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| Clinical data | |
|---|---|
| Trade names | Tessalon, others |
| Other names | Benzononatine; Egyt-13; KM-65[1] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682640 |
| License data | |
| Routes of administration | By mouth |
| Drug class | Antitussives;Local anesthetics;Sodium channel blockers |
| ATC code | |
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| Pharmacokinetic data | |
| Onset of action | 15–20 minutes[3][5] |
| Eliminationhalf-life | 1 hour[6][unreliable medical source?] |
| Duration of action | 3–8 hours[3][5] |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
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| ChemSpider |
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| UNII | |
| KEGG |
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| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.002.904 |
| Chemical and physical data | |
| Formula | C30H53NO11 |
| Molar mass | 603.750 g·mol−1 |
| 3D model (JSmol) | |
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Benzonatate (/bɛnˈzoʊnəteɪt/), sold under the brand nameTessalon among others, is a medication that is used for the symptomatic relief ofcough.[7][8] Benzonatate is takenby mouth.[7][5] Effects generally begin within 20 minutes and last between 3 and 8 hours.[7][3]
Side effects include sleepiness, dizziness, headache, upset stomach,skin rash,hallucinations, and allergic reactions.[7]Overdosage can result in seriousadverse effects includingseizures,irregular heartbeat,cardiac arrest, and death.[9][10] Overdose of only a small number of capsules can be fatal.[10] Chewing or sucking on the capsule, releasing the drug into the mouth, can also lead tolaryngospasm,bronchospasm, andcirculatory collapse.[7] It is unclear if use in pregnancy or breastfeeding is safe.[11] Benzonatate is alocal anesthetic andvoltage-gated sodium channelblocker.[6][unreliable medical source?] It is theorized to work by inhibitingstretch receptors in the lungs, in turn suppressing thecough reflex in the brain.[7] Benzonatate isstructurally related to other local anesthetics likeprocaine andtetracaine.[12][7]
Benzonatate was discovered in 1956 and was approved for medical use in the United States in 1958.[5][7] It is available as ageneric medication.[9] Availability worldwide is limited, with the drug remaining marketed only in the United States and Mexico.[13][12][14] In 2022, it was the 130th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[15][16] A 2023systematic review found that there is inadequate evidence to support the effectiveness and safety of benzonatate for cough and highlighted rising safety concerns.[17]
Benzonatate is a prescription non-opioid alternative for the symptomatic relief ofcough.[7][9] It has been found to improve cough associated with a variety of respiratory conditions includingasthma,bronchitis,pneumonia,tuberculosis,pneumothorax, opioid-resistant cough inlung cancer, andemphysema.[7][5][18]
Benzonatate also reduces the consistency and volume of sputum production associated with cough in those withchronic obstructive pulmonary disease (COPD).[5]
Compared tocodeine, benzonatate has been reported to be more effective in reducing the frequency of induced cough in experiments.[7]
Benzonatate does not treat the underlying cause of the cough.[19]
According to a 2001literature review, more than 29 clinical studies have assessed benzonatate for the treatment of cough in more than 2,100 patients.[5]
Asystematic review of the literature of benzonatate for cough was published in 2023.[17] The review identified 37 relevant articles including 21cohort studies, 5experimental studies, and 11case studies andseries.[17] The data were of very lowquality.[17] Most of the studies on benzonatate are decades old and were conducted shortly after its introduction.[12] The systematic review concluded that there is inadequate evidence to support theeffectiveness andsafety of benzonatate and emphasized rising safety concerns surrounding the drug.[17] It further concluded that there is a need for largeobservational studies orrandomized trials to assess the place of benzonatate in modern medicine.[17]
Benzonatate has been reported to be useful in the suppression of hiccups.[8]
Benzonatate acts as alocal anesthetic and the liquid inside the capsule can be applied in the mouth to numb theoropharynx for awake intubation.[7] However, there can be life-threatening adverse effects when the medication is absorbed by the oral mucosa, including choking, hypersensitivity reactions, and circulatory collapse.[7]
Benzonatate is available in the form of 100, 150, and 200 mgoralcapsules.[5][3][20]
Hypersensitivity to benzonatate or any related compounds is a contraindication to its administration.[3]
Benzonatate is generally well-tolerated[vague] if the liquid-capsule is swallowed intact.[7] Potentialadverse effects of benzonatate include:
Benzonatate is structurally related toanesthetic medications of thepara-aminobenzoic acid (PABA) class which includesprocaine andtetracaine.[3][22][12] Procaine and tetracaine, previously used heavily in the fields ofdentistry andanesthesiology, have fallen out of favor due to allergies associated with their metabolites.[22] Similarly, severe hypersensitivity reactions to benzonatate have been reported and include symptoms oflaryngospasm,bronchospasm, andcardiovascular collapse.[3][23] These reactions are possibly associated with chewing, sucking, or crushing the capsule in the mouth.[3][22]
Benzonatate should be swallowed whole.[3] Crushing or sucking on the liquid-filled capsule, or "softgel," will cause release of benzonatate from the capsule and can produce a temporarylocal anesthesia of theoral mucosa.[3] Rapid development of numbness of the tongue and choking can occur.[3][22] In severe cases, excessive absorption can lead tolaryngospasm,bronchospasm,seizures, andcirculatory collapse.[3][22] This may be due to a hypersensitivity reaction to benzonatate or a systemiclocal anesthetic toxicity, both of which have similar symptoms.[22] There is a potential for these adverse effects to occur at a therapeutic dose, that is, a single capsule if chewed or sucked on in the mouth.[22]
Isolated cases of bizarre behavior, mental confusion, and visual hallucinations have been reported during concurrent use with other prescribed medications.[3]Central nervous system effects associated with otherpara-aminobenzoic acid (PABA) derivative local anesthetics, for exampleprocaine ortetracaine, could occur with benzonatate and should be considered.[7]
Safety and efficacy in children below the age of ten have not been established.[3] Accidental ingestion resulting in death has been reported in children below the age of ten.[3] Benzonatate may be attractive to children due to its appearance, a round-shaped liquid-filled gelatin capsule, which looks like candy.[23][24] Chewing or sucking of a single capsule can cause death of a small child.[3][24] Signs and symptoms can occur rapidly after ingestion (within 15–20 minutes) and include restlessness, tremors,convulsions,coma, and cardiac arrest.[24] Death has been reported within one hour of ingestion.[21][24]
It is not known if benzonatate can cause fetal harm to a pregnant woman or if it can affect reproduction capacity.[3][11] Animal reproductive studies have not been conducted with benzonatate to evaluate itsteratogenicity.[3]
It is not known whether benzonatate is excreted in human milk.[3][11]
Benzonatate is chemically similar to otherlocal anesthetics such astetracaine andprocaine, and shares theirpharmacology andtoxicology.[22]
Benzonatate overdose is characterized by symptoms of restlessness, tremors,seizures,abnormal heart rhythms (cardiac arrhythmia),cerebral edema,absent breathing (apnea),fast heart beat (tachycardia), and in severe cases, coma and death.[7][3][25][19] Symptoms develop rapidly, typically within 5 minutes to 1 hour of ingestion.[3][19][10] Treatment focuses on the removal of gastric contents and managing symptoms of sedation, convulsions, apnea, and cardiac arrhythmia.[3]
Despite a long history of safe and appropriate usage, the safety margin of benzonatate is reportedly narrow.[22] Toxicity above the therapeutic dose is relatively low and ingestion of a small handful of pills can cause symptoms of overdose.[22][19] Children are at an increased risk for toxicity, which has occurred with administration of only one or two capsules.[24][25][19] Following cardiopulmonary collapse with benzonatate overdose, most people have significantneurological deficits or other end-organ damage.[10]
Due to increasing usage of benzonatate and the rapid onset of symptoms, there are accumulating cases of benzonatate overdose deaths, especially in children.[19][10]
Benzonatate is chemically similar to otherlocal anesthetics such astetracaine andprocaine, and shares theirpharmacology.[22]
Similar to otherlocal anesthetics, benzonatate is apotentvoltage-gated sodium channelblocker.[22] After absorption and circulation to the respiratory tract, benzonatate acts as alocal anesthetic, decreasing the sensitivity ofvagalafferent fibers andstretch receptors in thebronchi,alveoli, andpleura in thelower airway andlung.[7][8] This dampens their activity and reduces thecough reflex.[7][3] Benzonatate also has centralantitussive activity on the cough center in central nervous system at the level of themedulla.[7][5] However, there is minimal inhibition of therespiratory center at a therapeutic dosage.[3]
Theantitussive effect of benzonatate begins within 15 to 20 minutes afteroral administration and typically lasts between 3 and 8 hours.[3][5] Theelimination half-life of benzonatate has been reported to be 1 hour.[6][unreliable medical source?]
Benzonatate is hydrolyzed by plasmabutyrylcholinesterase (BChE) to the metabolite 4-(butylamino)benzoic acid (BABA) as well as polyethylene glycol monomethyl ethers.[22] Like many other local anesthetic esters, thehydrolysis of the parent compound is rapid.[22] There are concerns that those withpseudocholinesterase deficiencies may have an increased sensitivity to benzonatate as this hydrolysis is impaired, leading to increased levels of circulating medication.[22]
Aside from oral administration, benzonatate has also been used by a variety of otherroutes, includingrectal administration,subcutaneous injection,intramuscular injection, andintravenous infusion.[5]
Benzonatate is abutylamine,para-amino-benzoic acid, or long-chainpolyglycol,structurally related to otherester local anesthetics such asprocaine andtetracaine.[22][12] Themolecular weight of benzonatate is 603.7 g/mol.[3] However, the reference standard for benzonatate is a mixture of n-ethoxy compounds, differing in the abundance of 7 to 9 repeating units, with an average molecular weight of 612.23 g/mol.[22] There is also evidence that the compound is not uniform between manufacturers.[22]
Benzonatate was firstsynthesized in 1956 and was introduced as an antitussive in the United States in 1958.[5]
Benzonatate was first made available in the United States in 1958 as a prescription medication for the treatment of cough in individuals over the age of 10.[24][25] There is a variety of prescriptionopioid-based cough relievers, such ashydrocodone andcodeine, but have unwanted side effects and potential of abuse and diversion.[22] However, benzonatate is currently the onlyprescription non-opioidantitussive and its usage has been rapidly increasing.[22][19] The exact reasons of this increase are unclear.[19]
In the United States between 2004 and 2009, prescriptions increased 50% from 3.1 million to 4.7 million, the market share of benzonatate among antitussives increased from 6.3% to 13%, and the estimated number of children under the age of 10 years receiving benzonatate increased from 10,000 to 19,000.[22][19] Throughout this same period, greater than 90% of prescriptions were given to those 18 or older.[19] The majority of prescriptions were given by general, family, internal, and physicians with pediatricians accounting for about 3% of prescribed benzonatate.[19]
In 2022, it was the 130th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[15][16]
Tessalon is a brand name version of benzonatate manufactured by Pfizer.[22][19] It is available as perles (capsules).[3] Zonatuss was a brand name manufactured by Atley Pharmaceuticals, Inc. and Vertical Pharmaceuticals, Inc.[26][27] Other brand names of benzonatate include Exangit, Tessalin, Tesalon, Tusical, Tusitato, and Ventussin.[1]
Benzonatate is available in the United States and Mexico.[12][14]
