Mexiletine

Mexiletine is a generic medication for the drug :

Mexiletine medication comes in several different strengths; click on the strength you need to view prices from pharmacies competing to earn your business.

Mexiletine 100 mg	Mexiletine 150 mg	Mexiletine 200 mg
Mexiletine 250 mg

Technical Information

Drug Interactions

Mexiletine

Drug-Drug Interactions

Interacting Drug	Effect	Clinical Comment
Caffeine	Mexiletine inhibits the metabolism of caffeine, thereby predisposing patients to symptoms of caffeine excess (nausea, tremor, insomnia). Caffeine does not appreciably alter the pharmacokinetics of mexiletine.	When starting mexiletine, patients should be advised of the potential increase in sensitivity to caffeine.
Cigarette smoking	The t_½ of mexiletine decreased by 35% and the clearance increased by 32% in volunteers who smoked ≥15 cigarettes per day.	Patients may require larger than usual doses of mexiletine to achieve a therapeutic effect.
Fluvoxamine	Fluvoxamine, an inhibitor of CYP1A2, significantly increased the AUC and C_max of mexiletine in healthy volunteers.	Should fluvoxamine be added to the regimen of a patient receiving mexiletine, the patient should be closely monitored for signs of mexiletine excess and the dose titrated downward accordingly.
Lidocaine	Mexiletine may displace lidocaine from tissue binding sites thereby increasing plasma lidocaine concentrations.	Caution is advised when introducing mexiletine into patients receiving ongoing therapy with lidocaine.
Metoprolol	Mexiletine inhibits CYP2D6-mediated hydroxylation of metoprolol thereby decreasing clearance and increasing plasma levels of metoprolol.	The combination of mexiletine and metoprolol should be used with caution. Lower dosages of metoprolol may be required.
Opioids	Delay gastric emptying and prolong the time required for absorption of mexiletine from the gastrointestinal tract.	The onset of action of mexiletine may be delayed in patients receiving morphine during the treatment of a myocardial infarction.
Phenytoin	Phenytoin induces metabolism of mexiletine in non-smoking healthy volunteers resulting in a 55% decrease in AUC and 51% decrease in t_½ of mexiletine.	Higher doses of mexiletine may be required in patients receiving phenytoin.
Quinidine	In extensive metabolizers of mexiletine, quinidine inhibits CYP2D6 thereby significantly increasing the t_½ and decreasing clearance of mexiletine. In poor metabolizers quinidine has no significant effect on mexiletine pharmacokinetics.	The majority of the population are extensive metabolizers and thus susceptible to a significant interaction with quinidine. The dose of mexiletine should therefore be titrated carefully in patients receiving quinidine. Conversely, in patients receiving mexiletine the dose may need to be lowered after the introduction of quinidine.
Rifampin	Rifampin induces metabolism of mexiletine in healthy volunteers resulting in a 39% decrease in AUC and 41% decrease in t_½ of mexiletine.	Higher doses of mexiletine may be required in patients receiving rifampin.
Theophylline	Mexiletine inhibits CYP1A2-mediated demethylation of theophylline. This results in decreased clearance and increased plasma levels of theophylline and symptoms of theophylline toxicity.	The combination of mexiletine and theophylline should be used with caution. Lower dosages of theophylline may be required.
Urinary acidifiers (acetazolamide, ammonium chloride) and alkalinizers (sodium bicarbonate)	Mexiletine is a base. Changes in urinary pH may markedly alter serum concentrations of mexiletine in some patients. Acidification of urine significantly shortens the half-life and increases the fraction of unchanged drug excreted in urine.	Consider the effects of drugs that greatly alter the pH of urine in patients receiving mexiletine (e.g., sodium bicarbonate) and titrate the dose as necessary.

Drug-Food Interactions

As noted in Table 3, mexiletine may increase exposure to caffeine.

Mexiletine undergoes extensive hepatic metabolism mediated primarily by CYP2D6 and to a lesser extent by CYP1A2. Drugs that alter the function of these enzymes have the potential to alter the pharmacokinetics of mexiletine. Conversely, mexiletine may alter the pharmacokinetics of other drugs metabolized by CYP isozymes.

Concurrent administration of amiodarone did not significantly alter the pharmacokinetics of mexiletine in patients with supraventricular tachyarrhythmias.

Cimetidine did not significantly alter the pharmacokinetics of mexiletine in healthy volunteers.

Dosage and Administration

Hepatic Impairment

Clearance of mexiletine is significantly impaired in patients with hepatic dysfunction. The terminal elimination half-life is prolonged significantly and plasma concentrations are considerably higher in patients with hepatic cirrhosis compared with control patients with normal liver function. If the drug is used in patients with liver dysfunction (as judged by INR and serum bilirubin concentrations), the dose should be modified accordingly (low initial dose [i.e. 100 mg] with slow careful titration) and the patient closely monitored for signs and symptoms of mexiletine toxicity (cardiovascular, gastrointestinal and neurologic complaints).

Genetic Polymorphism

CYP2D6-mediated hepatic metabolism of mexiletine is affected by a genetic polymorphism (sparteine/debrisoquine polymorphism). Poor metabolizers lack the gene for CYP2D6 and thus do not produce the major hydroxylated metabolite of the drug. The clearance of the drug is prolonged compared with extensive metabolizers of the drug. This interaction is of potential clinical significance particularly with respect to certain drug-drug interactions.

Dosing Considerations

The dosage of mexiletine must be individualized based on the therapeutic response and tolerability, both of which are dose-dependent.

When used to treat ventricular arrhythmias it is essential to monitor the ECG (for prolongation of QRS and QTc intervals) and blood pressure closely during the first 24 hours. It is also prudent to monitor the ECG after steady state levels are reached (i.e. after approximately 5 half-lives, see Pharmacokinetics: Adults) initially and after each dose increase and again 7 days later to ensure no prolongation of QRS and QTc intervals.

It is recommended that mexiletine be taken with food.

Dosage in Dialysis

The terminal elimination half-life of mexiletine is not increased markedly by renal dysfunction. Thus dosage adjustments are not required in patients with severe renal dysfunction including those receiving dialysis.

Recommended Dose and Dosage Adjustment

Mexiletine

Dose in Adult Patients

Indication	Route	Initial Dose	Dose Titration	Usual Dose	Maximum Dose	Duration of Therapy	Clinical Comment
Ventricular arrhythmia	Oral	400 mg oral loading dose	The first maintenance dose may be given 2 to 6 hours after the loading dose depending on the clinical response.	400–800 mg divided in 2 or 3 equal doses	Varies. In some patients it may be as high as 1200 mg/day. In others, 300 to 600 mg/day may be sufficient.	Varies with severity of the condition and the response of the patient	In the case of ventricular arrhythmia, the therapeutic concentration in serum ranges from 0.5 to 2.0 mg/L [3–11 μmol/L], although the utility of routine serum concentration monitoring is questionable.
Neuropathy	Oral	200 mg once daily	Increase to 200 mg BID then 200 mg TID at 2 day intervals		Not to exceed 1200 mg/day	Varies according to the response	Given that neuropathy is not imminently life-threatening, slow titration of the dose improves tolerability and is preferred.

Adverse Reactions

Hepatic/Biliary/Pancreatic

elevated liver enzymes, jaundice, hepatic necrosis.

Neurologic/Central Nervous System

ataxia, dizziness, nystagmus, paresthesia, seizures, tremor.

Hematologic

agranulocytosis, leucopenia, neutropenia, thrombocytopenia.

Immune

allergic reactions, lupus-like symptoms.

Adverse Drug Reactions Overview

Like all anti-arrhythmic drugs, mexiletine can give rise to serious life-threatening arrhythmias.

Mexiletine

Abnormal Hematologic and Clinical Chemistry Findings

Test	Effect	Clinical Comment
Complete blood count	Aplastic anemia, neutropenia, leucopenia thrombocytopenia	Withdraw drug if possible, monitor CBC and provide supportive care as needed.
Liver enzymes	Elevated bilirubin, liver transaminases	Withdraw drug if possible, monitor transaminases.

Less Common Adverse Drug Reactions (<1%)

Ophthalmologic

abnormal vision.

Dermatologic

erythroderma, flushing, hypersensitivity, rash, Stevens-Johnson syndrome.

Mexiletine

More Common Adverse Drug Reactions (≥1%)

Body System	Effect	Clinical Comment
Digestive	Gastrointestinal Intolerance: heartburn, nausea, vomiting, constipation	Administer with food or after a meal.

Psychiatric

confusion, hallucination, somnolence, drug-induced psychosis.

Cardiovascular

arrhythmias, palpitations, atrial fibrillation, AV block, ventricular arrhythmias, torsades de pointes (polymorphic ventricular tachycardia), systolic heart failure, hypotension.

Indications and Clinical Use

Mexiletine is an orally administered class Ib antiarrhythmic agent used for the treatment of ventricular tachyarrhythmias alone or in combination with a class Ia antiarrhythmic agent. Mexiletine may also have a limited role in the treatment of some patients with congenital long QT syndromes. Mexiletine has not been shown to prevent recurrence of sustained life-threatening ventricular tachyarrhythmias.

Mexiletine has been used for the management of neuropathic pain of diverse origins. The evidence to support the use of this drug for this indication is limited to small studies.

Overdosage

For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.

The major toxic effects of mexiletine in overdose involve the cardiovascular system and include complete heart block, torsades de pointe and asystole. Seizures may also occur. Administration of activated charcoal may be helpful in preventing absorption of mexiletine from the gastrointestinal tract if given within two hours of overdose.

Management of mexiletine overdose is similar to that for other class Ib antiarrhythmic agents such as lidocaine. Supportive care is the mainstay of therapy. Monitor and manage the hemodynamic status of the patient. Pressors may be required to counteract hypotension. Patients with class Ib antiarrhythmic overdose typically do not respond well to atropine, so dopamine, norepinephrine or isoproterenol may be required to counteract bradyarrhythmias. External pacing may be helpful. Seizures should be treated with benzodiazepines. Cardiopulmonary bypass may be considered in selected cases.

Warnings and Precautions

Special Populations

Pregnant Women

Category C. Use only if the potential benefit outweighs the risk. When administered to a pregnant woman near term, detectable serum concentrations were produced in the newborn.

Nursing Women

Mexiletine is excreted in breast milk with a milk: plasma ratio of 1.45. Consider alternatives to breast feeding if administered to a lactating mother.

Monitoring and Laboratory Tests

When used for the treatment of ventricular arrhythmia: ECG, blood pressure.

Action and Clinical Pharmacology

Distribution

The volume of distribution of mexiletine is large (580-707 L in healthy volunteers), is independent of dose and varies greatly between individuals. Approximately 43% of the drug in circulation is bound to albumin and alpha₁-acid glycoprotein.

Absorption

Mexiletine is well absorbed from the gastrointestinal tract with an oral bioavailability of 90%. Maximum plasma concentrations (C_max) are achieved in approximately 1.5 to 4 hours after oral administration.

Mechanism of Action

Mexiletine is a class Ib antiarrhythmic agent with local anesthetic and membrane stabilizing properties. The drug is similar in structure and activity to lidocaine, but has a longer terminal elimination half-life, which makes oral administration feasible. The predominant effect on the action potential is mediated through the sodium channel. The drug binds to the sodium channel and impedes sodium influx during phase 0. This slows cardiac conduction. At high tissue concentrations, class Ib agents shorten the duration of the action potential and refractoriness.

Pharmacokinetics: Adults

Excretion

Renal excretion is of minor importance in the excretion of mexiletine, although acidification of urine can significantly increase the fraction of drug excreted in urine and decrease the terminal elimination half-life. Under normal physiologic conditions, approximately 5% of an administered dose is recovered unchanged in urine.

Metabolism

Mexiletine undergoes extensive hepatic metabolism mediated by cytochrome P450 (CYP) isozymes to form a large number of pharmacologically inactive metabolites.

The major metabolites of mexiletine are produced by CYP2D6-mediated hydroxylation. A well described polymorphism in the gene that produces CYP2D6 affects the metabolism of mexiletine. In individuals who lack the gene for CYP2D6 (“poor metabolizers”), mexiletine does not undergo hydroxylation and, thus, there are significant differences in the metabolic profile and in the rate of clearance of the drug in these individuals compared with “extensive metabolizers”. The frequency of the poor metabolizer phenotype is variable within any given population, but is generally reported to be <10%.

Mexiletine also undergoes CYP1A2-mediated oxidative metabolism.

The mean terminal elimination half-life has been reported to range from 6.7 to 17.2 hours.

Contraindications

Patients who are hypersensitive to mexiletine as demonstrated by rash, urticaria, or anaphylaxis

Cardiogenic shock

Bradycardia

High degree AV block (in the absence of a pacemaker)

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