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Mexiletine

Pronunciation

Pronunciation

(meks IL e teen)

Index Terms

  • Mexiletine HCl

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Generic: 150 mg, 200 mg, 250 mg

Pharmacologic Category

  • Antiarrhythmic Agent, Class Ib

Pharmacology

Class IB antiarrhythmic, structurally related to lidocaine, which inhibits inward sodium current, decreases rate of rise of phase 0, increases effective refractory period/action potential duration ratio

Absorption

Well absorbed

Distribution

Vd: 5 to7 L/kg

Metabolism

Hepatic via CYP2D6 metabolism to inactive metabolites (~90%) and major metabolites p-hydroxymexiletine, hydroxy-methylmexiletine, and N-hydroxy-mexiletine (minimal antiarrhythmic activity); low first-pass effect

Excretion

Urine (10% as unchanged drug); urinary acidification increases excretion, alkalinization decreases excretion

Onset of Action

30 to 120 minutes (with loading regimen)

Time to Peak

Serum: 2 to 3 hours

Half-Life Elimination

~10 to 12 hours; ~ 15 hours in severe renal impairment (CrCl < 10 ml/min); ~ 25 hours in moderate to severe hepatic impairment

Protein Binding

50% to 60%

Use: Labeled Indications

Ventricular arrhythmias: Management of life-threatening ventricular arrhythmias

Note: The American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) states that mexiletine may be considered for those with long QT syndrome who present with torsades de pointes (ACC/AHA/ESC [Zipes 2006])

Contraindications

Cardiogenic shock; second- or third-degree AV block (except in patients with a functioning artificial pacemaker)

Dosing: Adult

Ventricular arrhythmias (life-threatening): Oral: Initial: 200 mg every 8 hours (may load with 400 mg if necessary); adjust dose in 50 or 100 mg increments no more frequently than every 2 to 3 days; usual dose: 200 to 300 mg every 8 hours; maximum dose: 1.2 g/day. Note: Once controlled, patients may be transferred to an every 12-hour dosing schedule; do not exceed 450 mg every 12 hours with this regimen.

Conversion:

Switching from other oral antiarrhythmics (eg, disopyramide, quinidine sulfate): Initiate 200 mg dose of mexiletine 6 to 12 hours after the last dose of the former agent.

Switching from IV lidocaine: Initiate 200 mg dose of mexiletine when lidocaine infusion is stopped.

Switching from oral procainamide: Initiate a 200 mg dose of mexiletine 3 to 6 hours after the last dose of procainamide.

Premature ventricular complex (symptomatic) suppression (off-label use): Oral: 100 or 150 mg 3 times daily; if not controlled, may increase to 200 mg 3 times daily (Saikawa 1992; Tanabe 1991) or 100 or 200 mg 2 to 3 times daily; may progressively increase to a maximum dose of 500 mg 3 times daily (Rutledge 1985)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Patients with hepatic impairment or hepatic congestion secondary to heart failure may require dose reduction; half-life is approximately doubled in patients with hepatic impairment.

Extemporaneously Prepared

A 10 mg/mL oral suspension may be with made with capsules and either distilled water or sorbitol USP. Empty the contents of eight 150 mg capsules in a mortar and reduce to a fine powder if necessary. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a graduated cylinder, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well". Sorbitol suspension is stable in plastic prescription bottles for 2 weeks at room temperature and 4 weeks refrigerated; distilled water suspension is stable in plastic prescription bottles for 7 weeks at room temperature and 13 weeks refrigerated. Extended storage under refrigeration is recommended to minimize microbial contamination.

Nahata MC, Morosco RS, and Hipple TF, "Stability of Mexiletine in Two Extemporaneous Liquid Formulations Stored Under Refrigeration and at Room Temperature," J Am Pharm Assoc (Wash), 2000, 40(2):257-9.10730027

Administration

Administer around-the-clock rather than 3 times daily to promote less variation in peak and trough serum levels; administer with food or antacid

Dietary Considerations

Take with food.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Antihepaciviral Combination Products: May increase the serum concentration of Mexiletine. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Etravirine: May decrease the serum concentration of Mexiletine. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Mexiletine. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Phenytoin: May decrease the serum concentration of Mexiletine. Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Mexiletine. Exceptions: Sertraline. Consider therapy modification

Simeprevir: May increase the serum concentration of Mexiletine. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Theophylline Derivatives: Mexiletine may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Test Interactions

Abnormal liver function test, positive ANA, thrombocytopenia

Adverse Reactions

>10%:

Central nervous system: Lightheadedness (11% to 25%), dizziness (20% to 25%), nervousness (5% to 10%), incoordination (10%)

Gastrointestinal: GI distress (41%), nausea/vomiting (40%)

Neuromuscular & skeletal: Trembling, unsteady gait, tremor (13%), ataxia (10% to 20%)

1% to 10%:

Cardiovascular: Chest pain (3% to 8%), premature ventricular contractions (1% to 2%), palpitation (4% to 8%), angina (2%), proarrhythmia (10% to 15% in patients with malignant arrhythmia)

Central nervous system: Confusion, headache, insomnia (5% to 7%), depression (2%)

Dermatologic: Rash (4%)

Gastrointestinal: Constipation or diarrhea (4% to 5%), xerostomia (3%), abdominal pain (1%)

Neuromuscular & skeletal: Weakness (5%), numbness of fingers or toes (2% to 4%), paresthesia (2%), arthralgia (1%)

Ocular: Blurred vision (5% to 7%), nystagmus (6%)

Otic: Tinnitus (2% to 3%)

Respiratory: Dyspnea (3%)

<1% (Limited to important or life-threatening): Agranulocytosis, alopecia, AV block, cardiogenic shock, CHF, dysphagia, exfoliative dermatitis, hallucinations, hepatic necrosis, hepatitis, hypotension, impotence, leukopenia, myelofibrosis, pancreatitis (rare), psychosis, pulmonary fibrosis, seizure, sinus arrest, SLE syndrome, Stevens-Johnson syndrome, syncope, thrombocytopenia, torsade de pointes, upper GI bleeding, urinary retention, urticaria

ALERT: U.S. Boxed Warning

Mortality:

In the National Heart, Lung, and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind study in patients with asymptomatic non–life-threatening ventricular arrhythmias who had an myocardial infarction (MI) more than 6 days but less than 2 years previously, an excessive mortality or nonfatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to carefully matched placebo-treated groups (3%). The average duration of treatment with encainide or flecainide in this study was 10 months.

The applicability of the CAST results to other populations (eg, those without recent MI) is uncertain. Considering the known proarrhythmic properties of mexiletine and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of mexiletine as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.

Acute liver injury:

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

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: Rare marked leukopenia, agranulocytosis, and thrombocytopenia have been reported; often occurs in seriously ill patients receiving other medications that can cause these effects. If significant hematologic changes occur, discontinue therapy (blood counts usually return to normal within a month of discontinuation).

• Drug reactions with eosinophilia and systemic symptoms: Drug reactions with eosinophilia and systemic symptoms (DRESS) has been reported. Discontinue if DRESS is suspected. Symptoms of DRESS include eosinophilia, fever, rash, and/or lymphadenopathy in association with other organ involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.

• Hepatotoxicity: [US Boxed Warning]: Abnormal liver function tests have been reported, some in the first few weeks of therapy. Most of these have been observed in the setting of congestive heart failure or ischemia and their relationship to mexiletine has not been established. Marked elevations of AST (>1000 units/L) and rare instances of severe liver injury, including hepatic necrosis, have also been reported. Carefully monitor patients who develop abnormal LFTs or who have signs/symptoms of liver dysfunction. If persistent or worsening elevation of hepatic enzymes occurs, consider discontinuing therapy.

• Proarrhythmic effects: Proarrhythmia may occur with the use of mexiletine especially in those with life-threatening arrhythmias (eg, sustained ventricular tachycardia). Aggravation of arrhythmia may also occur; monitor for proarrhythmic effects (Podrid 1987; Podrid 1999; Velebit 1982).

Disease-related concerns:

• Conduction disturbances: Use with caution in patients with intraventricular conduction delays, first-degree heart block and/or preexisting sinus node dysfunction. Use is contraindicated in patients with second- or third-degree AV block (except in patients with a functioning artificial pacemaker).

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy (Podrid 1999).

• Heart failure (HF): Use with caution in patients with severe HF; may precipitate or exacerbate condition.

• Hepatic impairment: Use with caution in patients with hepatic impairment; may prolong the elimination half-life of mexiletine and increase the risk of adverse effects.

• Seizure: Use with caution in patients with seizure disorder.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Initiate therapy in the hospital when used to treat life-threatening arrhythmias. Treatment of patients with asymptomatic ventricular premature contractions should be avoided. Has not been shown to enhance survival in patients with ventricular arrhythmias.

• CAST trial: [U.S. Boxed Warning]: In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, nonlife-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias. In a double-blind placebo controlled trial in patients with recent MI, the use of mexiletine to reduce premature ventricular contractions demonstrated a numerically greater number of deaths compared to placebo (IMPACT Research Group, 1984).

• Urinary pH: Alterations in urinary pH may change urinary excretion; avoid dietary regimens that may markedly alter urinary pH.

Monitoring Parameters

Liver function tests, ECG

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. A few case reports have demonstrated safe use of mexiletine in pregnant women (Gregg 1988; Lownes 1987; Timmis 1980).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience anxiety, heartburn, vomiting, or nausea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), tremors, vision changes, angina, severe dizziness, passing out, shortness of breath, excessive weight gain, swelling of arms or legs, tachycardia, bradycardia, arrhythmia, seizures, chills, swollen glands, urinary retention, change in amount of urine passed, bruising, bleeding, loss of strength and energy, muscle pain, joint pain, or change in balance (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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