Absorption, Distribution and Excretion
Following oral administration, benzonatate is absorbed into the systemic circulation via the gastrointestinal tract. In healthy Chinese volunteers, the peak plasma concentration (Cmax) of benzonatate after oral administration of 100 mg was 1063 ± 460 ng/mL. Limited information is available regarding the elimination pathway of benzonatate. Limited information is available regarding the volume of distribution of benzonatate. Limited information is available regarding the clearance rate of benzonatate. Metabolism/Metabolites Benzonatate is hydrolyzed to its major metabolite, 4-(butanylamino)benzoic acid (BABA), by plasma butyrylcholinesterase (BChE). Biological Half-Life The half-life of benzonatate after oral administration of 100 mg in healthy Chinese volunteers was 1.01 ± 0.41 h.

Protein Binding
Information on the protein binding profile of benzonatate is limited. Interactions Benzonatate is chemically related to para-aminobenzoic acid anesthetics (e.g., procaine, tetracaine) and may be associated with adverse central nervous system reactions, possibly due to prior sensitivity to these drugs or interactions with concomitant medications.

[1]. Benzonatate toxicity in a teenager resulting in coma, seizures, and severe metabolic acidosis. J Pediatr Pharmacol Ther. 2012;17(3):270-273.

[2]. The Antitussive Benzonatate Is Not Tumorigenic in Rodent Carcinogenicity Studies. Toxicol Pathol. 2018;46(6):683-692.

Benzonatate is an ester formed by the condensation of 4-butanaminobenzoic acid and nonyl glycol monomethyl ether. Its structure is similar to procaine and benzocaine, and it has an anesthetic effect on pulmonary stretch receptors, making it suitable as a non-narcotic antitussive. It possesses both antitussive and anesthetic properties. Benzonatate is a benzoic acid ester, belonging to the class of substituted aniline and secondary amino compounds. Its function is related to 4-(butanamino)benzoic acid and nonyl glycol monomethyl ether. Benzonatate is an oral antitussive used to relieve and suppress cough in patients aged 10 years and older. Currently, Benzonatate is the only prescription-available non-narcotic antitussive. It works by reducing the sensitivity of lung and pleural tissues involved in the cough reflex. Benzonatate was approved by the U.S. Food and Drug Administration (FDA) in 1958 under the brand name Tessalon Perles. Due to its chemical structure being similar to para-aminobenzoic acid anesthetics such as procaine and tetracaine, Benzonatate has anesthetic or paralytic effects. Although benzonatate is not easily abused or misused, there is still a risk of serious poisoning and overdose, especially in children. Benzonatate is a non-narcotic antitussive. Its physiological action is achieved by reducing the activity of tracheobronchial stretch receptors. Benzonatate is a synthetic butylaminobenzoic acid derivative associated with tetracaine and is a peripherally acting non-narcotic antitussive. It reduces the cough reflex by anesthetizing and inhibiting mechanoreceptors in the airways, lungs, and pleura. It is recommended for relieving coughs caused by the common cold, bronchitis, pneumonia, and chronic coughs such as asthma. (NCI04)
See also: Ethylene oxide (monomers).

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Drug Indications
Benzonatate is indicated for the relief of cough symptoms.

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Mechanism of Action
Benzonatate is a local anesthetic that exerts its peripheral action by anesthetizing and reducing the activity of vagal stretch receptors or nerve fibers located in the airways, lungs, and pleura. Once stretch receptors are stimulated, they transmit impulses to the cough center in the medulla oblongata via afferent pathways composed of sensory nerve fibers or the vagus nerve. This generates an efferent signal that transmits the impulse to the expiratory muscles, resulting in a cough. Benzonatate anesthetizes these receptors, thereby inhibiting the cough reflex and the generation of a cough. Benzonatate also inhibits the transmission of cough reflex impulses in the vagus nucleus of the medulla oblongata. Benzonatate has multiple mechanisms of action; it is also a potent voltage-gated sodium channel inhibitor. Benzonatate apparently inhibits cough generation by anesthetizing stretch receptors in the vagus nerve afferent fibers that mediate the cough reflex in the bronchi, alveoli, and pleura; the drug also inhibits the cough reflex at the medullary level, where afferent impulses are transmitted to motor nerves. The relationship between the local anesthetic effect and its peripheral effects on sensory nerve endings is unclear.
Therapeutic Uses
Antidote
Tessalon is indicated for the relief of cough symptoms.
/Included in US Product Label/

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Drug Warnings
There have been reports of fatalities from accidental ingestion of Tessalon in children under 10 years of age. Overdose symptoms and signs usually appear within 15–20 minutes, and deaths are usually reported within 1 hour of ingestion. If accidental ingestion occurs, seek immediate medical attention.
The safety and efficacy of this product in children under 10 years of age have not been established. There have been reports of fatalities from accidental ingestion in children under 10 years of age. Keep out of reach of children.
Serious allergic reactions (including bronchospasm, laryngospasm, and cardiovascular failure) have been reported, which may be related to local anesthesia caused by sucking or chewing the capsule rather than swallowing. Severe reactions require vasopressors and supportive care.
Benzona ester is chemically related to para-aminobenzoic acid anesthetics (such as procaine, tetracaine) and may be associated with adverse central nervous system reactions, which may be related to a history of allergy to related drugs or interactions with concomitant medications. For more complete (8) drug warnings regarding benzonatate, please visit the HSDB record page.

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Pharmacodynamics
Benzonatate suppresses cough induced by acute and chronic respiratory illnesses. Its mechanism of action is to desensitize pulmonary stretch receptors involved in the cough reflex. Clinical trials of benzonatate are limited; however, early studies have shown that benzonatate can suppress experimentally induced cough and subjectively measured pathological cough. At the recommended dose, benzonatate does not suppress the respiratory center. It has an onset of action within 15 to 20 minutes after administration, and its duration of action is approximately 3 to 8 hours.

C30H53NO11

603.74192

603.362

C, 59.68; H, 8.85; N, 2.32; O, 29.15

104-31-4

119568-55-7 (HCl);104-31-4;

7699

Colorless to light yellow oily liquid

1.096 g/cm3

346.3ºC

9.98E-17mmHg at 25°C

1.495

2.907

1

12

33

42

565

0

CCCCNC1=CC=C(C=C1)C(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOC

MAFMQEKGGFWBAB-UHFFFAOYSA-N

InChI=1S/C30H53NO11/c1-3-4-9-31-29-7-5-28(6-8-29)30(32)42-27-26-41-25-24-40-23-22-39-21-20-38-19-18-37-17-16-36-15-14-35-13-12-34-11-10-33-2/h5-8,31H,3-4,9-27H2,1-2H3

2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-(butylamino)benzoate

Benzonatate; Tessalon; KM65; KM 65; KM-65; Exangit; Ventussin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~165.63 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.14 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)