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MEXILETINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Mexiletine is a primary amine similar to lidocaine, but orally active. It's primary use is as a Class 1B antiarrhythmic drug with electrophysiologic properties similar to lidocaine, but dissimilar from quinidine, procainamide, and disopyramide. It is used to control ventricular dysrhythmias.

Specific Substances

    1) Mexiletine hydrochloride
    2) Mexiletene
    3) Methyl-2-(2,6-xylyloxy) ethylamine Hydrochloride
    4) CAS 31828-71-4 (mexiletine)
    5) CAS 5370-10-4 (mexiletine hydrochloride)

Available Forms Sources

    A) FORMS
    1) Mexiletine is available in 150, 200, and 250 mg capsules (Prod Info mexiletine HCl oral capsules, 2006).
    B) USES
    1) Mexiletine is indicated for the treatment of documented, life-threatening ventricular dysrhythmias, such as sustained ventricular tachycardia (Prod Info mexiletine HCl oral capsules, 2006).

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: Mexiletine is indicated for the treatment of documented, life-threatening ventricular dysrhythmias, such as sustained ventricular tachycardia.
    B) PHARMACOLOGY: Mexiletine hydrochloride is a local anesthetic and Class 1B antiarrhythmic agent that has structural and pharmacological similarities to lidocaine, but dissimilar from quinidine, procainamide, and disopyramide. Mexiletine hydrochloride reduces the rate of rise of the action potential, Phase 0, by inhibiting the inward sodium current. The drug lowers the effective refractory period (ERP) in Purkinje fibers to a lesser degree than the reduction in action potential duration (APD), resulting in an increase in the ERP/APD ratio. Mexiletine has no significant negative inotropic effect.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, heartburn, hiccup, unpleasant taste, dizziness, lightheadedness, tremors, nervousness, coordination difficulties, ataxia, confusion, and nervousness. RARE: Blurred vision/visual disturbances, hypotension, dysrhythmias (eg, bradycardia, sinus arrest, AV nodal or ventricular rhythms, second and third degree heart block, and asystole), ECG changes (eg, heart block [increased PR interval] or conduction delay [increased QRS interval]), rash, urticaria, Stevens-Johnson syndrome, exfoliative dermatitis, elevated liver enzymes, hepatic necrosis, seizures, hypersensitivity reactions, pulmonary infiltration or pulmonary fibrosis.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Drowsiness, dizziness, disorientation, paresthesias of the tongue, agitation, hallucinations, nausea.
    2) SEVERE TOXICITY: Bradycardia, hypotension, heart block, sinus arrest, nodal and ventricular dysrhythmias, QRS widening, respiratory failure, seizures, asystole, cardiovascular collapse, coma.
    0.2.20) REPRODUCTIVE
    A) Mexiletine is classed as FDA Pregnancy Category C due to the lack of data on teratogenesis.

Laboratory Monitoring

    A) Obtain serial ECGs, and institute continuous cardiac monitoring.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes, CBC with differential, and liver enzymes.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. The primary areas of concern are reversal of heart block, controlling seizures, and maintenance of respiratory and CNS status. Manage mild hypotension with IV fluids. Control agitation and confusion with benzodiazepines.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat hypotension with IV fluids, dopamine, or norepinephrine. Treat bradycardia with temporary pacemaker (first choice), atropine, or isoproterenol. Monitor for atrioventricular conduction disturbances or heart block. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with serious toxicity or life-threatening cardiac dysrhythmias.
    E) ANTIDOTE
    1) None.
    F) HYPOTENSIVE EPISODE
    1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine.
    G) SEIZURES
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    H) BRADYCARDIA
    1) Insertion of a temporary pacemaker is the treatment of choice for bradycardia induced by drugs of this class. Also consider atropine or isoproterenol. In one case report, isoproterenol was administered along with epinephrine to reverse heart block after a 4.4 gram ingestion of mexiletine and was unsuccessful.
    I) VENTRICULAR DYSRHYTHMIA
    1) Administer sodium bicarbonate for QRS widening. 1 to 2 mEq/kg IV is a reasonable starting dose. Monitor arterial blood gases, titrate to pH of 7.45 to 7.55. Cardiovert unstable rhythms. Institute cardiopulmonary bypass, extracorporeal membrane oxygenation or aortic balloon pump for patients with refractory dysrhythmias or hypotension.
    J) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    K) ENHANCED ELIMINATION
    1) Mexiletine has a protein binding of approximately 50% to 60% and volume of distribution of 5 to 7 liters/kg. Hemodialysis is unlikely to be of value because of the large volume of distribution. Two studies indicated that the use of peritoneal dialysis did not significantly alter the rate of removal of mexiletine. A man ingested 4 g of mexiletine and developed myotonia, hypotension, bradycardia, stupor, and dysarthria. He underwent hemodialysis 3 hours postingestion and his condition improved rapidly.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) OBSERVATION CRITERIA: Patients with an overdose should be referred to a healthcare facility, need to be monitored for several hours to assess cardiac function. Patients that remain asymptomatic after 6 hours can be discharged.
    3) ADMISSION CRITERIA: Patients with persistent cardiac dysrhythmias, mental status changes, seizures, and respiratory failure should be admitted to an ICU setting.
    4) CONSULT CRITERIA: A medical toxicologist or poison control center should be consulted in cases that involve cardiac or CNS toxicity, or in whom the diagnosis is not clear.
    M) PITFALLS
    1) When managing a suspected mexiletine overdose, the possibility of a coingestant(s) should be considered. Patients receiving Class 1a (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol) antiarrhythmic agents, beta blockers, calcium channel blockers, or a history of a slowed heart rate, ischemic heart disease or congestive heart failure may be at increased risk to develop bradycardia, heart block or dysrhythmias.
    N) PHARMACOKINETICS
    1) Tmax: 2 to 3 hours after ingestion. Rapidly and well absorbed (greater than 90%). Plasma protein binding: approximately 50% to 60%. Vd: 5 to 7 L/kg. Metabolism: hepatic (first pass); P450 CYP2D6 (primary) and CYP1A2; aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Excretion: 7.5% to 15% is excreted unchanged in the urine within 72 hours. Elimination half-life: 10 to 12 hours in normal subjects.
    O) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose ingestions of cardiac agents or substances that may produce significant bradycardia, heart block or dysrhythmias.

Range Of Toxicity

    A) TOXICITY: Therapeutic blood concentration is 1 to 2 mcg/mL. Blood concentration twice the therapeutic range resulted in only mild symptoms. Levels of 34 to 37 mcg/mL were found in a fatal case. ADULTS: A fatality was reported after ingestion of 4.4 g. Ingestions of 1.8 to 2.4 grams resulted in only mild CNS symptoms. An overdose of 18 g resulted in repetitive seizures in a woman. She remained hemodynamically stable throughout her hospital course. A man who took 12.4 grams of mexiletine, along with nifedipine and nitroglycerin, experienced a seizure and second and third degree AV block, but fully recovered. ADOLESCENT: An overdose of 8 g resulted in cardiac arrest and survival in a 17-year-old.
    B) THERAPEUTIC DOSES: ADULTS: Loading dose: 400 mg orally; maintenance, 200 to 300 mg orally every 8 hours; MAX 1200 mg/day. CHILDREN: The manufacturer indicated that safety and efficacy of mexiletine have not been established in children. However, mexiletine oral doses of 1.4 to 5 mg/kg/dose (mean: 3.3 mg/kg/dose) every 8 hours have been used in children. In one study, dosage of 15 to 25 mg/kg was needed in two pediatric patients with refractory supraventricular tachycardia. Dosages were determined based on plasma concentrations.

Clinical Effects

Summary Of Exposure

    A) USES: Mexiletine is indicated for the treatment of documented, life-threatening ventricular dysrhythmias, such as sustained ventricular tachycardia.
    B) PHARMACOLOGY: Mexiletine hydrochloride is a local anesthetic and Class 1B antiarrhythmic agent that has structural and pharmacological similarities to lidocaine, but dissimilar from quinidine, procainamide, and disopyramide. Mexiletine hydrochloride reduces the rate of rise of the action potential, Phase 0, by inhibiting the inward sodium current. The drug lowers the effective refractory period (ERP) in Purkinje fibers to a lesser degree than the reduction in action potential duration (APD), resulting in an increase in the ERP/APD ratio. Mexiletine has no significant negative inotropic effect.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, heartburn, hiccup, unpleasant taste, dizziness, lightheadedness, tremors, nervousness, coordination difficulties, ataxia, confusion, and nervousness. RARE: Blurred vision/visual disturbances, hypotension, dysrhythmias (eg, bradycardia, sinus arrest, AV nodal or ventricular rhythms, second and third degree heart block, and asystole), ECG changes (eg, heart block [increased PR interval] or conduction delay [increased QRS interval]), rash, urticaria, Stevens-Johnson syndrome, exfoliative dermatitis, elevated liver enzymes, hepatic necrosis, seizures, hypersensitivity reactions, pulmonary infiltration or pulmonary fibrosis.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Drowsiness, dizziness, disorientation, paresthesias of the tongue, agitation, hallucinations, nausea.
    2) SEVERE TOXICITY: Bradycardia, hypotension, heart block, sinus arrest, nodal and ventricular dysrhythmias, QRS widening, respiratory failure, seizures, asystole, cardiovascular collapse, coma.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) VISUAL DISTURBANCES: In a 4-week, double-blind, crossover, placebo controlled trial, blurred vision/visual disturbances were reported in 7.5% of mexiletine treated patients (n=53) vs in 2% of controls (n=49). The incidence of blurred vision/visual disturbances with mexiletine treatment 5.7% (n=430) compared with quinidine (3.1%, n=262), procainamide (5.1%, n=78) and disopyramide (7.2%, n=69) in 12-week double-blind trials (Prod Info mexiletine HCl oral capsules, 2006).
    2) VISUAL ACUITY DEFICITS were reported in two patients after receiving mexiletine 300 mg three times daily. One patient developed transient blindness with residual visual acuity disturbances and was subsequently diagnosed with acute pigmentary retinopathy. Symptoms were described as a shadow or clouding of vision. The patient's vision improved following discontinuation of mexiletine (Leong et al, 2001).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia has rarely been reported in patients taking mexiletine (Prod Info mexiletine HCl oral capsules, 2006).
    2) WITH POISONING/EXPOSURE
    a) Bradycardia has been reported in association with heart block following overdose (Mackintosh & Jequier, 1977; Chambers et al, 1982; Prod Info Mexitil(R), mexiletine hydrochloride, 1998).
    b) CASE REPORT: A 23-year-old man who was taking mexiletine 200 mg once daily, presented 1 hour after ingesting 4 g of mexiletine. He was alert, oriented, and cooperative. Despite supportive care, including gastric lavage and activated charcoal, he developed hypotension and bradycardia. He was treated with vasopressors, atropine, and transcutaneous pacing. At this time, he became stuporous and developed dysarthria. He underwent hemodialysis 3 hours postingestion and his condition improved rapidly (Akinci et al, 2011).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has rarely been reported in patients taking mexiletine (Prod Info mexiletine HCl oral capsules, 2006).
    2) WITH POISONING/EXPOSURE
    a) Hypotension may occur in patients with bradycardia (Mackintosh & Jequier, 1977), or as a result of reduced vascular resistance (Denaro & Benowitz, 1989). Hypotension and cardiovascular collapse have been associated with mexiletine overdose (Prod Info Mexitil(R), mexiletine hydrochloride, 1998).
    b) Hypotension may result due to decreased cardiac output and/or to decreased systemic vascular resistance (Denaro & Benowitz, 1989).
    c) CASE REPORT: A 23-year-old man who was taking mexiletine 200 mg once daily, presented 1 hour after ingesting 4 g of mexiletine. He was alert, oriented, and cooperative. Despite supportive care, including gastric lavage and activated charcoal, he developed hypotension and bradycardia. He was treated with vasopressors, atropine, and transcutaneous pacing. At this time, he became stuporous and developed dysarthria. He underwent hemodialysis 3 hours postingestion and his condition improved rapidly (Akinci et al, 2011).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Dysrhythmias may include sinus bradycardia, sinus arrest, AV nodal or ventricular rhythms, second and third degree heart block, and asystole (Prod Info mexiletine HCl oral capsules, 2006; Denaro & Benowitz, 1989). ECG changes may include those related to heart block (increased PR interval) or conduction delay (increased QRS interval) (Nora et al, 1989; Denaro & Benowitz, 1989).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Asystole was reported after ingestion of 8 grams in a 17-year-old (Hruby & Missliwetz, 1985).
    D) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Patients may occasionally suffer aggravation of cardiac failure even at therapeutic doses (Denaro & Benowitz, 1989).
    b) CASE REPORT: A patient with an automatic implantable cardioverter/defibrillator had his defibrillation threshold raised beyond the capacity of his device after beginning mexiletine therapy (Marinchak et al, 1988).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) Respiratory failure may occur secondary to heart block following an overdose (Hruby & Missliwetz, 1985a; Mackintosh & Jequier, 1977).
    B) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Pulmonary infiltration or pulmonary fibrosis was reported with mexiletine therapy in post-marketing experience (Prod Info mexiletine HCl oral capsules, 2006).
    b) CASE REPORT: Pulmonary fibrosis was reported in a 75-year-old man following 3 months of mexiletine therapy. Three other cases have been reported to the manufacturer (Bero & Rihn, 1991).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Central nervous system toxicity has occurred in up to 50% of patients treated with mexiletine, primarily lightheadedness, dizziness, hand tremors, ataxia, and confusion (Carlier, 1984; Heger et al, 1980; Waspe et al, 1983; Fenster & Kern, 1983; Esterbrooks et al, 1983; Schoenfeld et al, 1984). The incidence of CNS toxicity increases with serum concentrations above 2 mcg/mL (Waspe et al, 1983; Chew et al, 1979; Talbot et al, 1976; Campbell et al, 1973; Campbell et al, 1977; Talbot et al, 1973; Carlier, 1984a).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 23-year-old man who was taking mexiletine 200 mg once daily, presented 1 hour after ingesting 4 g of mexiletine. He was alert, oriented, and cooperative. Despite supportive care, including gastric lavage and activated charcoal, he developed hypotension and bradycardia. He was treated with vasopressors, atropine, and transcutaneous pacing. At this time, he became stuporous and developed dysarthria. He underwent hemodialysis 3 hours postingestion and his condition improved rapidly (Akinci et al, 2011).
    b) Drowsiness, dizziness, and disorientation were seen in 3 patients that overdosed on 1.8 to 2.4 g. Symptoms started at 1 to 2 hours postingestion, and lasted 6 hours (Chambers et al, 1982).
    c) Agitation and hallucinations, which gradually subsided over 24 hours, have been reported following ingestion of an unknown quantity of mexiletine in a suicide attempt in a 17-year-old (Kozer et al, 2000).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have rarely been reported in patients taking mexiletine (Prod Info mexiletine HCl oral capsules, 2006). Seizures occurred both in patients with and without a history of prior seizures (Prod Info mexiletine HCl oral capsules, 2006; Koppe, 1977).
    2) WITH POISONING/EXPOSURE
    a) A clinical manifestation of mexiletine overdose may include seizures (Prod Info mexiletine HCl oral capsules, 2006).
    b) CASE REPORT: Seizures began within one hour after ingestion of 4.4 grams by a 22-year-old man (Mackintosh & Jequier, 1977).
    c) CASE REPORT: A tonic-clonic seizure was reported in a 50-year-old man who ingested mexiletine 12.4 grams, in combination with nifedipine and nitroglycerin (Frank & Snyder, 1991).
    d) CASE REPORT: Repetitive seizures were reported in a 41-year-old woman who ingested up to 18,000 mg of mexiletine in a suicide attempt. The seizures responded to diazepam and phenobarbital. Noteworthy in this case is the fact that her ECG and blood pressure remained normal during status epilepticus. She remained hemodynamically stable during her entire hospital course (Nelson & Hoffman, 1994).
    e) CASE REPORT: A 17-year-old boy was admitted to the hospital in status epilepticus following a suicide attempt with an unknown amount of mexiletine. Following repeated intravenous doses of diazepam the seizures subsided after one hour. Serum mexiletine level was reported to be 44.4 micromols/liter (Kozer et al, 2000).
    C) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In a 4-week, double-blind, crossover, placebo controlled trial, paresthesias/numbness was reported in 3.8% of mexiletine treated patients (n=53) vs in 2% of placebo-treated patients (n=49). The incidence of paresthesias/numbness with mexiletine treatment was 2.4% ( n=430) compared with quinidine (2.3%, n=262), procainamide (2.6%, n=78) and disopyramide (0%, n=69) in 12-week double-blind trials (Prod Info mexiletine HCl oral capsules, 2006).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Paresthesias of the tongue were reported as an early symptom (within 30 minutes) in a fatal overdose of 4.4 g in a young adult (Mackintosh & Jequier, 1977).
    D) ATAXIA
    1) WITH THERAPEUTIC USE
    a) One study reported side effects of mexiletine in 27 of 44 patients receiving oral therapy in recommended doses. Withdrawal of mexiletine was required in 14% of patients. Neurologic symptoms were observed in 22 patients (50%), including ataxia (20%). CNS symptoms occurred early in the course of therapy (1 to 7 days) and usually resolved with a reduction of 100 to 200 mg in each 8 hourly dose. However, persistent lightheadedness, ataxia and/or tremor despite a decrease in dose were the primary or partial cause of treatment discontinuation in all patients (Waspe et al, 1983).
    E) TREMOR
    1) WITH THERAPEUTIC USE
    a) In a 4-week, double-blind, crossover, placebo controlled trial, tremor was reported in 13.2% of mexiletine treated patients (n=53) vs in 0% of placebo-treated patients (n=49). The incidence of tremor with mexiletine treatment was also higher (13.2%, n=430) when compared with quinidine (2.3%, n=262), procainamide (3.8%, n=78) and disopyramide (1.4%, n=69) in 12-week double-blind trials. This effect was dose-related and reversible with a reduction in dosage or discontinuation of therapy (Prod Info mexiletine HCl oral capsules, 2006).
    F) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a 4-week, double-blind, crossover, placebo controlled trial, dizziness/lightheadedness was reported in 26.4% of mexiletine treated patients (n=53) vs in 14.3% of placebo-treated patients (n=49). The incidence of lightheadedness with mexiletine treatment was also higher (10.5%, n=430) when compared with quinidine (14.1%, n=262), procainamide (14.1%, n=78) and disopyramide (2.9%, n=69) in 12-week double-blind trials. This effect was dose-related and reversible with a reduction in dosage or discontinuation of therapy (Prod Info mexiletine HCl oral capsules, 2006).
    2) WITH POISONING/EXPOSURE
    a) Drowsiness, dizziness, and disorientation were seen in 3 patients that overdosed on 1.8 to 2.4 g. Symptoms started at 1 to 2 hours postingestion, and lasted 6 hours (Chambers et al, 1982).
    G) COORDINATION PROBLEM
    1) WITH THERAPEUTIC USE
    a) In a 4-week, double-blind, crossover, placebo controlled trial, coordination difficulties were reported in 9.4% of mexiletine-treated patients (n=53) vs in 0% of placebo-treated patients (n=49). The incidence of coordination difficulties with mexiletine treatment was also higher (9.7%, n=430) when compared with quinidine (1.1%, n=262), procainamide (1.3%, n=78) and disopyramide (0%, n=69) in 12-week double-blind trials. This effect was dose-related and reversible with a reduction in dosage or discontinuation of therapy (Prod Info mexiletine HCl oral capsules, 2006).
    2) WITH POISONING/EXPOSURE
    a) Drowsiness, dizziness, and disorientation were seen in 3 patients that overdosed on 1.8 to 2.4 g. Symptoms started at 1 to 2 hours postingestion, and lasted 6 hours (Chambers et al, 1982).
    H) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) In a 4-week, double-blind, crossover, placebo controlled trial, nervousness was reported in 11.3% of mexiletine treated patients (n=53) vs in 6.1% of placebo-treated patients (n=49). However, the incidence of nervousness with mexiletine treatment was 5% (n=430) compared with quinidine (5.3%, n=262), procainamide (7.7%, n=78) and disopyramide (2.9%, n=69) in 12-week double-blind trials (Prod Info mexiletine HCl oral capsules, 2006).
    2) WITH POISONING/EXPOSURE
    a) Agitation and hallucinations, which gradually subsided over 24 hours, have been reported following ingestion of an unknown quantity of mexiletine in a suicide attempt in a 17-year-old (Kozer et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) GI upset occurs frequently with elevated therapeutic levels (generally over 2 mcg/mL). These symptoms include nausea, vomiting, hiccup, and unpleasant taste (Carlier, 1984). Approximately 15% to 40% of patients receiving oral therapy will experience gastrointestinal toxicity (Prod Info mexiletine HCl oral capsules, 2006; Carlier, 1984a; Waspe et al, 1983)
    b) In comparative clinical trials, nausea, vomiting or heartburn occurred in 39.3% of mexiletine-treated patients as compared to an incidence of 21.4%, 33.3% and 14.5% in patients receiving quinidine, procainamide or disopyramide, respectively. In a 4-week double-blind crossover trial, nausea, vomiting or heartburn occurred in 39.6% of mexiletine treated patients vs 6.1% in those taking placebo. These reactions were generally not serious, and were dose-related and reversible with a reduction in dosage, therapy discontinuation, or by taking the drug with food or antacid (Prod Info mexiletine HCl oral capsules, 2006).
    2) WITH POISONING/EXPOSURE
    a) Nausea has been reported with mexiletine overdose (Prod Info mexiletine HCl oral capsules, 2006; Mackintosh & Jequier, 1977).
    B) ESOPHAGITIS
    1) WITH THERAPEUTIC USE
    a) Pill esophagitis has been reported (Adler & Goldberg, 1990; Rudolph, 1983).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) Rare cases of severe hepatic necrosis have been reported during therapeutic use of mexiletine. Elevations of SGOT (greater than 3 times normal) occurred in 1% to 2% of patients receiving mexiletine during clinical trials (Prod Info mexiletine HCl oral capsules, 2006).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 64-year-old man developed elevated serum liver enzymes (total bilirubin 3.7 mg/dL, ALT 317 IU/L, AST 242 IU/L, LDH 2246 IU/L) 30 days following mexiletine therapy (300 mg/day). A hypersensitivity syndrome was diagnosed and all abnormal liver function tests resolved after discontinuation of the drug (Higa et al, 1997).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) In a compassionate use program described by the manufacturer involving over 10,000 patients, leukopenia, neutropenia, agranulocytosis, and thrombocytopenia were rarely (1 or 2 per 1000) reported in patients receiving mexiletine. It is unclear if mexiletine was the definite cause of these blood dyscrasias. Procainamide (particularly the sustained-release preparation) was given with mexiletine in several instances of agranulocytosis and may have been contributory or the sole cause. Blood counts have returned to normal within 1 to 2 months after withdrawal of drug (Prod Info mexiletine HCl oral capsules, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) MACULOPAPULAR ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A generalized morbilliform skin eruption with fever and eosinophilia developed within 30 days of initiation of mexiletine therapy (300 mg/day) in a 64-year-old man. Hypersensitivity syndrome was diagnosed following results of a patch test (Higa et al, 1997).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) A case of contact urticaria induced by mexiletine in a 76-year-old man receiving iontophoresis has been reported. The reaction occurred only at a site where a mexiletine-soaked pad was placed during iontophoresis therapy. This reaction could not be reproduced on rechallenge with mexiletine alone or iontophoresis alone. The urticarial reaction was dose-dependent (Yamazaki et al, 1994).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Rare cases of Stevens-Johnson syndrome have been reported in a compassionate use trial of over 10,000 patients (Prod Info mexiletine HCl oral capsules, 2006).
    D) ERYTHRODERMA
    1) WITH THERAPEUTIC USE
    a) Rare cases of exfoliative dermatitis have been reported in a compassionate use trial of over 10,000 patients (Prod Info mexiletine HCl oral capsules, 2006).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) There have been isolated reports of hypersensitivity reactions in post-marketing experience (Prod Info mexiletine HCl oral capsules, 2006).
    b) CASE REPORT: A 64-year-old man taking mexiletine 300 mg/day developed a generalized morbilliform skin eruption, eosinophilia (51.0%), fever, atypical lymphocytosis and liver dysfunction. A patch test was positive for mexiletine and a diagnosis of hypersensitivity syndrome was made (Higa et al, 1997).

Reproductive

    3.20.1) SUMMARY
    A) Mexiletine is classed as FDA Pregnancy Category C due to the lack of data on teratogenesis.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) FDA Pregnancy Category C (Prod Info Mexitil(R), mexiletine hydrochloride, 1998). The magnitude of the teratogenic risk is undetermined and the quality and quantity of data are poor (TERIS , 1991).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    MEXILETINEC
    Reference: Briggs et al, 1998; Prod Info Mexitil(R), 1998
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Mexiletine is secreted in breast milk. The milk/plasma ratio is approximately 1.45. The small amounts secreted are unlikely to be harmful to an infant (Carlier, 1984).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain serial ECGs, and institute continuous cardiac monitoring.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes, CBC with differential, and liver enzymes.

Methods

    A) CHROMATOGRAPHY
    1) Automated high-performance liquid chromatography (HPLC) has been shown to provide accurate measurements of urine and serum levels of mexiletine (Kozer et al, 2000).
    B) IMMUNOASSAY
    1) Immunoassays for urinary drug screening may be inaccurate for mexiletine due to cross-reactivity with amphetamines. Kozer et al (2000) reported a case where a positive amphetamine urinary screen was shown by a fluorescence polarization immunoassay system. Follow-up urinary screen by HPLC revealed no amphetamines, but large amounts of mexiletine.

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) Patients with persistent cardiac dysrhythmias, mental status changes, seizures, and respiratory failure should be admitted to an ICU setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) There is no role for home management.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A medical toxicologist or poison control center should be consulted in cases that involve cardiac or CNS toxicity, or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with an overdose should be referred to a healthcare facility to be monitored for several hours to assess cardiac function. Patients that remain asymptomatic after 6 hours can be discharged.

Monitoring

    A) Obtain serial ECGs, and institute continuous cardiac monitoring.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes, CBC with differential, and liver enzymes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) 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.
    2) 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).
    3) Arimori et al (1993) studied the in-vitro adsorption of mexiletine onto activated charcoal in macrogol-electrolyte solution. They reported a maximum adsorptive capacity of activated charcoal for mexiletine to be 328 and 284 mg/gram of charcoal in PEG-ELS and JP XII second medium, respectively. While this suggests that whole bowel irrigation with a PEG solution does not interfere with adsorption of mexiletine by activated charcoal, whole bowel irrigation is not recommended as routine decontamination as mexiletine is not sustained release and is not known to form bezoars. It should be considered in patients with worsening toxic effects despite activated charcoal (Arimori et al, 1993).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Obtain serial ECGs, and institute continuous cardiac monitoring.
    2) Monitor vital signs and mental status.
    3) Monitor serum electrolytes, renal function, liver enzymes and CBC following a significant exposure.
    B) BRADYCARDIA
    1) Isoproterenol has been used to manage lidocaine toxicity (Denaro & Benowitz, 1989). It was administered along with epinephrine to reverse heart block after a 4.4 gram ingestion of mexiletine and was unsuccessful (Mackintosh & Jequier, 1977).
    2) Insertion of a temporary pacemaker is the treatment of choice for bradyarrhythmias induced by drugs of this class (Denaro & Benowitz, 1989).
    a) Right ventricular pacing was attempted and the pacer successfully placed after a 4.4 gram ingestion of mexiletine, without reversing the heart block (Mackintosh & Jequier, 1977).
    3) Atropine may be considered in patients with bradycardia or hypotension (Prod Info Mexitil(R), mexiletine hydrochloride, 1998).
    4) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    5) ISOPROTERENOL INDICATIONS
    a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    C) 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).
    D) 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, 2010; 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).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    E) VENTRICULAR ARRHYTHMIA
    1) Administer sodium bicarbonate for QRS widening. 1 to 2 mEq/kg IV is a reasonable starting dose. Monitor arterial blood gases, titrate to pH of 7.45 to 7.55. Cardiovert unstable rhythms. Institute cardiopulmonary bypass, extracorporeal membrane oxygenation or aortic balloon pump for patients with refractory dysrhythmias or hypotension.
    F) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) SUMMARY
    1) Mexiletine has a protein binding of approximately 50% to 60% and volume of distribution of 5 to 7 liters/kg. Hemodialysis is unlikely to be of value because of the large volume of distribution. Two studies indicated that the use of peritoneal dialysis did not significantly alter the rate of removal of mexiletine. A man ingested 4 g of mexiletine and developed myotonia, hypotension, bradycardia, stupor, and dysarthria. He underwent hemodialysis 3 hours postingestion and his condition improved rapidly.
    B) HEMODIALYSIS
    1) CASE REPORT: A 23-year-old man who was taking mexiletine 200 mg once daily, presented 1 hour after ingesting 4 g of mexiletine. He was alert, oriented, and cooperative. Despite supportive care, including gastric lavage and activated charcoal, he developed hypotension and bradycardia. He was treated with vasopressors, atropine, and transcutaneous pacing. At this time, he became stuporous and developed dysarthria. He underwent hemodialysis 3 hours postingestion and his condition improved rapidly. Clearance from dialysis was not calculated (Akinci et al, 2011).
    C) PERITONEAL DIALYSIS
    1) In one case where peritoneal dialysis was tried, 6 liters of fluid over a 12 hour period removed 1% of an administered dose. When 12 hours of continuous dialysis was tried (36 liters of dialysate) 6% was removed (Jones et al, 1983).
    2) Only 2.8% of the daily dose was cleared by peritoneal dialysis in a patient receiving therapeutic doses of mexiletine (Guay et al, 1985).
    D) URINARY ACIDIFICATION/NOT RECOMMENDED
    1) Although urinary acidification will enhance the renal clearance of mexiletine (Prod Info Mexitil(R), mexiletine hydrochloride, 1998), it is unlikely to be of clinical significance, and risks aggravating acidemia and other adverse renal effects in convulsing patients outweigh theoretical benefit (Denaro & Benowitz, 1989).

Abstracts

Case Reports

    A) ADULT
    1) A healthy 22-year-old ingested 4.4 g of mexiletine. Within one half hour, he had paresthesias of the tongue, and within an hour he had become nauseated and had a seizure of 5 minutes duration. On arrival in a medical facility, he had no recordable blood pressure, a heart rate of 15 beats per minute, and was cyanotic and convulsing. ECG showed complete heart block. He was given isoproterenol, epinephrine and right ventricular pacing. None of these reversed the heart block, and the patient died (Mackintosh & Jequier, 1977).
    2) A 64-year-old man with a malfunctioning automatic implantable cardioverter/defibrillator (AICD), and on digoxin, was found to have had his defibrillation threshold raised beyond the capacity of his device two months after starting mexiletine therapy (100 mg four times a day). Originally measured at 15 joules during implantation the year before, his threshold had been raised to 40 joules. Three weeks after discontinuing mexiletine his defibrillation threshold returned to 15 to 20 joules, allowing a new AICD to be successfully implanted (Marinchak et al, 1988).
    3) A 50-year-old man with a history of two myocardial infarctions in the previous three years consumed 12.4 grams of mexiletine, 620 mg of nifedipine, and 50 to 100 tablets of 0.4 mg nitroglycerin. He experienced a tonic/clonic seizure that responded to 5 mg of midazolam, then second and third degree atrioventricular block with periods of ventricular arrest. He was initially treated with atropine, epinephrine, and calcium gluconate, then subsequently with infusions of dopamine, phenylephrine, and epinephrine. Forced diuresis with mannitol and furosemide was begun eight hours after overdose. He was discharged from intensive care as fully recovered roughly 36 hours postingestion (Frank & Snyder, 1991).
    4) A 65-year-old woman with coronary artery disease and chronic renal failure demonstrated mexiletine toxicity after being dosed with 200 mg every eight hours. Her renal insufficiency may have contributed to an elevated plasma level of mexiletine (5.3 mcg/mL vs 2 mcg/mL or less for normal therapeutic range) (Nora et al, 1989).
    5) A 41-year-old woman ingested up to 18,000 mg mexiletine in a suicide attempt. No co-ingestants were suspected. Repetitive seizures occurred with NO hemodynamic or ECG abnormalities. Seizures responded to diazepam and phenobarbital. Mexiletine serum levels drawn on admission were reported to be 20 mcg/mL (therapeutic 1-2 mcg/mL). The patient remained hemodynamically stable throughout her hospitalization (Nelson & Hoffman, 1994).

Range Of Toxicity

Summary

    A) TOXICITY: Therapeutic blood concentration is 1 to 2 mcg/mL. Blood concentration twice the therapeutic range resulted in only mild symptoms. Levels of 34 to 37 mcg/mL were found in a fatal case. ADULTS: A fatality was reported after ingestion of 4.4 g. Ingestions of 1.8 to 2.4 grams resulted in only mild CNS symptoms. An overdose of 18 g resulted in repetitive seizures in a woman. She remained hemodynamically stable throughout her hospital course. A man who took 12.4 grams of mexiletine, along with nifedipine and nitroglycerin, experienced a seizure and second and third degree AV block, but fully recovered. ADOLESCENT: An overdose of 8 g resulted in cardiac arrest and survival in a 17-year-old.
    B) THERAPEUTIC DOSES: ADULTS: Loading dose: 400 mg orally; maintenance, 200 to 300 mg orally every 8 hours; MAX 1200 mg/day. CHILDREN: The manufacturer indicated that safety and efficacy of mexiletine have not been established in children. However, mexiletine oral doses of 1.4 to 5 mg/kg/dose (mean: 3.3 mg/kg/dose) every 8 hours have been used in children. In one study, dosage of 15 to 25 mg/kg was needed in two pediatric patients with refractory supraventricular tachycardia. Dosages were determined based on plasma concentrations.

Therapeutic Dose

    7.2.1) ADULT
    A) Loading dose: 400 mg orally; maintenance, 200 to 300 mg orally every 8 hours; MAX 1200 mg/day (Prod Info mexiletine HCl oral capsules, 2006).
    7.2.2) PEDIATRIC
    A) The manufacturer indicated that safety and efficacy of mexiletine have not been established in children (Prod Info mexiletine HCl oral capsules, 2006).
    1) However, mexiletine oral doses of 1.4 to 5 mg/kg/dose (mean: 3.3 mg/kg/dose) every 8 hours have been used in children (Taketomo et al, 2002).
    2) In one study, dosage of 15 to 25 mg/kg was needed in two pediatric patients with refractory supraventricular tachycardia. Dosages were determined based on plasma concentrations (Holt et al, 1979).

Minimum Lethal Exposure

    A) CASE REPORTS: A fatality was reported after ingestion of 4.4 g (Mackintosh & Jequier, 1977).
    B) Levels of 34 to 37 mcg/mL were found in a fatal case (Mackintosh & Jequier, 1977).

Maximum Tolerated Exposure

    A) Therapeutic serum levels are reported to be 1 to 2 mcg/mL (Nelson & Hoffman, 1994; Mackintosh & Jequier, 1977).
    B) MILD EFFECTS
    1) Ingestions of 1.8 to 2.4 grams resulted in mild CNS symptoms only (Chambers et al, 1982).
    2) Plasma levels twice the therapeutic range resulted in only mild symptoms (Mackintosh & Jequier, 1977).
    C) MODERATE TO SERIOUS EFFECTS
    1) An overdose of 8 g resulted in cardiac arrest and survival in a 17-year-old (Hruby & Missliwetz, 1985).
    2) An overdose of 18 g resulted in repetitive seizures in a 41-year-old woman. She remained hemodynamically stable throughout her hospital course (Nelson & Hoffman, 1994).
    3) CASE REPORT: A 23-year-old man ingested 4 g of mexiletine and developed hypotension, bradycardia, stupor, and dysarthria. He underwent hemodialysis 3 hours postingestion and his condition improved rapidly. (Akinci et al, 2011).
    D) MIXED OVERDOSE
    1) A 50-year-old man took 12.4 grams of mexiletine, along with nifedipine and nitroglycerin, experienced a seizure and second and third degree AV block, but fully recovered (Frank & Snyder, 1991).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) Therapeutic serum levels are reported to be 1 to 2 mcg/mL (Nelson & Hoffman, 1994; Mackintosh & Jequier, 1977).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) MILD EFFECTS: Plasma levels twice the therapeutic range resulted in only mild symptoms. Levels of 34 to 37 mcg/mL were found in a fatal case (Mackintosh & Jequier, 1977).
    b) SERIOUS EFFECTS: Increased adverse effects may be noted with plasma levels greater than 2 mcg/mL (Carlier, 1984).
    1) Serum mexiletine level of 20 mcg/mL was reported in a 41-year-old female following the intentional ingestion of 18,000 milligrams (Nelson & Hoffman, 1994).
    c) Serum mexiletine level of 44.4 micromols/L was reported in a 17-year-old following ingestion of an unknown quantity in a suicide attempt. The boy was treated for seizures and recovered (Kozer et al, 2000).
    d) POSTMORTEM: Postmortem blood concentrations of 2.1 mg/100 g were reported in a 20-year-old (Hruby & Missliwetz, 1985). Postmortem blood levels of 3.7 mg/100 g were reported after an overdose of 4.4 grams (Mackintosh & Jequier, 1977).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 114 mg/kg (RTECS , 2002a)
    2) LD50- (ORAL)MOUSE:
    a) 320 mg/kg (RTECS , 2002a)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Mexiletine hydrochloride is a local anesthetic and Class 1B antiarrhythmic agent that has structural and pharmacological similarities to lidocaine, but dissimilar from quinidine, procainamide, and disopyramide. Mexiletine hydrochloride reduces the rate of rise of the action potential, Phase 0, by inhibiting the inward sodium current. The drug lowers the effective refractory period (ERP) in Purkinje fibers to a lesser degree than the reduction in action potential duration (APD), resulting in an increase in the ERP/APD ratio (Prod Info mexiletine HCl oral capsules, 2006).

Physicochemical

Physical Characteristics

    A) Mexiletine is a white to off-white crystalline powder with a slightly bitter taste. It is freely soluble in water and in alcohol (Prod Info Mexitil(R), mexiletine hydrochloride, 1998).

Molecular Weight

    A) 179.29 (RTECS , 2002)
    B) HCl SALT: 215.7

References

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