Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

BENZONATATE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Benzonatate, a nonnarcotic oral antitussive, that acts peripherally by anesthetizing the stretch receptors located in the respiratory passage, lungs, and pleura by dampening their activity and thereby reducing the cough reflex at its source. It begins to act within 15 to 20 minutes. It is structurally related to tetracaine and other local anesthetics.

Specific Substances

    1) Benzononatine
    2) KM-65
    3) Methoxypoly(ethyleneoxy)ethyl p-butylaminobenzoate
    4) Molecular formula: C13-H18-NO2(OCH2CH2)-n-OCH3
    5) CAS 104-31-4
    6) Benzonatato (Mexico)
    7) Benzonatine
    1.2.1) MOLECULAR FORMULA
    1) C30H53NO11

Available Forms Sources

    A) FORMS
    1) Benzonatate is a clear, pale yellow, and viscous liquid with a faint characteristic odor. It is soluble in most organic solvents with the exception of aliphatic hydrocarbons (Budavari, 1996).
    2) Benzonatate is available as Tessalon(R) perles containing 100 mg benzonatate and as a capsule containing 200 mg benzonatate (Prod Info TESSALON(R) oral perles, capsules, 2010).
    B) USES
    1) Benzonatate is a cough suppressant used for the symptomatic relief of a nonproductive cough (Prod Info TESSALON(R) oral perles, capsules, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Benzonatate is used as an antitussive medication. It has previously been used in small doses as a topical anesthetic for oral or pharyngeal pain.
    B) PHARMACOLOGY: It suppresses cough by its topical anesthetic action on respiratory stretch receptors.
    C) TOXICOLOGY: As its structure is very similar to other local anesthetics, such as procaine and tetracaine, it is thought that its toxic effects, especially to the central nervous and cardiovascular systems is caused by sodium channel blockade (as with other local anesthetics).
    D) EPIDEMIOLOGY: There are at least a few hundred exposures to benzonatate every year; the majority of these have minor or no effects, but a few deaths have been reported.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Adverse effects (1% to 10% of users) may include the following: sedation, headache, rash, constipation, nausea, vomiting, GI upset, chest numbness, burning sensation in the eyes and nasal congestion.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients with mild exposures will only exhibit the normal effects of the drug (ie, local anesthesia of the exposed area) which will most commonly occur in the oropharyngeal region due to oral ingestion. There is a small subset of the population that might experience a hypersensitivity reaction to benzonatate or the compounds used in its formulation; in such cases, one might see a local reaction such as a rash to the exposed area.
    2) SEVERE TOXICITY: Severe toxicity is rare (occurring in 1% or less of patients), but can result in death. Significant clinical effects include tachycardia, agitation, seizures, coma, ventricular dysrhythmias, cardiac arrest, hypotension and asystole. Fatalities tend to be secondary to cardiac dysrhythmias rather than seizures, though cases of status epilepticus have been reported.
    0.2.20) REPRODUCTIVE
    A) Benzonatate is classified FDA pregnancy category C. No adverse effects were attributed to the use of benzonatate during the first 4 months of pregnancy and there was not an increased risk of congenital defects.

Laboratory Monitoring

    A) Monitor neurologic status and ECG, and institute continuous cardiac monitoring. In asymptomatic, inadvertent ingestions with no or mild symptoms, no laboratory studies, are needed. However, any intentional overdoses merit a standard overdose panel of labs: metabolic panel, acetaminophen and salicylate level and ECG.
    B) Benzonatate levels can be obtained at specialized labs, but are not clinically useful to manage a patient.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The majority of benzonatate exposures require only supportive care. If patients present soon after exposure, activated charcoal may be considered; however, as the drug is rapidly absorbed and there is a risk of seizures after exposure, one should only give charcoal, if the patient is alert, able to protect the airway, and the exposure has just recently occurred. The majority of these exposures will have mild symptoms only (ie, local anesthesia to the oropharynx) and require only observation to ensure patients do not choke or go on to have severe toxicity. For those experiencing a hypersensitivity reaction to benzonatate or the compounds related to it formulation, treatment should be stand decontamination (such as washing with soap and water) and other standard medications used to treat allergic reactions (eg, antihistamines and steroids).
    B) MANAGEMENT OF SEVERE TOXICITY:
    1) Patients with CNS depression, recurrent seizures or hemodynamic instability require early intubation. Treat QRS widening or ventricular dysrhythmias initially with sodium bicarbonate, 1 to 2 mEq/kg initial dose. Monitor arterial blood gases and serial ECG, maintain pH between 7.45 to 7.55. Follow ACLS protocol for ventricular dysrhythmias not responsive to bicarbonate. Consider intravenous lipid therapy early for patients with ventricular dysrhythmias or hypotension. Treat seizures with benzodiazepines, if seizures persist or recur add propofol or barbiturates.
    C) DERMAL EXPOSURE
    1) Wash with soap and water. If a patient experiences a hypersensitivity reaction, treat with antihistamines and steroids.
    D) OCULAR EXPOSURE
    1) Irrigate with water.
    E) DECONTAMINATION
    1) PREHOSPITAL: Prehospital activated charcoal should generally be avoided because of the risk of seizures and subsequent aspiration Wash exposed skin and irrigate exposed eyes with water.
    2) HOSPITAL: Consider using activated charcoal if the ingestion was large and relatively recent (within in an hour) and the patient is alert and able to protect the airway and tolerate liquids.
    F) AIRWAY MANAGEMENT
    1) The majority of these exposures should not require any emergent airway management. Patients with recurrent seizures, dysrhythmias or hemodynamic instability require early endotracheal intubation.
    G) ANTIDOTE
    1) There is no universally accepted antidote for benzonatate overdoses. However, 20% lipid emulsion solutions have been used for episodes of cardiac toxicity for other local anesthetics, and may be a reasonable therapy in cases of cardiac toxicity from benzonatate. Lipid Emulsion: Dose: Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
    H) ENHANCED ELIMINATION
    1) There is no evidence for the use of enhanced elimination techniques such as dialysis, hemoperfusion urinary alkalinization or multiple dose activated charcoal for benzonatate exposures.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions of an extra dose or two can be managed at home. Asymptomatic children with ingestions of a single perle (100 mg) can be observed at home.
    2) OBSERVATION CRITERIA: All intentional exposures, symptomatic patients and all children with ingestions of more than a single 100 mg perle should be sent to a health care facility. Observation should occur for at least 4 to 6 hours or until patient's symptoms show clear improvement. If patients are asymptomatic for 4 to 6 hours or show clear improvement during observation, they may be discharged home or cleared for psychiatric evaluation.
    3) ADMISSION CRITERIA: Most patients should not need admission to the hospital unless they exhibit severe toxicity (seizures or cardiac dysrhythmias). If patients do exhibit such severe symptoms they should be admitted to the ICU. Criteria for hospital discharge include return to baseline functioning or clear improvements from potential complications of their toxicity.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in who the diagnosis is uncertain. Neurologists, cardiologists and critical care physicians may need to be involved in patients who exhibit severe toxicity.
    J) PITFALLS
    1) Benzonatate may be fatal in small children even in small doses, so one should take such exposures seriously. Due to the risk of seizures, one should seriously consider the risks of benefits before giving activated charcoal.
    K) PHARMACOKINETICS
    1) Onset of action for therapeutic dosing is 15 to 20 minutes with a duration of action of 3 to 8 hours. Ester linked local anesthetics such as benzonatate are rapidly hydrolyzed by plasma cholinesterases and have short half-lives.
    L) PREDISPOSING CONDITIONS
    1) Benzonatate is not approved for children under the age of ten. More severe outcomes, including death have been reported in children under the age of 2 years old, from exposure to 1 to 2 capsules.
    M) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis for this overdose would include other local anesthetics (eg, lidocaine, tetracaine, procaine) that can cause similar local numbing effects as well as systemic toxicities to multiple organ systems via sodium channel blockade.
    0.4.4) EYE EXPOSURE
    A) Irrigate with water.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash with soap and water. If a patient experiences a hypersensitivity reaction, treat with antihistamines and steroids.

Range Of Toxicity

    A) TOXICITY: Mild toxicity may occur with a single ingestion of a 100 mg capsule, especially in pediatric patients less than 6 years old. More severe outcomes, including death, have been associated with doses ranging from 200 mg to the thousands of milligrams, most often in children less than 6 years old.
    1) ADULT: An adult survived an ingestion of 3600 mg after experiencing seizures and unstable ventricular tachycardia.
    2) CHILDREN: Death has been reported in an 18-month-old child who ingested 2 to 10 capsules of benzonatate. Ingestion of 1 or 2 capsules in children less than 2 years of age may result in overdose. An adolescent developed seizures and cardiac arrest but was resuscitated after ingesting at least 2000 mg benzonatate.
    B) THERAPEUTIC DOSE: ADULT: 100 to 200 mg orally 3 times daily as needed; maximum dose is 600 mg/day. CHILDREN (10 years of age and older): 100 to 200 mg orally 3 times daily as needed; maximum dose is 600 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Benzonatate is used as an antitussive medication. It has previously been used in small doses as a topical anesthetic for oral or pharyngeal pain.
    B) PHARMACOLOGY: It suppresses cough by its topical anesthetic action on respiratory stretch receptors.
    C) TOXICOLOGY: As its structure is very similar to other local anesthetics, such as procaine and tetracaine, it is thought that its toxic effects, especially to the central nervous and cardiovascular systems is caused by sodium channel blockade (as with other local anesthetics).
    D) EPIDEMIOLOGY: There are at least a few hundred exposures to benzonatate every year; the majority of these have minor or no effects, but a few deaths have been reported.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Adverse effects (1% to 10% of users) may include the following: sedation, headache, rash, constipation, nausea, vomiting, GI upset, chest numbness, burning sensation in the eyes and nasal congestion.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients with mild exposures will only exhibit the normal effects of the drug (ie, local anesthesia of the exposed area) which will most commonly occur in the oropharyngeal region due to oral ingestion. There is a small subset of the population that might experience a hypersensitivity reaction to benzonatate or the compounds used in its formulation; in such cases, one might see a local reaction such as a rash to the exposed area.
    2) SEVERE TOXICITY: Severe toxicity is rare (occurring in 1% or less of patients), but can result in death. Significant clinical effects include tachycardia, agitation, seizures, coma, ventricular dysrhythmias, cardiac arrest, hypotension and asystole. Fatalities tend to be secondary to cardiac dysrhythmias rather than seizures, though cases of status epilepticus have been reported.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Transient postural hypotension and dizziness has been noted following 200 mg allowed to dissolve in the mouth in an adult (Deutsch & Arneson, 1965). Benzonatate ingestion in a toddler has resulted in hypotension (Sheen et al, 1997).
    b) INCIDENCE: According to a retrospective review of benzonatate overdose ingestions reported to the National Poison Center Database System (NPDS) over a 7-year period, hypotension was reported in 8 of 2172 patients (0.3%) (Winter et al, 2010).
    c) CASE REPORT: Hypotension (78/43 mmHg) occurred in a 39-year-old woman who ingested 3000 mg benzonatate, 1200 mg ibuprofen, and 1000 mg acetaminophen (Morgan & Wittler, 2015).
    d) CASE REPORT (ADOLESCENT): A 13-year-old girl presented to the emergency department comatose (Glasgow Coma Scale of 3), with hypotension (96/42 mmHg), tachycardia, and diaphoresis after ingesting 40 100-mg benzonatate capsules, and 5 4-mg chlorphineramine/30-mg dextromethorphan tablets. An ECG, performed 1 hour post-presentation, revealed sinus tachycardia (127 beats/minute), a QRS of 96 ms, and a QTc interval of 499 msec, and laboratory data indicated metabolic acidosis. A urine toxicology screen was conducted, but was not capable to detect benzonatate or dextromethorphan; however, it was negative for drugs of abuse including amphetamines, barbiturates, cocaine, opiates, phencyclidine, and cannabinoids. With supportive care, the patient recovered and was discharged on hospital day 3 (Thimann et al, 2012).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Significant overdose may result in unstable ventricular tachycardia/fibrillation and cardiac arrest (Crouch et al, 1998; Shropshire et al, 1999).
    b) INCIDENCE: According to a retrospective review of benzonatate overdose ingestions reported to the National Poison Center Database System (NPDS) over a 7-year period, tachycardia was reported in 31 of 2172 patients (1%). Other cardiovascular events including ventricular dysrhythmias, cardiac arrest, and asystole were reported in 9 (0.4%), 8 (0.3%), and 6 (0.2%) patients, respectively. In this study, all fatalities (4 patients or 0.2%) were secondary to cardiac dysrhythmias (Winter et al, 2010).
    c) The Adverse Event Reporting System (AERS) database of the Food and Drug Administration reported 31 overdose cases associated with benzonatate ingestion in patients ranging in age from 1 to 66 years. Cardiac arrest, coma, and seizures were the most common adverse events reported following overdose, with symptoms occurring within one hour of ingestion. The amounts ingested ranged from 1 to 30 capsules (United States Food and Drug Administration, 2010).
    d) CASE REPORTS
    1) PEDIATRIC: Seizures and full cardiac arrest were reported in a 12-month-old infant who ingested an unknown quantity of benzonatate. Resuscitative measures were unsuccessful (Crouch et al, 1998).
    2) ADOLESCENT: A 13-year-old girl presented to the emergency department comatose (Glasgow Coma Scale of 3), with hypotension, tachycardia, and diaphoresis after ingesting 40 100-mg benzonatate capsules, and 5 4-mg chlorphineramine/30-mg dextromethorphan tablets. An ECG, performed 1 hour post-presentation, revealed sinus tachycardia (127 beats/minute), a QRS of 96 ms, and a QTc interval of 499 msec, and laboratory data indicated metabolic acidosis. A urine toxicology screen was conducted, but was not capable to detect benzonatate or dextromethorphan; however, it was negative for drugs of abuse including amphetamines, barbiturates, cocaine, opiates, phencyclidine, and cannabinoids. With supportive care, the patient recovered and was discharged on hospital day 3 (Thimann et al, 2012).
    3) ADOLESCENT: A 17-year-old girl experienced 3 witnessed seizures and subsequent cardiac arrest, that was successfully cardioverted, after ingesting at least 10 200-mg benzonatate capsules in a suicide attempt. With supportive care, the patient stabilized hemodynamically; however, she developed blindness and generalized confabulations that persisted following transfer to a rehabilitation facility approximately 20 days postingestion (Cohen et al, 2009).
    4) ADULT: Seizures and unstable ventricular tachycardia were reported in a 39-year-old man following the ingestion of 3600 mg benzonatate. Following direct current cardioversion, the patient reverted to sinus tachycardia with a wide QRS complex (110 msec) and an incomplete bundle branch block pattern; his condition soon stabilized (Crouch et al, 1998).
    5) ADULT: Intravenous administration of the contents of 2 or 3 benzonatate capsules resulted in ventricular fibrillation which progressed to asystole in a 21-year-old man. Continued resuscitation in the emergency department resulted in VT with pulse, then sinus tachycardia (120 bpm) and a blood pressure of 100/70 on dopamine. EEG was consistent with brain death (Shropshire et al, 1999).
    6) ADULT: A 39-year-old woman presented to the emergency department with altered mental status, hypotension, and agonal respirations after ingesting 3000 mg benzonatate, 1200 mg ibuprofen, and 1000 mg acetaminophen. She experienced a generalized tonic-clonic seizure that lasted 30 seconds and spontaneously terminated. An initial ECG indicated a wide-complex bradycardia. Following 2 100-mEq IV sodium bicarbonate boluses, her QRS complex narrowed; however, the QRS widening recurred, requiring repeated IV bolus doses of sodium bicarbonate. The total sodium bicarbonate dose given within one hour was 550 mEq (11 ampules). With continued supportive care, the patient gradually recovered and was discharged on hospital day 2 without neurologic sequelae (Morgan & Wittler, 2015).
    C) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Bronchospasm, laryngospasm, and cardiovascular collapse may occur due to the local anesthetic action resulting from chewing or sucking benzonatate capsules (Prod Info benzonatate oral capsules, 2014).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSRHYTHMIA
    a) Administration of doses larger than 2 mg/kg intravenously resulted in cardiac dysrhythmias and hypotension in rats (Thoren & Oberg, 1981).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY OBSTRUCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Death was reported in a 2-1/2 year old child who chewed and ingested up to 10 capsules. Nasopharyngeal muscle paralysis and subsequent airway obstruction were thought to be the cause of death (Pers Comm., 1984).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Acute pulmonary edema was reported in an adult fatality following intravenous injection of benzonatate (Shropshire et al, 1999).
    C) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm, laryngospasm, and cardiovascular collapse may occur due to the local anesthetic action resulting from chewing or sucking benzonatate capsules (Prod Info benzonatate oral capsules, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CNS stimulation (restlessness and tremors followed by seizures) followed by CNS depression may occur due to similarity of this agent to tetracaine. Seizures have been reported in human overdoses (Morgan & Wittler, 2015; Prod Info benzonatate oral capsules, 2014; Thimann et al, 2012; Crouch et al, 1998; Sheen et al, 1997).
    b) INCIDENCE: According to a retrospective review of benzonatate overdose ingestions reported to the National Poison Center Database System (NPDS) over a 7-year period, seizures were reported in 23 of 2172 patients (1%) (Winter et al, 2010).
    c) CASE REPORT: A 12-month-old infant developed generalized tonic-clonic seizures within minutes following ingestion of 1 or 2 Tessalon(R) Perles containing benzonatate. He was admitted to the emergency department postictal with rhonchus breath sounds. His level of consciousness returned to baseline after 90 minutes (Sheen et al, 1997).
    d) CASE REPORT: A 12-month-old infant experienced seizures and cardiac arrest following ingestion of an unknown quantity of benzonatate. Resuscitation was unsuccessful (Crouch et al, 1998).
    e) CASE REPORT: A 39-year-old man developed disorientation followed by a grand mal seizure after the ingestion of 3600 mg of benzonatate and beer. He fully recovered following supportive measures (Crouch et al, 1998).
    f) CASE REPORT: A 17-year-old girl experienced 3 seizures, all of which were witnessed by her father, after intentionally ingesting at least 10 200-mg benzonatate capsules. She subsequently developed cardiac arrest and was successfully resuscitated. With supportive care, she stabilized hemodynamically; however, she developed blindness and generalized confabulations that persisted following transfer to a rehabilitation facility approximately 20 days postingestion (Cohen et al, 2009).
    g) The Adverse Event Reporting System (AERS) database of the Food and Drug Administration reported 31 overdose cases associated with benzonatate ingestion in patients ranging in age from 1 to 66 years. Cardiac arrest, coma, and seizures were the most common adverse events reported following overdose, with symptoms occurring within one hour of ingestion. The amounts ingested ranged from 1 to 30 capsules (United States Food and Drug Administration, 2010).
    B) ABSENCE OF SENSATION
    1) WITH POISONING/EXPOSURE
    a) Benzonatate is a local anesthetic and may produce numbness of the buccal mucosa, tongue and pharynx when the capsules are chewed or dissolved in the mouth. Oropharyngeal anesthesia will develop rapidly (Prod Info benzonatate oral capsules, 2014).
    b) CASE REPORT: Death was reported in a 2-1/2 year old child who chewed and ingested up to 10 capsules. Nasal pharyngeal paralysis and subsequent airway obstruction were thought to be the cause of death (Pers Comm., 1984).
    C) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Sedation, dizziness, mental confusion, and visual hallucinations have been reported as adverse effects or as toxic effects due to mild overdoses (Prod Info benzonatate oral capsules, 2014; Prod Info Tessalon(R), benzonatate perles, 1998).
    b) INCIDENCE: According to a retrospective review of benzonatate overdose ingestions reported to the National Poison Center Database System (NPDS) over a 7-year period, agitation and coma were reported in 30 (1%) and 14 (0.6%) of 2172 patients, respectively (Winter et al, 2010).
    c) The Adverse Event Reporting System (AERS) database of the Food and Drug Administration reported 31 overdose cases associated with benzonatate ingestion in patients ranging in age from 1 to 66 years. Cardiac arrest, coma, and seizures were the most common adverse events reported following overdose, with symptoms occurring within one hour of ingestion. The amounts ingested ranged from 1 to 30 capsules (United States Food and Drug Administration, 2010).
    d) CASE REPORT (ADOLESCENT): A 13-year-old girl presented to the emergency department comatose (Glasgow Coma Scale of 3), with hypotension, tachycardia, and diaphoresis after ingesting 40 100-mg benzonatate capsules, and 5 4-mg chlorphineramine/30-mg dextromethorphan tablets. An ECG, performed 1 hour post-presentation, revealed sinus tachycardia (127 beats/minute), a QRS of 96 ms, and a QTc interval of 499 msec, and laboratory data indicated metabolic acidosis. A urine toxicology screen was conducted, but was not capable to detect benzonatate or dextromethorphan; however, it was negative for drugs of abuse including amphetamines, barbiturates, cocaine, opiates, phencyclidine, and cannabinoids. With supportive care, the patient recovered and was discharged on hospital day 3 (Thimann et al, 2012).
    D) CORTICAL BLINDNESS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old girl experienced 3 witnessed seizures and cardiac arrest, that was successfully cardioverted, following intentional ingestion of at least 10 200-mg benzonatate capsules. With supportive care, the patient was stabilized hemodynamically; however, an MRI of her brain revealed infarcts of the basal ganglia and occipital lobes (involving the visual cortex) and frontal lobe hypoxia, indicative of anoxic injuries that occurred during cardiac arrest. Although, the patient had full strength in her upper and lower extremities, she was blind, unable to close her eyes, and she had no purposeful extraocular movement or tracking. In addition, she also experienced generalized confabulation. The patient's blindness and confabulations continued to persist following her transfer to a rehabilitation facility approximately 20 days postingestion (Cohen et al, 2009).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures were noted in rats given doses greater than 2 mg/kg IV (Thoren & Oberg, 1981).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Nausea, constipation, and GI upset may occur with therapeutic doses (Prod Info benzonatate oral capsules, 2014).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis has been reported in patients with seizures after benzonatate overdose.
    b) CASE REPORT: Severe metabolic acidosis (pH of 6.97) has been reported following an overdose of 3600 mg benzonatate in a 39-year-old man. The patient also suffered a grand mal seizure and unstable ventricular tachycardia. Following supportive care, the patient recovered (Crouch et al, 1998).
    c) CASE REPORT: Severe lactic acidosis (pH 6.85, pCO2 46 mmHg, pO2 101 mmHg, HCO3 8, lactic acid greater than 20 mmol/L) developed in a 17-year-old girl who had 3 seizures and then a cardiac arrest following intentional ingestion of at least 10 200-mg benzonatate capsules (Cohen et al, 2009).
    d) CASE REPORT (ADOLESCENT): Metabolic acidosis (pH 7, PCO2 32 mmHg, HCO3 8 mEq/L, base excess -23 mmol/L, serum lactate 1.9 mmol/L) occurred in a 13-year-old girl who ingested 40 100-mg benzonatate capsules, and 5 4-mg chlorphineramine/30-mg dextromethorphan tablets. She recovered with supportive care (Thimann et al, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Mild erythema and transient skin itching have been described (Prod Info benzonatate oral capsules, 2014) (Wilson et al, 1958).

Reproductive

    3.20.1) SUMMARY
    A) Benzonatate is classified FDA pregnancy category C. No adverse effects were attributed to the use of benzonatate during the first 4 months of pregnancy and there was not an increased risk of congenital defects.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any teratogenic potential of this agent (Prod Info benzonatate oral capsules, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any potential effects of exposure to this agent during pregnancy in humans (Prod Info benzonatate oral capsules, 2014).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified benzonatate as FDA pregnancy category C. There are no adequate and well-controlled studies of benzonatate use during pregnancy. Animal studies have not been conducted (Prod Info benzonatate oral capsules, 2014). During the Collaborative Perinatal Project, there were no adverse effects attributed to benzonatate use during the first 4 months of pregnancy (Heinonen et al, 1977). Due to the lack of human data, benzonatate should be used during pregnancy only if clearly needed .(Prod Info benzonatate oral capsules, 2014).
    C) LACK OF EFFECT
    1) The Collaborative Perinatal Project found no association between the use of benzonatate during gestation and an increased risk of congenital defects. No adverse effects were attributed to the use of benzonatate during the first 4 months of pregnancy (Heinonen et al, 1977).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether benzonatate is excreted into human milk. Caution is advised when administering benzonatate to a nursing mother (Prod Info benzonatate oral capsules, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) Reproduction studies have not been conducted with benzonatate (Prod Info benzonatate oral capsules, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor neurologic status and ECG, and institute continuous cardiac monitoring. In asymptomatic, inadvertent ingestions with no or mild symptoms, no laboratory studies, are needed. However, any intentional overdoses merit a standard overdose panel of labs: metabolic panel, acetaminophen and salicylate level and ECG.
    B) Benzonatate levels can be obtained at specialized labs, but are not clinically useful to manage a patient.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Benzonatate plasma levels are not widely available or clinically useful.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) In cases of chewing or dissolving perles in the mouth, monitor for local oropharyngeal anesthesia that may result in decreased gag reflex.
    b) Monitor for CNS stimulation (seizures) followed by profound CNS depression in all overdose cases.
    c) Monitor vital signs for hypotension following toxic ingestions.
    d) Obtain an ECG and institute continuous cardiac monitoring after significant exposure.

Methods

    A) CHROMATOGRAPHY
    1) A high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method for the confirmation and quantification of benzonatate in human plasma has been described. Routine laboratory analysis is not usually readily available because benzonatate is not a single chemical structure, and can contain as many as 8 structural analogs (Crouch et al, 1998).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Most patients should not need admission to the hospital unless they exhibit severe toxicity (seizures or cardiac dysrhythmias). If patients do exhibit such severe symptoms they should be admitted to the ICU. Criteria for hospital discharge include return to baseline functioning or clear improvements from potential complications of their toxicity.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestions of an extra dose or two can be managed at home. Asymptomatic children with ingestions of a single perle (100 mg) can be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in who the diagnosis is uncertain. Neurologists, cardiologists and critical care physicians may need to be involved in patients who exhibit severe toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All intentional exposures, symptomatic patients and all children with ingestions of more than a single 100 mg perle should be sent to a health care facility. Observation should occur for at least 4 to 6 hours or until patient's symptoms show clear improvement. If patients are asymptomatic for 4 to 6 hours or show clear improvement during observation, they may be discharged home or cleared for psychiatric evaluation.
    B) According to a retrospective review of benzonatate overdose ingestions reported to the National Poison Center Database System (NPDS) over a 7-year period, involving 2172 patients ranging in age from 1 to 93 years-old (mean age 20 years; 30% of patients less than 6 years of age), moderate to severe outcomes (ie, tachycardia, agitation, seizure, coma, hypotension, cardiac arrest, asystole) occurred following ingestion of benzonatate median doses ranging from 200 to 1000 mg (Winter et al, 2010).

Monitoring

    A) Monitor neurologic status and ECG, and institute continuous cardiac monitoring. In asymptomatic, inadvertent ingestions with no or mild symptoms, no laboratory studies, are needed. However, any intentional overdoses merit a standard overdose panel of labs: metabolic panel, acetaminophen and salicylate level and ECG.
    B) Benzonatate levels can be obtained at specialized labs, but are not clinically useful to manage a patient.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL/NOT RECOMMENDED
    1) Prehospital activated charcoal should generally be avoided because of the risk of seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) SUMMARY: Consider using activated charcoal if the ingestion was large and relatively recent (within in an hour) and the patient is alert, able to protect the airway and able to tolerate liquids.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) The majority of benzonatate exposures require only supportive care. If patients present soon after exposure, activated charcoal may be considered; however, as the drug is rapidly absorbed and there is a risk of seizures after exposure, one should only give charcoal, if the patient is alert and awake and the exposure has just recently occurred.
    2) The majority of these exposures will have mild symptoms only (ie, local anesthesia to the oropharynx) and require only observation to ensure patients do not choke or go on to have severe toxicity.
    3) Patients with CNS depression, recurrent seizures or hemodynamic instability require early intubation. Treat QRS widening or ventricular dysrhythmias initially with sodium bicarbonate, 1 to 2 mEq/kg initial dose. Monitor arterial blood gases and serial ECG, maintain pH between 7.45 to 7.55. Follow ACLS protocol for ventricular dysrhythmias not responsive to bicarbonate.
    B) MONITORING OF PATIENT
    1) Monitor neurologic status and ECG, and institute continuous cardiac monitoring. In asymptomatic, inadvertent ingestions with no or mild symptoms, no laboratory studies, are needed. However, any intentional overdoses merit a standard overdose panel of labs: metabolic panel, acetaminophen and salicylate level and ECG.
    2) Benzonatate levels can be obtained at specialized labs, but are not clinically useful to manage a patient.
    C) AIRWAY MANAGEMENT
    1) The majority of these exposures should not require any emergent airway management. Patients with recurrent seizures, dysrhythmias or hemodynamic instability require early endotracheal intubation.
    D) ANTIDOTE
    1) SUMMARY
    a) There is NO universally accepted antidote for benzonatate overdoses. However, 20% lipid emulsion solutions have been used for episodes of cardiac toxicity for other local anesthetics, and may be a reasonable therapy in cases of cardiac toxicity from benzonatate.
    2) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
    3) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):
    a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
    b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
    c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
    d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
    E) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    G) VENTRICULAR ARRHYTHMIA
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias. In patients unresponsive to bicarbonate, consider lidocaine.
    2) SERUM ALKALINIZATION
    a) Administer sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg by intravenous bolus, repeated as needed. Maintain arterial pH between 7.45 and 7.55. Monitor serial ECGs and arterial blood gases frequently.
    b) CASE REPORT: A 39-year-old woman presented to the emergency department with altered mental status, hypotension, and agonal respirations after ingesting 3000 mg benzonatate, 1200 mg ibuprofen, and 1000 mg acetaminophen. She experienced a generalized tonic-clonic seizure that lasted 30 seconds and spontaneously terminated. An initial ECG indicated a wide-complex bradycardia. Following 2 100-mEq IV sodium bicarbonate boluses, her QRS complex narrowed; however, the QRS widening recurred, requiring repeated IV bolus doses of sodium bicarbonate. The total sodium bicarbonate dose given within one hour was 550 mEq (11 ampules). With continued supportive care, the patient gradually recovered and was discharged on hospital day 2 without neurologic sequelae (Morgan & Wittler, 2015).
    3) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

Enhanced Elimination

    A) SUMMARY
    1) There is no evidence for the use of enhanced elimination techniques such as dialysis, hemoperfusion urinary alkalinization or multiple dose activated charcoal for benzonatate exposures.

Range Of Toxicity

Summary

    A) TOXICITY: Mild toxicity may occur with a single ingestion of a 100 mg capsule, especially in pediatric patients less than 6 years old. More severe outcomes, including death, have been associated with doses ranging from 200 mg to the thousands of milligrams, most often in children less than 6 years old.
    1) ADULT: An adult survived an ingestion of 3600 mg after experiencing seizures and unstable ventricular tachycardia.
    2) CHILDREN: Death has been reported in an 18-month-old child who ingested 2 to 10 capsules of benzonatate. Ingestion of 1 or 2 capsules in children less than 2 years of age may result in overdose. An adolescent developed seizures and cardiac arrest but was resuscitated after ingesting at least 2000 mg benzonatate.
    B) THERAPEUTIC DOSE: ADULT: 100 to 200 mg orally 3 times daily as needed; maximum dose is 600 mg/day. CHILDREN (10 years of age and older): 100 to 200 mg orally 3 times daily as needed; maximum dose is 600 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) COUGH
    1) The recommended dose is 100 or 200 orally 3 times daily as needed, up to a maximum of 600 mg daily (Prod Info benzonatate oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) COUGH
    1) OLDER THAN 10 YEARS OF AGE: The recommended dose is 100 or 200 mg orally 3 times daily as needed, up to a maximum of 600 mg daily (Prod Info benzonatate oral capsules, 2014). The maximum single dose is 200 mg (United States Food and Drug Administration, 2010).
    2) 10 YEARS OF AGE OR YOUNGER: Safety and efficacy have not been established (Prod Info benzonatate oral capsules, 2014).

Minimum Lethal Exposure

    A) According to a retrospective review of benzonatate overdose ingestions reported to the National Poison Center Database System (NPDS) over a 7-year period, involving 2172 patients ranging in age from 1 to 93 years-old (mean age 20 years), one fatality occurred following a benzonatate ingestion of 3000 mg. It is not clear whether the patient was a child or an adult (Winter et al, 2010).
    B) TODDLER
    1) An 18 month-old-child died after ingesting an unknown quantity of benzonatate. It was estimated that 2 capsules may have been chewed and that it was likely that up to 3 to 10 capsules total may have been consumed (Cohan et al, 1986).
    C) CHILDREN
    1) According to a search of the Adverse Event Reporting System (AERS) database of the Food and Drug Administration, 7 of 31 reported benzonatate overdose cases involved unintentional ingestions in children, with 5 of the ingestions resulting in death in children 2-years-old or younger. The two surviving children were 12 months and 4 years of age. Although the amounts ingested in the 31 overdose cases ranged from 1 to 30 capsules, the amounts ingested in the 7 pediatric cases were not specified (United States Food and Drug Administration, 2010).
    D) ADULT
    1) An 18-year-old man died after taking a handful of Tessalon(R) and 20 Dilantin(R) (phenytoin). He reported feeling dizzy, drunk, and nauseated (Cohan et al, 1986).

Maximum Tolerated Exposure

    A) According to a retrospective review of benzonatate overdose ingestions reported to the National Poison Center Database System (NPDS) over a 7-year period, involving 2172 patients ranging in age from 1 to 93 years-old (mean age 20 years), moderate to severe outcomes (ie, tachycardia, agitation, seizure, coma, hypotension, cardiac arrest, asystole) occurred following ingestion of benzonatate median doses ranging from 200 to 1000 mg (Winter et al, 2010).
    B) The Adverse Event Reporting System (AERS) database of the Food and Drug Administration reported 31 overdose cases associated with benzonatate ingestion in patients ranging in age from 1 to 66 years. Cardiac arrest, coma, and seizures were the most common adverse events reported following overdose, with symptoms occurring within one hour of ingestion. The amounts ingested ranged from 1 to 30 capsules (United States Food and Drug Administration, 2010).
    C) INFANT
    1) A 12-month-old infant developed tonic-clonic seizures following ingestion of 1 or 2 benzonatate (100 mg each) gel capsules (Sheen et al, 1997).
    D) PEDIATRIC
    1) A 17-year-old girl experienced 3 seizures followed by cardiac arrest after intentionally ingesting at least 10 200-mg benzonatate capsules. She was resuscitated, but had anoxic brain injury with blindness and confabulation, which persisted following transfer to a rehabilitation facility approximately 20 days postingestion (Cohen et al, 2009).
    2) A 13-year-old girl presented to the emergency department comatose (Glasgow Coma Scale of 3), with hypotension, tachycardia, and diaphoresis after ingesting 40 100-mg benzonatate capsules, and 5 4-mg chlorphineramine/30-mg dextromethorphan tablets. An ECG, performed 1 hour post-presentation, revealed sinus tachycardia (127 beats/minute), a QRS of 96 ms, and a QTc interval of 499 msec, and laboratory data indicated metabolic acidosis. A urine toxicology screen was conducted, but was not capable to detect benzonatate or dextromethorphan; however, it was negative for drugs of abuse including amphetamines, barbiturates, cocaine, opiates, phencyclidine, and cannabinoids. With supportive care, the patient recovered and was discharged on hospital day 3 (Thimann et al, 2012).
    E) ADULT
    1) A 39-year-old man experienced grand mal seizures and unstable ventricular tachycardia, which responded to direct current cardioversion, following an ingestion of 36 benzonatate 100 mg capsules (Crouch et al, 1998).
    2) A 39-year-old woman presented to the emergency department with altered mental status, hypotension, and agonal respirations after ingesting 3000 mg benzonatate, 1200 mg ibuprofen, and 1000 mg acetaminophen. She experienced a generalized tonic-clonic seizure that lasted 30 seconds and spontaneously terminated. An initial ECG indicated a wide-complex bradycardia. Following 2 100-mEq IV sodium bicarbonate boluses, her QRS complex narrowed; however, the QRS widening recurred, requiring repeated IV bolus doses of sodium bicarbonate. The total sodium bicarbonate dose given within one hour was 550 mEq (11 ampules). With continued supportive care, the patient gradually recovered and was discharged on hospital day 2 without neurologic sequelae (Morgan & Wittler, 2015).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ACUTE
    a) Toxicologic analyses were reported for 2 fatal cases. An 18-month-old child with a history of ingestion estimated to be from 2 to 10 capsules resulted in 184 mg benzonatate in the stomach content, 4 mg/L in blood, 30 mg/kg in liver and 5 mg/kg of brain (Cohan et al, 1986).
    b) An 18-year-old man reported to have ingested a "handful" of benzonatate resulted in 35 mg/L of benzonatate in blood, 1.5 mg/kg in kidney, and 22 mg/kg in the brain. The phenytoin serum concentration was reported as 2.9 mcg/mL (Cohan et al, 1986).
    c) A 39-year-old man was reported to have an estimated plasma concentration of 2.5 mcg/mL following the ingestion of 3600 mg of benzonatate (Crouch et al, 1998).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 400 mg/kg (RTECS, 1999)
    b) 700 mg/kg (Cohan et al, 1986)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Benzonatate is chemically related to tetracaine, with the addition of a polyethylene glycol moiety. Its mechanism of action appears to involve both local and central effects. Locally it produces an anesthetic effect on the stretch receptors of the vagal afferent fibers in the bronchi, alveoli, and pleura, thus blocking the cough reflex. Centrally it suppresses transmission of the cough reflex at the junction of the vagal afferent fibers and the motor nerves in the medulla (Prod Info TESSALON(R) oral perles, capsules, 2010; Prod Info Tessalon(R), benzonatate perles, 1998).

Physicochemical

Physical Characteristics

    A) This compound is a clear, pale yellow, viscous liquid with a disagreeable bitter taste and faint characteristic odor (Prod Info Tessalon(R), benzonatate perles, 1998; Budavari, 1996).

Molecular Weight

    A) 603.7 (Prod Info TESSALON(R) oral capsules, 2005)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) American College of Medical Toxicology : ACMT Position Statement: Interim Guidance for the Use of Lipid Resuscitation Therapy. J Med Toxicol 2011; 7(1):81-82.
    3) American College of Medical Toxicology: ACMT position statement: guidance for the use of intravenous lipid emulsion. J Med Toxicol 2016; Epub:Epub-.
    4) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    5) Budavari S: The Merck Index, 12th ed, Merck & Co, Inc, Whitehouse Station, NJ, 1996.
    6) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    7) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    8) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    9) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    10) Cohan JA, Manning TJ, & Lukash L: Two fatalities resulting from Tessalon (Benzonatate). Vet Hum Toxicol 1986; 28:543-544.
    11) Cohen V, Jellinek SP, Stansfield L, et al: Cardiac arrest with residual blindness after overdose of tessalon(R) (benzonatate) perles. J Emerg Med 2009; epub:epub-.
    12) Crouch BI, Knick KA, & Crouch DJ: Benzonatate overdose associated with seizures and arrhythmias. Clin Toxicol 1998; 36:713-718.
    13) Deutsch DL & Arneson LA: Tessalon as a local anesthetic in preoral endoscopy. Gastrointestinal Endoscopy 1965; 12:25.
    14) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    15) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    16) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    17) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    18) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    19) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    20) Heinonen OP, Slone D, & Shapiro SHeinonen OP, Slone D, & Shapiro S (Eds): Birth Defects and Drugs in Pregnancy, Publishing Sciences Group, Littleton, MA, 1977, pp 378.
    21) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    22) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    23) Lavonas EJ, Drennan IR, Gabrielli A, et al: Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S501-S518.
    24) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    25) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    26) Morgan C & Wittler M: Benzonatate Overdose Treated with Sodium Bicarbonate. Clin Toxicol (Phila) 2015; 53(7):703.
    27) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    28) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    29) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    30) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    31) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    32) Product Information: TESSALON(R) oral capsules, benzonatate oral capsules. Forest Pharmaceuticals,Inc, St. Louis, MO, 2005.
    33) Product Information: TESSALON(R) oral perles, capsules, benzonatate oral perles, capsules. Catalent Pharma Solutions and Pfizer Inc, St. Petersburg, FL, 2010.
    34) Product Information: Tessalon(R), benzonatate perles. Forest Pharmaceuticals, Inc, St Louis, MO, 1998.
    35) Product Information: benzonatate oral capsules, benzonatate oral capsules. Caraco Pharmaceutical Laboratories, Ltd. (per DailyMed), Detroit, MI, 2014.
    36) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    37) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    38) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    39) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    40) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    41) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    42) Sheen S, Osterhoudt K, & Birenbaum D: Seizures in a toddler associated with benzonatate ingestion (abstract). J Tox Clin Tox 1997; 35(5):493.
    43) Shropshire A, Clifton J II, & Aks S: Death from intentional IV administration of benzonatate (abstract). J Toxicol-Clin Toxicol 1999; 37:652.
    44) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    45) Thimann DA, Huang CJ, Goto CS, et al: Benzonatate toxicity in a teenager resulting in coma, seizures, and severe metabolic acidosis. J Pediatr Pharmacol Ther 2012; 17(3):270-273.
    46) Thoren P & Oberg B: Studies on the endoanesthetic effects of lidocaine and benzonatate on non-medullated nerve endings in the left ventricle. Acta Physiol Scand 1981; 111:51-58.
    47) United States 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. United States Food and Drug Administration. Rockville, MD. 2010. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm236651.htm. As accessed 2010-12-14.
    48) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    49) Winter ML, Spiller HA, & Griffith JR: Benzonatate Ingestion Reported to the National Poison Center Database System (NPDS). J Med Toxicol 2010; 6(4):398-402.
    50) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.