaining toxicology did not support a drug cause of death by other substances. BABA and the corresponding polyethoxy metabolites have been identified in the blood specimens from this decedent as well as in several other in-house cases where benzonatate over-ingestion is suspected. Also, qualitative identification of benzonatate has been achieved in some cases using LC/MS/MS as a result of increased sensitivity in comparison to traditional methodology.
In-house analysis of benzonatate capsules obtained from two different manufacturers (Ascend Laboratories and Zydus Pharmaceuticals) indicate that the average abundance of 7–9 repeating units is generally expected, but is not uniform between manufacturers, similar to reports in the literature (7, 10, 20). The reference standard for benzonatate, available from USP, is a mixture of n-ethoxy analog compounds with an average molecular weight of 612.23 g/mol (28). Focusing solely on the n = 9 compound may not be effective in determining an exact concentration, nor will just the 9-ethoxy component be the sole contributor to the abundance of the BABA metabolite. Evans et al. have demonstrated the inability of the BABA metabolite to block voltage-gated sodium currents at 100 µM, and other mechanisms may be at work; however, this metabolite will be the best candidate for detection of benzonatate exposure (7, 21). Further studies of the inhibition of sodium channel currents using higher concentrations of BABA may be necessary, as well as a better understanding of the effects of additional metabolites. Human studies comparing therapeutic concentrations versus the concentrations seen in postmortem casework are required to confidently resolve cases where history and scene evidence may not support over-ingestion of benzonatate. The pseudocholinesterase deficient portion of the population may be prone to increased sensitivities of this cough medication (16) because of diminished ability to hydrolyze the parent compound and thus potential prolongation of increased benzonatate activity. Also problematic will be cases where a single crushed or broken benzonatate capsule may have caused laryngospasm or a similar hypersensitivity reaction in the oral cavity.
Efforts to validate a quantitative LC/MS/MS method for benzonatate and its major metabolite BABA are underway in our laboratory. Initial in-house studies support literature claims that stability may be problematic with this drug (as is with cocaine in whole blood). Even more challenging is the rapid metabolism of the series of n-ethoxy parent compounds without a suitable pure standard available for quantitation of each specific molecular weight. Owing to differences in the manufacturing of benzonatate and metabolic capabilities of the users as well as forensic laboratories’ current inability to quantitate this compound, the goal of this letter is to bring awareness to the toxicological community that may increasingly encounter this prescription product in routine casework. Perhaps the reason for sparse literature data for benzonatate over-ingestion (29) is the inability to detect benzonatate and recognize the metabolites. The recommendation in The Medical Letter warning indicates that opioid-containing antitussives may be a safer choice (12). Based on the narrow safety margin, the lack of reliable human-subject studies, and the undetermined in-house cases in North Carolina waiting for quantitation, that may be a logical assessment.
1 Reynolds, S.M. , Mackenzie, A.J. , Spina, D. , Page, C.P. (2004) The pharmacology of cough. Trend in Pharmacological Sciences, 25, 569–576. 2 Dicpinigaitis, P.V. (2009) Currently available antitussives. Pulmonary Pharmacology & Therapeutics, 22, 148–151. 3 Dicpinigaitis, P.V. , Gayle, Y.E. , Solomon, G. , Gibert, R.D. (2009) Inhibition of cough-reflex sensitivity by benzonatate and guaifenesin in acute viral cough. Respiratory Medicine, 102, 902–906. 4 Dicpinigaitis, P.V. (2015) Clinical perspective-cough: an unmet need. Current Opinion in Pharmacology, 22, 24–28. 5 Understanding the Epidemic. Drug Overdose deaths in the United States hit record numbers in 2014. (2016, December 6). Retrieved from https://www.cdc.gov/drugoverdose/epidemic/ 6 MW1, McLawhorn , Goulding, M.R. , Gill, R.K. , Michele, T.M. (2013) Analysis of benzonatate overdoses among adults and children from 1969–2010 by the United States Food and Drug Administration. Pharmacotherapy, 33, 38–43. 7 Evans, M.S. , Maglinger, G.B. , Fletcher, A.M. , Johnson, S.R. (2016) Benzonatate inhibition of voltage-gated sodium currents. Neuropharmcology, 101, 179–187. 8 Tessalon® . Pfizer, Inc., Madison, NJ; 2010. 9 Baselt, R.C. (ed). Disposition of Toxic Drugs and Chemicals in Man, 9th edition. Biomedical Publications: Seal Beach, CA, 2011; p.158. 10 Crouch, B.I. , Knick, K.A. , Crouch, D.J. , Matsumura, K.S. , Rollins, D.E. (1998) Benzonatate overdose associated with seizures and arrhythmias. Clinical Toxicology, 36, 713–718. 11 Food and Drug Administration. FDA Drug Safety Communication: death resulting from overdose after accidental ingestion of Tessalon (benzonatate) by children under 10 years of age. http://www.fda.gov/drugs/drugsafety/ucm236651.htm (accessed Aug 12, 2016). 12 Abramowicz, Mark (2011) In brief: benzonatate warning. The Medical Letter on Drugs and Therapeutics, 53, 9. 13 Thimann, D.A. , Huang, C.J. , Goto, C.S. , Feng, S.Y. (2012) Benzonatate toxicity in a teenager resulting in coma, seizures and severe metabolic acidosis. The Journal of Pediatric Pharmacology and Therapeutics, 17, 270–273. 14 Fuchs, A. (2011, February 4) Benzonatate: A cough Suppressant so dangerous, you’d rather just cough . Retrieved from http://www.jewishjournal.com/nicejewishdoctor/item/benzonatate_a_cough_suppressant_so_dangerous_youd_rather_just_cough_2011020 15 Becker, D.E. (2012) Local anesthetics: review of pharmacological considerations. Anesthesia Progress, 59, 90–102. 16 Eggleston, S.T. , Lush, L.W. (1996) Understanding allergic reactions to local anesthetics. The Annals of Pharmacotherapy, 30, 851–857. 17 Speca, S.J. , Boynes, S.G. , Cuddy, M.A. (2010) Allergic reactions to local anesthetic formulations. Dental Clinics of North America, 54, 655–664. 18 Bhole, M.V. , Manson, A.L. , Seneviratne, S.L. , Misbah, S.A. (2012) IgE-mediated allergy to local anaesthetics: separating fact from perception: a UK perspective. British Journal of Anaestheisa, 108, 903–911. 19 Malamed, S.F. Handbook of Local Anesthesia, 6th edition. Mosby/Elsevier, St. Louis, MO. 20 Cohen, V. , Jellinek, S.P. , Stansfield, L. , Truong, H. , Baseluos, C. , Marshall, J.P. (2011) Cardiac arrest with residual blindness after overdose of Tessalon® (benzonatate) perles. The Journal of Emergency Medicine, 41, 166–171. 21 Lin, W.J. , Chen, Y.Y. , Chen, R.R. (1999) Degradation kinetics of benzonatate in aqueous solutions. International Journal of Pharmaceutics, 176, 179–186. 22 Cohan, J.A. , Manning, T.J. , Lukash, L. , Long, C. , Ziminski, K.R. , Conradi, S.E. (1986) Two fatalities resulting from Tessalon (benzonatate). Veterinary and Human Toxicology, 28, 543–544. 23 Felice, K.L. , Schumann, H.M. (2008) Intravenous lipid emulsion for local anesthetic toxicity. Journal of Medical Toxicology, 4, 184–191. 24 Yoshioka, I. , Surmaitis, R. , Katz, K.D. (2016) A 17-year-old girl with cough-pulseless after drug overdose. Pediatric Emergency Care, 32, 197–199. 25 Ciechanowicz, S. , Patil, V. (2012) Lipid emulsion for local anetstetic systemic toxicity. Anesthesiology Research and Practice, 2012, 1–11. 26 Bishop-Freeman, S.C. , Miller, A. , Hensel, E.M. , Winecker, R.E. (2015) Postmortem metaxalone (Skelaxin®) data from North Carolina. Journal of Analytical Toxicology, 39, 629–636. 27 Bishop-Freeman, S.C. , Feaster, M.S. , Miller, A. , Beal, J.L. , Hargrove, R. , Brower, J.O. et al. . (2016) Loperamide-related deaths in North Carolina. Journal of Analytical Toxicology, 40, 677–686. 28 Benzonatate . U.S. Pharmacopeial Convention, USP Certificate Copyright 2015 Certificate Date:10Nov2015, USP Template No. CERT1_4-03. Catalog No.: 1056005. 29 Winter, M.L. , Spiller, H.A. , Griffith, J.R. (2010) Benzonatate ingestion reported to the National Poison Center Database System (NPDS). Journal of Medical Toxicology: Official Journal of the American College of Medical Toxicology, 6, 398–402. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Medical Editor: John P. Cunha, DO, FACOEP
Last reviewed on RxList 12/17/2018
Benzonatate is a nonnarcotic antitussive (anti-cough) drug used to relieve cough symptoms. Benzonatate is available in generic form. Common side effects of benzonatate include:
- stomach upset,
- stuffy nose,
- hypersensitivity reactions,
- visual hallucinations,
- skin breakouts,
- burning in the eyes, and
The usual dose of benzonatate for adults and children over 10 years of age is one 100 mg softgel three times daily as required. If necessary, up to 6 softgels daily may be given. Benzonatate may interact with other medications that cause drowsiness including, cough and cold medications, antihistamines, anti-seizure drugs, medicine for sleep or anxiety, muscle relaxants, narcotics, or psychiatric medicines. Tell your doctor all medications and supplements you use. During pregnancy, benzonatate should be used only if prescribed. It is unknown if this drug is excreted in breast milk. Consult your doctor before breastfeeding.
Our Benzonatate Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
February 7, 2011 (Issue: 1357) Select a term to see related articles benzonatate Codeine Dextromethorphan Drug Safety Tessalon Perles
The FDA recently warned that accidental ingestion of the antitussive benzonatate (Tessalon Perles, and others) by children less than 10 years old can be fatal.1 This widely prescribed oral agent, which has been available in the US since 1958, can also cause severe morbidity and death in older children and adults, and not only in overdosage.
Benzonatate is a polyglycol derivative structurally related to procaine and tetracaine. It acts peripherally on stretch receptors in the lower respiratory tract to suppress the cough reflex. If the patient chews or sucks the liquid-filled capsules or “softgels”, the drug can cause laryngospasm, bronchospasm and circulatory collapse. Adverse effects that can occur after swallowing an intact capsule include a feeling of numbness in the chest, mental confusion, a sensation of burning in the eyes, and visual hallucinations.
Taken in overdose, benzonatate can rapidly cause seizures, cardiac arrhythmias and death. Serious adverse outcomes reported to the National Poison Center between 2000 and 2006 occurred in 116 patients (41 in children <6 years old), with 4 deaths.2 The 5 children known to the FDA who died from benzonatate ingestion were ≤2 years old and some apparently took only one or two capsules. In one well-documented case report, a 17-year-old girl who intentionally took 10 or more 200-mg capsules developed seizures, cardiac arrest from which she was resuscitated, and then blindness, which persisted.3 When a cough suppressant is truly necessary, dextromethorphan or even codeine might be a safer choice.
Benzonatate is the generic name of the brand-name drug Tessalon (the gelcaps are called Tessalon Perles). The medication is a non-narcotic, prescription cough medicine.
Benzonatate belongs to a subgroup of cough medications known as antitussives, which control your cough by numbing and suppressing reflexes in your airways and lungs.
Benzonatate is chemically similar to medications that are called “ester-type local anesthetics.” These include the painkillers procaine, tetracaine, and lidocaine, which numb the skin, muscles, or gums before medical and dental procedures.
Tessalon was originally approved by the Food and Drug Administration (FDA) in 1958, and is manufactured by Pfizer.
In 2010, the FDA issued a new warning to keep the drug away from young children because of accidental overdoses and deaths.
There have been an unusual number of cases where children have taken benzonatate, resulting in death. Children may be attracted to the way the capsule looks.
The FDA says that parents should keep the pills in child-proof containers, and out of the sight and reach of kids.
Some people have had life-threatening allergic reactions to benzonatate, causing the muscles in their throats to spasm and constrict, making it hard to breathe, or creating a sudden and dangerous drop in blood pressure.
Get emergency medical help immediately if you experience any of these symptoms, and make sure your doctor knows about all your allergies before you take benzonatate.
Benzonatate may cause severe reactions or death if you chew or suck on the medication, instead of immediately swallowing it with water. So you should be sure to swallow benzonatate capsules without chewing or sucking on them.
Although it is uncommon, benzonatate may cause confusion, hallucinations, or strange behavior. Get medical help right away if you experience any of these.
Pregnancy and Benzonatate
Benzonatate falls under the FDA’s Pregnancy Category C, which means we don’t know if this medication will cause harm to a fetus. You should tell your doctor if you are pregnant or plan to become pregnant before taking this medication.
It’s not known whether benzonatate crosses into breast milk. Be sure to tell your doctor if you are breastfeeding or plan to breastfeed before taking benzonatate.