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  • CLASSES

    Non-Opioid Antitussives

    DEA CLASS

    Rx

    DESCRIPTION

    Oral nonnarcotic antitussive agent; chemically related to the ester-type local anesthetics; effective in suppressing cough particularly in cases of chronic cough resistant to opiate agonists; off-label use includes topical application to the oropharynx to obliterate the gag reflex prior to intubation or endoscopy.

    COMMON BRAND NAMES

    Tessalon Perles, Zonatuss

    HOW SUPPLIED

    Benzonatate/Tessalon Perles/Zonatuss Oral Cap: 100mg, 150mg, 200mg

    DOSAGE & INDICATIONS

    For the symptomatic treatment of cough.
    Oral dosage
    Adults, Adolescents and Children 10 years and older

    100 mg, 150 mg, or 200 mg PO 3 times daily is the normal dosage. Maximum dosage is 600 mg/day PO.

    For the treatment of intractable singultus (hiccups)† unresponsive to standard therapies.
    Oral dosage
    Adults, Adolescents and Children 10 years and older

    Anecdotal reports suggest a dosage of 100 mg PO as a single dose. May repeat in 4 hours if needed. Dose of 100 mg PO may be given up to every 4 hours; do not exceed 600 mg/day PO.

    For topical anesthesia† of the oropharyngeal region prior to awake endotracheal intubation† or prior to endoscopy†.
    NOTE: This route should only be used by health care professionals trained in anesthesia and intubation. Specialized references should be consulted for specific procedures and administration techniques. Resuscitative equipment and drugs used in the management of adverse reactions should be immediately available.
    Oropharyngeal topical dosage†
    Adults

    A dose of 200 mg applied topically to the oropharyngeal area, followed by 4% lidocaine translaryngeally has been used. This route should only be used by those trained in anesthesia and intubation. In 1 study, a shorter time period was required to obtain the loss of gag reflex in the benzonatate-treated group (i.e., roughly 1 minute) vs. the 5 to 6 minutes required in those patients receiving superior laryngeal nerve block with 1% lidocaine.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO.

    Geriatric

    600 mg/day PO.

    Adolescents

    600 mg/day PO.

    Children

    10 years and older: 600 mg/day PO.
    9 years and younger: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Swallow whole. Do not break, chew, or dissolve in the mouth as this could cause temporary anesthesia of the mouth and throat and could cause choking.

    STORAGE

    Generic:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tessalon Perles:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zonatuss :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Ester local anesthetic hypersensitivity, paraben hypersensitivity

    Benzonatate is chemically related to tetracaine and other ester-type local anesthetics. Use of benzonatate is contraindicated in those patients with ester local anesthetic hypersensitivity or a previous history of reaction to benzonatate. The benzonatate formulation also contains methyl- and propylparaben; these may be a problem for patients with paraben hypersensitivity. Severe hypersensitivity reactions have been reported with benzonatate use. In some cases local anesthesia resulting from the sucking or chewing of the capsule has been responsible for bronchospasm or laryngospasm. Patients should always swallow benzonatate capsules whole, do not chew or dissolve in the mouth.

    Children, infants, neonates, potential for overdose or poisoning

    Children 10 years of age or older may receive benzonatate with careful administration instructions to avoid chewing or dissolving the dose in the mouth. Safe and effective use of benzonatate has not been established in neonates, infants, or children under the age of 10 years. Accidental ingestion of benzonatate liquid capsules poses a significant potential for overdose or poisoning to pediatric patients younger than 10 years of age due in part to the candy-like appearance. Signs and symptoms of overdose have been reported within 15 to 20 minutes, and death has been reported within one hour of ingestion. Advise patients to store this medication out of reach of children in a child-resistant container and to seek medical help immediately if accidental ingestion is suspected. The Adverse Event Reporting System database of the FDA includes 7 cases of accidental pediatric exposure reported between 1982 and May 2010, including 5 deaths in children less than 2 years of age. Overdose has occurred in children under 2 years after accidental ingestion of one or two benzonatate capsules. In addition, the benzonatate dosage form could represent a choking hazard to young children.

    Driving or operating machinery

    Benzonatate is occasionally associated with CNS sedation, mental confusion, visual hallucinations or other bizarre behaviors. Patients should be advised to use caution with driving or operating machinery or performing other activities requiring mental alertness until they know how this medication affects them. Concomitant medications could increase the risk of these types of adverse reactions.

    Labor, obstetric delivery, pregnancy

    Benzonatate is classified as FDA pregnancy risk category C. Animal studies to evaluate carcinogenic and mutagenic potential and effect on gestation and fertility have not been performed. Due to a lack of available data on the safety of benzonatate during pregnancy, the drug should be administered to a pregnant woman only if clearly needed. The effects of benzonatate during labor and obstetric delivery are unknown. However, benzonatate is chemically related to anesthetic agents such as procaine and similar effects could be observed if enough absorption takes place. Local anesthetics rapidly cross the placenta and can cause varying degrees of maternal, fetal, and neonatal toxicity when used for paracervical or pudendal block anesthesia during labor and delivery. The use of some local anesthetics during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life in the newborn. The long-term significance of these observations is unknown.

    Breast-feeding

    According to the manufacturer, it is not known if benzonatate is excreted in human milk, and caution is recommended if the drug is used during breast-feeding. The effects of benzonatate on a nursing infant are unknown, and the American Academy of Pediatrics (AAP) has not issued any specific recommendations relating to benzonatate and breast-feeding. Because no breast-feeding information is available, an alternate anti-tussive may be preferred, especially while nursing a newborn or premature infant. Despite the lack of published data, some experts consider dextromethorphan to be compatible with breast-feeding when usual adult doses are taken by the mother. Dextromethorphan products containing alcohol should be avoided. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Para-aminobenzoic acid, PABA hypersensitivity

    Cautious use of benzonatate may be warranted for patients with para-aminobenzoic acid, PABA hypersensitivity. Benzonatate is chemically related to anesthetic agents of the para-aminobenzoic acid class such as procaine and tetracaine. Benzonatate has been associated with adverse CNS effects possibly related to a prior sensitivity to related agents or to an interaction with concomitant medication.

    Dysphagia, geriatric

    Geriatric patients taking benzonatate should be able to swallow the capsules as directed, as inadvertant release of capsule contents in the mouth can produce a temporary local anesthesia of the oral mucosa and choking or other serious side effects could occur. The medication is advised to be avoided if dysphagia is present. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities. According to the OBRA guidelines, cough medications should be used only for a limited duration (less than 14 days) unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected.

    ADVERSE REACTIONS

    Severe

    laryngospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    constipation / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known

    Mild

    nausea / Early / Incidence not known
    rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    drowsiness / Early / Incidence not known
    dizziness / Early / Incidence not known
    headache / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    chills / Rapid / Incidence not known
    nasal congestion / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Acetaminophen; Codeine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Acetaminophen; Hydrocodone: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Acetaminophen; Oxycodone: (Moderate) Coadministration of oxycodone and benzonatate may result in additive CNS depression.
    Acetaminophen; Propoxyphene: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Alfentanil: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Aliskiren; Amlodipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Ambenonium Chloride: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Amide local anesthetics: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Amlodipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Amlodipine; Atorvastatin: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Amlodipine; Benazepril: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Amlodipine; Olmesartan: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Amlodipine; Telmisartan: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Amlodipine; Valsartan: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Articaine; Epinephrine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Aspirin, ASA; Oxycodone: (Moderate) Coadministration of oxycodone and benzonatate may result in additive CNS depression.
    Atracurium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with benzonatate can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with benzonatate can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Edrophonium: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Belladonna; Opium: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Bupivacaine Liposomal: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Bupivacaine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Bupivacaine; Lidocaine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Calcium-channel blockers: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Chloroprocaine: (Major) Caution is advised if chloroprocaine is used concurrently with other local anesthetics. The toxic effects of the drugs are additive.
    Chlorpheniramine; Codeine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Chlorpheniramine; Hydrocodone: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Chlorthalidone; Clonidine: (Moderate) Epidural clonidine may prolong the duration of action of local anesthetics, including both sensory and motor blockade.
    Cholinesterase inhibitors: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Cisatracurium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Clevidipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Clonidine: (Moderate) Epidural clonidine may prolong the duration of action of local anesthetics, including both sensory and motor blockade.
    Cocaine: (Moderate) The actions of benzonatate could be additive to those of other local anesthetics.
    Codeine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Codeine; Guaifenesin: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Codeine; Phenylephrine; Promethazine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Codeine; Promethazine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Diltiazem: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Donepezil: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Donepezil; Memantine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Doxacurium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Edrophonium: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Enalapril; Felodipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Felodipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Galantamine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Guaifenesin; Hydrocodone: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Homatropine; Hydrocodone: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Hydrocodone: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Hydrocodone; Ibuprofen: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Hydrocodone; Phenylephrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Hydrocodone; Pseudoephedrine: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Hydromorphone: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Ibuprofen; Oxycodone: (Moderate) Coadministration of oxycodone and benzonatate may result in additive CNS depression.
    Isradipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Levobupivacaine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Levorphanol: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Lidocaine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Magnesium Salts: (Moderate) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with local anesthetics.
    Meperidine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Meperidine; Promethazine: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Mepivacaine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Mepivacaine; Levonordefrin: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Mivacurium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Monoamine oxidase inhibitors: (Major) These drugs should be prescribed with caution. It may be advisable to avoid the use of benzonatate, which is structurally similar to local anesthetic agents, in patients receiving a monoamine oxidase inhibitor (MAOI). Consider alternatives to benzonatate. Patients receiving a MAOI concurrently with local anesthetics may have an increased risk of hypotension or CNS-related effects. If co-use is medically necessary, observe the patient for additive effects such as low blood pressure, sedation, dizziness, mental confusion, or other side effects.
    Neostigmine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Neuromuscular blockers: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Nicardipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Nifedipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Nimodipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Nisoldipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Oxycodone: (Moderate) Coadministration of oxycodone and benzonatate may result in additive CNS depression.
    Oxymorphone: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Pancuronium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Perindopril; Amlodipine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Physostigmine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Prilocaine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Prilocaine; Epinephrine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Procaine: (Major) Caution is advised if procaine is used concurrently with other local anesthetics. The toxic effects of local anesthetics are additive.
    Procarbazine: (Moderate) These drugs should be prescribed with caution. It may be advisable to avoid the use of benzonatate, which is structurally similar to local anesthetic agents, in patients receiving MAOIs. Consider alternatives to benzonatate. Procarbazine is a drug with monoamine oxidase inhibitor (MAOI) activity. Use of a drug with MAOI activity with local anesthetics may increase the risk of hypotension or CNS-related effects. If co-use is medically necessary, observe the patient for additive effects such as low blood pressure, sedation, dizziness, mental confusion, or other side effects.
    Propofol: (Minor) Propofol potentiates CNS depression and may enhance the sedative, respiratory depressive, and hypotensive effects of local anesthetics. A reduced dose of propofol may be needed for induction if it is used in conjunction with other medications that cause CNS depression.
    Propoxyphene: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Pyridostigmine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Rapacuronium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Remifentanil: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Rivastigmine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Rocuronium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Ropivacaine: (Major) Caution is advised if amide local anesthetics are used concurrently with benzonatate. The toxic effects of local anesthetics are additive.
    Saquinavir: (Major) The FDA recommends that saquinavir boosted with ritonavir should not be used in combination with other drugs that may prolong the QT interval. Benzonatate has a low, but possible risk for QT prolongation and torsades de pointes.
    Succinylcholine: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Sufentanil: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Tacrine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Tetracaine: (Major) The actions of benzonatate could be additive to those of other local anesthetics. Benzonatate is structurally related to tetracaine, which would explain additive pharmacodynamic effects.
    Trandolapril; Verapamil: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Tubocurarine: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Vancomycin: (Moderate) The concurrent administration of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions.
    Vecuronium: (Moderate) Benzonatate may enhance the neuromuscular blocking action of nondepolarizing agents.
    Verapamil: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Benzonatate is classified as FDA pregnancy risk category C. Animal studies to evaluate carcinogenic and mutagenic potential and effect on gestation and fertility have not been performed. Due to a lack of available data on the safety of benzonatate during pregnancy, the drug should be administered to a pregnant woman only if clearly needed. The effects of benzonatate during labor and obstetric delivery are unknown. However, benzonatate is chemically related to anesthetic agents such as procaine and similar effects could be observed if enough absorption takes place. Local anesthetics rapidly cross the placenta and can cause varying degrees of maternal, fetal, and neonatal toxicity when used for paracervical or pudendal block anesthesia during labor and delivery. The use of some local anesthetics during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life in the newborn. The long-term significance of these observations is unknown.

    MECHANISM OF ACTION

    Benzonatate acts peripherally by anesthetizing the stretch receptors of vagal afferent fibers located in the alveoli of the lungs, the bronchi, and the pleura. The drug may also act centrally by inhibiting the transmission of the cough reflex at the level of the medulla where the vagal afferent impulse is transmitted to the motor nerves. In patients with asthma, intravenously administered benzonatate increased minute ventilation, rate and depth of respiration. However, overall lung volume and expiratory flow rate were not altered. At recommended oral dosages, benzonatate has no inhibitory effect on the respiratory center; however, in overdosage, the pharmacology of benzonatate resembles that of other ester-type local anesthetics. Clinical effects include initial CNS stimulation, which is followed by CNS depression and respiratory compromise.
     
    When applied locally, as in the oropharynx prior to intubation or endoscopy, benzonatate acts like other local anesthetics. The drug blocks the generation and conduction of nerve impulses at the level of the cell membrane. Local anesthetics bind directly within the intracellular portion of voltage-gated sodium channels. This decreases the rate of membrane depolarization, thereby increasing the threshold for electrical excitability. The blockade affects all nerve fibers in the following sequence: autonomic, sensory, and motor, with effects diminishing in reverse order. Loss of nerve function clinically is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone. Direct nerve membrane penetration is necessary for effective anesthesia, which is achieved by applying benzonatate around the nerve trunks or ganglia supplying the area to be anesthetized. Benzonatate provides anesthesia in roughly 1—2 minutes after direct topical application to the oropharynx, noticeable clinically as the loss of the gag reflex.

    PHARMACOKINETICS

    Benzonatate is usually administered orally. The onset of action is 15 to 20 minutes, and antitussive effects last for approximately 3—8 hours. It is assumed that benzonatate, like other ester-type local anesthetics, is hydrolyzed to para-aminobenzoic acid (PABA) by plasma esterases. However, the absorption, distribution, metabolism and excretion of benzonatate are not well characterized.