Section 06 · Monograph

Mexiletine

Reviewed Nov 2026FDA label

MexitilNa+ channel blocker (Class IB)

Black Box Warning

In the Cardiac Arrhythmia Suppression Trial (CAST), use of antiarrhythmics in patients with asymptomatic non-life-threatening ventricular arrhythmias after MI was associated with excess mortality, attributed to a class effect of antiarrhythmic drugs
Although mexiletine has not been studied in CAST, its use should be reserved for patients with life-threatening ventricular arrhythmias because of the demonstrated proarrhythmic potential of this drug class

Treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardiaFDA-labeled

Painful diabetic peripheral neuropathy (off-label; supported by randomized placebo-controlled trials)Off-label
Other refractory neuropathic pain syndromes with a presumed sodium-channelopathy component (e.g. erythromelalgia)Off-label
Myotonic disorders (e.g. myotonic dystrophy, nondystrophic myotonias)Off-label

Class IB antiarrhythmic; structurally and pharmacologically related to lidocaine
Blocks voltage-gated fast inward sodium channels in cardiac and neuronal cell membranes, reducing conduction in depolarized/ischemic tissue while having minimal effect on normal conduction
In neuropathic pain, presumed mechanism is use-dependent blockade of abnormally expressed voltage-gated sodium channels in injured peripheral nerves, reducing ectopic neuronal firing
Undergoes extensive first-pass hepatic metabolism primarily via CYP2D6

FDA-labeled (arrhythmia): initiate at 200 mg orally every 8 hours with food or antacid; usual maintenance 200-300 mg every 8 hours; maximum 1200 mg/day
Off-label neuropathic pain dosing: typically initiated at 150 mg once or twice daily and titrated slowly by 150 mg increments every 3-7 days to a usual target of 150-300 mg two to three times daily
Therapeutic plasma level range historically cited as 0.5-2 mcg/mL for arrhythmia indication
Obtain baseline and periodic ECG given proarrhythmic and conduction effects

Cardiogenic shock
Pre-existing second- or third-degree AV block in patients without a functioning pacemaker
Known hypersensitivity to mexiletine or to amide-type local anesthetics

CYP2D6 inhibitors can significantly increase mexiletine plasma concentrations and toxicity risk
Hepatic enzyme inducers (phenytoin, rifampin, phenobarbital) can increase mexiletine clearance and reduce efficacy
Mexiletine inhibits CYP1A2 and can increase theophylline levels by roughly 70%
Additive cardiodepressant/proarrhythmic effects with other Class I antiarrhythmics and with amide local anesthetics
Urinary alkalinizers can decrease renal elimination and raise levels

Animal reproduction studies have shown adverse fetal effects at maternally toxic doses; no adequate well-controlled human studies exist
Use during pregnancy only if potential benefit justifies potential risk to the fetus
Mexiletine crosses the placenta
Excreted into human breast milk at concentrations similar to maternal plasma; decision should be made whether to discontinue nursing or discontinue the drug