Mexiletine

— THERAPEUTIC CATEGORIES —
  • CHF and arrhythmias
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Mexiletine Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Mexiletine HCl 150mg, 200mg, 250mg; caps.

    Pharmacological Class

    Class IB antiarrhythmic.

    How Supplied

    Contact supplier.

    Manufacturer

    Various generic manufacturers

    Mexiletine Indications

    Indications

    Documented life-threatening ventricular arrhythmias.

    Indications

    Mexiletine Hydrochloride Capsules USP are indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgment of the physician, are life- threatening. 

    The use of mexiletine for lesser arrhythmias is generally not recommended because of its proarrhythmic effects. Avoid treating patients with asymptomatic ventricular premature contractions.

    Initiation of mexiletine treatment used to treat life-threatening arrhythmias, should be carried out in the hospital. Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

    Mexiletine Dosage and Administration

    Adult

    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.

    Adult

    Must individualize the dosage of mexiletine hydrochloride on the basis of response and tolerance, both of which are dose-related. Administration with food or antacid is recommended. 

    Initiate mexiletine 200 mg every 8 hours when rapid control of arrhythmia is not essential. A minimum of 2 to 3 days between dose adjustments is recommended. Dose may be adjusted in 50 or 100 mg increments up or down.

    Obtain clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment.

    Most patients achieve satisfactory control by 200 to 300 mg given every 8 hours with food or antacid. If satisfactory response has not been achieved at 300 mg every 8 hours and tolerable, may administer a dose of 400 mg every 8 hours. As the severity of CNS side effects increases with total daily dose, the dose should not exceed 1200 mg/day.

    In general, patients with renal failure will require the usual doses of mexiletine hydrochloride. Patients with severe liver disease may require lower doses and must be monitored closely. Similarly, marked right-sided congestive heart failure can reduce hepatic metabolism and reduce the needed dose. 

    Loading Dose

    • If rapid control of ventricular arrhythmia is essential: give an initial loading dose of mexiletine hydrochloride 400 mg, followed by 200 mg in 8 hours. Onset of therapeutic effect is usually observed within 30 minutes to two hours.

    Q12H Dosage Schedule

    • To improve convenience and compliance, some patients responding to mexiletine may be transferred to a 12 hour dosage schedule. 

    • If adequate suppression is achieved on a mexiletine hydrochloride dose of 300 mg or less every 8 hours, the same total daily dose may be given in divided doses every 12 hours while carefully monitoring the degree of suppression of ventricular ectopy. This dose may be adjusted up to a maximum of 450 mg every 12 hours to achieve the desired response.

    Transferring to Mexiletine Hydrochloride

    • The following dosage schedule is based on theoretical considerations rather than experimental data:

      • Transferring patients from other Class I oral antiarrhythmic agents to mexiletine: Initiate mexiletine hydrochloride 200 mg dose and titrate to response as described above, 6 to 12 hours after the last dose of quinidine sulfate, 3 to 6 hours after the last dose of procainamide, 6 to 12 hours after the last dose of disopryramide or 8 to 12 hours after the last dose of tocainide.

      • In patients in whom withdrawal of the previous antiarrhythmic agent is likely to produce life-threatening arrhythmias: Hospitalization of the patient is recommended.

      • When transferring from lidocaine to mexiletine: Stop the lidocaine infusion when the first oral dose of mexiletine hydrochloride is administered. The infusion line should be left open until suppression of the arrhythmia appears to be satisfactorily maintained. Consider the similarity of the adverse effects of lidocaine and mexiletine and the possibility that they may be additive.

    Children

    Not established.

    Mexiletine Contraindications

    Contraindications

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

    Mexiletine Boxed Warnings

    Boxed Warning

    Mortality. Acute liver injury.

    Boxed Warning

    Mortality

    • The applicability of the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST) results to other populations (eg, those without recent myocardial infarction) is uncertain. 

    • Reserve the use of mexiletine as well as other antiarrhythmic agents for patients with life-threatening ventricular arrhythmia due to the known proarrhythmic properties of mexiletine and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias.

    Acute Liver Injury

    • In postmarketing experience abnormal liver function tests have been reported, some in the first few weeks of therapy with mexiletine hydrochloride. Most of these have been observed in the setting of congestive heart failure or ischemia and their relationship to mexiletine hydrochloride has not been established.

    Mexiletine Warnings/Precautions

    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.

    Warnings/Precautions

    General

    • May use mexiletine hydrochloride in patients with second or third degree heart block if a ventricular pacemaker is operative, and if continuously monitored. Use caution when mexiletine is used in such patients or in patients with preexisting sinus node dysfunction or intraventricular conduction abnormalities.

    • Like other antiarrhythmics, mexiletine hydrochloride can cause worsening of arrhythmias. This has been uncommon in patients with less serious arrhythmias, but is of greater concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia.

    • Use caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.

    • Monitor carefully if mexiletine is used in patients with liver disease. The same caution should be observed in patients with hepatic dysfunction secondary to congestive heart failure.

    • Avoid concurrent drug therapy or dietary regimens which may markedly alter urinary pH during mexiletine hydrochloride therapy. The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of mexiletine.

    SGOT Elevation and Liver Injury

    • Rare instances of severe liver injury, including hepatic necrosis, have been reported in association with mexiletine treatment. 

    • Evaluate carefully in patients in whom an abnormal liver test has occurred, or who have signs of symptoms suggesting liver dysfunction. 

    • Consider discontinuing mexiletine therapy if persistent or worsening elevation of hepatic enzymes is detected.

    Blood Dyscrasias

    • Evaluate carefully if significant hematologic changes are observed, and discontinue treatment if warranted. Blood counts usually return to normal within a month of discontinuation.

    • Use caution in patients with known seizure disorder. Convulsions were reported in patients with and without a prior history of seizures. 

    Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS)

    • Drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking mexiletine. 

    • Discontinue mexiletine if DRESS is suspected.

    Pregnancy Considerations

    There are no adequate and well-controlled studies in pregnant women; this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Nursing Mother Considerations

    Mexiletine appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of mexiletine hydrochloride is deemed essential, an alternative method of infant feeding should be considered.

     

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Mexiletine Pharmacokinetics

    Absorption

    Mexiletine is well absorbed (~90%) from the gastrointestinal tract. Unlike lidocaine, its first-pass metabolism is low. Peak blood levels are reached in two to three hours.

    The absorption rate of mexiletine is reduced in clinical situations such as acute myocardial infarction in which gastric emptying time is increased. Narcotics, atropine and magnesium-aluminum hydroxide have also been reported to slow the absorption of mexiletine. Metoclopramide has been reported to accelerate absorption.

    Distribution

    Mexiletine is 50 to 60% bound to plasma protein, with a volume of distribution of 5 to 7 liters/kg.

    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.

    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.

    Mexiletine Interactions

    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.

    Mexiletine Adverse Reactions

    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.

    Mexiletine Clinical Trials

    See Literature

    Mexiletine Note

    Notes

    Formerly known under the brand name Mexitil.

    Mexiletine Patient Counseling

    See Literature

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