CHF and arrhythmias:

Indications for: Mexiletine

Documented life-threatening ventricular arrhythmias.

Adult Dosage:

Take with food or antacid. Initially 200mg every 8hrs when rapid control of arrhythmia is not essential. Adjust dose if needed at not less than 2–3 day intervals in 50–100mg increments. Usual dose: 200–300mg every 8hrs; max 1.2g/day. May increase to 400mg every 8hrs if unsatisfactory response. When rapid control of ventricular arrhythmia is essential: may give initial loading dose of 400mg, followed by 200mg after 8hrs. If adequate response is achieved by ≤300mg every 8hrs, may give same total daily dose in divided doses every 12hrs; up to max 450mg every 12hrs. For rapid induction, transferring from other antiarrhythmics: see full labeling.

Children Dosage:

Not established.

Mexiletine Contraindications:

Cardiogenic shock. 2nd- or 3rd- degree AV block unless paced.

Boxed Warning:

Mortality. Acute liver injury.

Mexiletine Warnings/Precautions:

Risk of mortality, acute liver injury. Evaluate if abnormal liver function tests or signs/symptoms suggesting liver dysfunction occur. Consider discontinuing if persistent or worsening elevation of hepatic enzymes is detected. Discontinue if drug reactions with eosinophilia and systemic symptoms (DRESS) is suspected. Preexisting sinus node dysfunction or intraventricular conduction abnormalities. Hypotension. Severe congestive heart failure. Seizure disorder. Monitor ECG, blood counts. If warranted, discontinue if significant hematologic changes are observed. Hepatic impairment. Pregnancy. Nursing mothers: not recommended; consider alternative infant feeding method if therapy is needed.

Mexiletine Classification:

Class IB antiarrhythmic.

Mexiletine Interactions:

May potentiate other antiarrhythmics, theophylline. Slowly titrate mexiletine dose to desired effect when concomitant propafenone. Monitor control if used with phenytoin or other hepatic enzyme-inducing drugs (eg, rifampin, phenobarbital). Monitor closely if used with cimetidine. Avoid drugs or diets that alter urinary pH.

Adverse Reactions:

Upper GI distress, dizziness/lightheadedness, tremor, nervousness, coordination difficulties, chest pain, palpitations, changes in sleep habits, blurred vision/visual disturbances, headache; acute liver injury, DRESS, blood dyscrasias.

Note:

Formerly known under the brand name Mexitil.

Metabolism:

Mexiletine is mainly metabolized in the liver, the primary pathway being CYP2D6 metabolism, although it is also a substrate for CYP1A2. With involvement of CYP2D6, there can be either poor or extensive metabolizer phenotypes. Since approximately 90% of mexiletine hydrochloride is metabolized in the liver into inactive metabolites, pathological changes in the liver can restrict hepatic clearance of mexiletine hydrochloride and its metabolites. The metabolic degradation proceeds via various pathways including aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Several of the resulting metabolites are submitted to further conjugation with glucuronic acid (phase II metabolism); among these are the major metabolites p-hydroxymexiletine, hydroxy-methylmexiletine and N-hydroxy-mexiletine.

Drug Elimination:

In normal subjects, the plasma elimination half-life of mexiletine is approximately 10 to 12 hours. 

Approximately 10% is excreted unchanged by the kidney. While urinary pH does not normally have much influence on elimination, marked changes in urinary pH influence the rate of excretion: acidification accelerates excretion, while alkalinization retards it.

Hepatic impairment prolongs the elimination half-life of mexiletine. In eight patients with moderate to severe liver disease, the mean half-life was approximately 25 hours.

Consistent with the limited renal elimination of mexiletine, little change in the half-life has been detected in patients with reduced renal function. In eight patients with creatinine clearance less than 10 mL/min, the mean plasma elimination half-life was 15.7 hours; in seven patients with creatinine clearance between 11 to 40 mL/min, the mean half-life was 13.4 hours.

How Supplied:

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