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Mexiletine

Class: Class Ib Antiarrhythmics
VA Class: CV300
Chemical Name: 1-(2,6-Dimethylphenoxy)-2-propanamine hydrochloride
Molecular Formula: C11H17NO•HCl
CAS Number: 5370-01-4
Brands: Mexitil

Medically reviewed by Drugs.com on Nov 4, 2020. Written by ASHP.

Introduction

Antiarrhythmic agent; a local anesthetic-type, class 1B agent.

Uses for Mexiletine

Ventricular Arrhythmias

Treatment of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia). Use for less severe arrhythmias is notrecommended.

Can reduce ventricular premature contractions (VPCs), paired VPCs, and nonsustained ventricular tachycardia and can suppress the recurrence of ventricular tachycardia and/or fibrillation in patients with ventricular tachycardia and/or fibrillation. Avoid treatment of asymptomatic VPCs.

Has been effective in some patients for the treatment of ventricular arrhythmias unresponsive to other antiarrhythmic agents.

Diabetic Neuropathy

Has been used with equivocal results in the management of painful diabetic neuropathy; pending further accumulation of data from well-designed studies, use only in patients who do not respond to or cannot tolerate more established therapies.

Mexiletine Dosage and Administration

General

Ventricular Arrhythmias

  • Individualize dosage carefully according to individual response, tolerance, general condition, and cardiovascular status.

  • Clinical and ECG evaluation (e.g., Holter monitoring) is recommended to determine whether the desired antiarrhythmic effect has been achieved and to guide dosage titration and adjustment.

  • Initiate therapy in a hospital. Patients at high risk for developing life-threatening arrhythmias after discontinuance of existing antiarrhythmic therapy should be hospitalized.

Administration

Oral Administration

Administer orally, generally every 8 hours.

Administer with food or antacids to minimize adverse GI effects.

Dosage

Available as mexiletine hydrochloride; dosage expressed in terms of the salt.

Adults

Ventricular Arrhythmias
Oral

If rapid control of arrhythmia is essential, 400-mg loading dose followed by 200 mg in 8 hours. If rapid control of arrhythmia is not essential, initial dosage of 200 mg every 8 hours.

If necessary, adjust dosage at intervals of at least 2–3 days in increments or decrements of 50 or 100 mg. 200–300 mg every 8 hours usually results in satisfactory control of arrhythmias. If satisfactory control is not achieved and patient tolerates 300 mg every 8 hours, increase dosage to 400 mg every 8 hours.

If adequate control of arrhythmia has been achieved at doses ≤300 mg every 8 hours, total dosage may be administered twice daily (every 12 hours) with close monitoring of degree of ventricular ectopy suppression.

Switching from Another Class I Antiarrhythmic Agent
Oral

200 mg as a single dose, administered 6–12 hours after last dose of quinidine sulfate or disopyramide, 3–6 hours after last dose of procainamide, or 8–12 hours after last dose of tocainide. Adjust subsequent doses according to individual requirements.

When switching to mexiletine from IV lidocaine, discontinue lidocaine infusion at the time of administration of the first dose of mexiletine; however, keep infusion line open until arrhythmia appears to be satisfactorily suppressed. Closely monitor patient.

Diabetic Neuropathy†
Oral

Initial dosage of 200 mg once daily has been used; dosage increased at 2-day intervals to 200 mg twice daily and then 200 mg 3 times daily.

Prescribing Limits

Adults

Ventricular Arrhythmias
Oral

Maximum 400 mg every 8 hours (1.2 g daily).

If given twice daily, maximum 450 mg every 12 hours.

Diabetic Neuropathy†
Oral

Dosage generally should not exceed 1.2 g daily.

Special Populations

Hepatic Impairment

Consider dosage reduction in patients with hepatic impairment (including those with hepatic dysfunction secondary to CHF).

Renal Impairment

Dosage adjustment not required.

Cautions for Mexiletine

Contraindications

  • Second- or third-degree AV block (unless a cardiac pacemaker is in place).

  • Cardiogenic shock.

Warnings/Precautions

Warnings

Mortality

In CAST study, excessive rate of mortality and nonfatal cardiac arrest reported in patients with asymptomatic, non-life-threatening ventricular arrhythmias and recent MI (>6 days but <2 years previously) who were receiving encainide or flecainide compared with placebo.

Limit use of mexiletine in patients with ventricular arrhythmias to those with life-threatening arrhythmias due to mexiletine’s arrhythmogenic potential (see Cardiovascular Effects under Cautions) and the lack of evidence for improved survival for class I antiarrhythmic agents. Use for treatment of less severe arrhythmias currently is not recommended; avoid treatment of asymptomatic VPCs.

Major Toxicities

Cardiovascular Effects

Possible development or exacerbation of arrhythmias; clinical and ECG evaluations are essential prior to and during therapy. Initiate therapy in a hospital.

Use with caution in patients with preexisting first-degree AV block, sinus node dysfunction, or intraventricular conduction disturbances. Continuous monitoring recommended for patients with second- or third-degree AV block and an operative ventricular pacemaker. (See Contraindications under Cautions.)

Possible exacerbation of hypotension and CHF; use with caution in patients with these conditions.

Hepatic Effects

Possible abnormal liver function test results (AST elevations ≥3 times the ULN), especially during initial weeks of therapy in patients with CHF or AMI and/or patients who have received blood transfusions or other drug therapies. Discontinuance of therapy usually is not required. Severe hepatic injury, including hepatic necrosis, reported rarely.

Carefully evaluate patients who develop elevated serum concentrations of hepatic enzymes and those with signs or symptoms suggestive of liver dysfunction; consider discontinuance of therapy if enzyme elevations are persistent or increasing.

Hematologic Effects

Possible leukopenia, agranulocytosis, and thrombocytopenia, especially in severely ill patients receiving concurrent therapy with drugs known to cause adverse hematologic effects (e.g., procainamide, vinblastine).

Carefully evaluate patients in whom substantial hematologic changes occur; consider discontinuing therapy. Blood cell counts generally return to normal within 1 month following discontinuance.

General Precautions

Seizures

Seizures reported rarely; discontinuance of therapy may be necessary. Use with caution in patients with a history of seizure disorder.

Effects on Urinary Excretion

Substantial changes in urinary pH may affect urinary excretion of mexiletine; avoid concomitant drug therapy or dietary regimens that may markedly affect urinary pH.

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Hepatic Impairment

Possible prolonged elimination. Careful monitoring recommended (including in those with hepatic impairment secondary to CHF). Consider dosage reduction.

Common Adverse Effects

Nausea, vomiting, heartburn, dizziness or lightheadedness, tremor, nervousness, chest pain, coordination difficulties, headache, blurred vision/visual disturbances.

Interactions for Mexiletine

Metabolized by various CYP isoenzymes, principally by CYP2D and CYP1A2.

Drugs Affecting Hepatic Microsomal Enzymes

Hepatic enzyme inducers: Potential pharmacokinetic interaction (decreased plasma mexiletine concentrations).

Hepatic enzyme inhibitors: Potential pharmacokinetic interaction (decreased mexiletine clearance).

Drugs Affecting Gastric Emptying

Drugs that delay gastric emptying may reduce rate of mexiletine absorption (since mexiletine is absorbed in the small intestine ); conversely, drugs that accelerate gastric emptying may increase rate of mexiletine absorption.

Drugs Affecting Urinary pH

Drugs that markedly alter urinary pH may affect elimination of mexiletine; urinary acidification accelerates elimination; alkalinization slows elimination. Avoid concomitant drug therapy that markedly affects urinary pH.

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum- and magnesium-containing)

Possible decreased rate of absorption of mexiletine

Antianginal agents

Adverse pharmacokinetic interactions not reported

Antiarrhythmic agents (e.g., quinidine, propranolol)

Possible improved control of ventricular ectopy; prolongation of PR and QT intervals or QRS complex not reported with concomitant propranolol use

Anticoagulants

Adverse pharmacokinetic interactions not reported

Antihypertensive agents

Adverse pharmacokinetic interactions not reported

Atropine

Possible decreased rate of absorption of mexiletine

Benzodiazepines

Pharmacokinetic interactions not reported

Cimetidine

Possible increased, decreased, or unchanged plasma mexiletine concentrations

Closely monitor plasma mexiletine concentrations

Digoxin

Prolongation of PR and QT intervals or QRS complex not reported

Diuretics

Prolongation of PR and QT intervals or QRS complex not reported

Fluvoxamine

Reduced mexiletine clearance

Monitor patient closely and monitor serum mexiletine concentrations

Lidocaine

Potential additive adverse effects

Close monitoring recommended when patients are switched from IV lidocaine to mexiletine

Methylxanthines (caffeine, theophylline)

Possible decreased methylxanthine clearance and increased plasma theophylline concentrations

Monitor plasma theophylline concentrations; adjust theophylline dosage if necessary

Metoclopramide

Possible increased rate of absorption of mexiletine

Opiate agonists

Possible decreased rate of absorption of mexiletine

Phenobarbital

Possible decreased plasma mexiletine concentrations

Closely monitor plasma mexiletine concentrations

Phenytoin

Possible decreased plasma mexiletine concentrations

Closely monitor plasma mexiletine concentrations

Propafenone

Possible increased plasma mexiletine concentrations

Rifampin and rifapentine

Possible decreased plasma mexiletine concentrations

Closely monitor plasma mexiletine concentrations

Mexiletine Pharmacokinetics

Absorption

Bioavailability

About 90% absorbed following oral administration, with peak plasma concentrations attained in 2–3 hours. Undergoes low first-pass metabolism.

Onset

Onset of action is usually within 30–120 minutes.

Plasma Concentrations

Plasma mexiletine concentrations of ≥0.5 mcg/mL generally required to suppress ventricular arrhythmias; concentrations >2 mcg/mL associated with adverse CNS effects.

Special Populations

Decreased rate of absorption in patients with AMI or other conditions that delay gastric emptying.

Distribution

Plasma Protein Binding

50–60%.

Elimination

Metabolism

Extensively metabolized in the liver by various CYP isoenzymes, including CYP2D and CYP1A2. Pharmacologic activity results principally from the parent drug.

Elimination Route

About 8–15% of a dose is excreted in urine as unchanged drug.

Half-life

10–12 hours.

Special Populations

In patients with hepatic impairment, possible decreased metabolism and prolonged elimination.

Stability

Storage

Oral

Capsules

20–25°C.

Actions

  • Combines with fast sodium channels within the myocardium and inhibits rapid sodium influx, which decreases the maximal rate of depolarization of phase 0 of the action potential.

  • Inhibits recovery after repolarization in a time- and voltage-dependent manner, which is associated with subsequent dissociation of the drug from the sodium channels.

  • Increases the effective refractory period (ERP) relative to the duration of the action potential (ERP/APD) and reduces ventricular automaticity by raising the threshold for spontaneous firing of ventricular pacemaker cells.

  • Exhibits electrophysiologic effects characteristic of class IB antiarrhythmic agents, which rapidly attach to and dissociate from transmembrane sodium channels.

  • Causes little or no prolongation of PR and QT intervals or QRS complex. Has no clinically important effect on heart rate, systemic arterial BP, or myocardial function in healthy individuals or patients with cardiovascular disease.

Advice to Patients

  • Potential for toxicity (e.g., cardiovascular, hepatic).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Mexiletine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

150 mg*

Mexiletine Hydrochloride Capsules

Mexitil

Boehringer Ingelheim

200 mg*

Mexiletine Hydrochloride Capsules

Mexitil

Boehringer Ingelheim

250 mg*

Mexiletine Hydrochloride Capsules

Mexitil

Boehringer Ingelheim

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 14, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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