Who should not take mexiletine?: Understanding contraindications and risks

October 10, 2025 •

4 min read

According to the FDA, certain antiarrhythmic drugs like mexiletine can carry a boxed warning due to an increased risk of death, especially in patients who have had a recent heart attack. It is critical for patients to understand who should not take mexiletine and the serious health conditions that serve as absolute contraindications.

Quick Summary

This article details the absolute contraindications for mexiletine, including specific heart conditions and allergies. It also examines major precautions related to liver disease, seizure disorders, and drug-drug interactions. Special consideration for at-risk patient populations is emphasized.

Key Points

Cardiac Conditions: Do not take mexiletine if you have untreated second- or third-degree AV block or are in cardiogenic shock.
Recent Heart Attack: Caution is advised for patients with a recent myocardial infarction, as there is an increased risk of mortality.
Liver Disease: Patients with severe liver impairment may have prolonged drug clearance, increasing the risk of toxicity.
Drug Interactions: Certain drugs, like dofetilide, phenytoin, and theophylline, can have serious or significant interactions with mexiletine.
Pregnancy & Breastfeeding: Mexiletine is not recommended for pregnant or breastfeeding individuals due to unestablished safety and potential infant exposure.
Allergic Reactions: Be aware of rare but severe hypersensitivity reactions, including DRESS syndrome.
Seizure Risk: Use with caution in patients with a history of seizures, as mexiletine can sometimes cause convulsions.

Mexiletine is an oral antiarrhythmic medication used primarily to treat life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. It functions by blocking sodium channels to help stabilize the heart's rhythm. However, because of its mechanism and metabolic pathways, the medication is not suitable for everyone and carries significant risks that necessitate strict patient selection and monitoring. Individuals with certain pre-existing conditions and those taking specific medications should avoid mexiletine entirely.

Absolute Cardiac Contraindications

Several severe heart conditions serve as absolute contraindications for the use of mexiletine, primarily due to the drug's potential to worsen the condition or increase mortality risk.

Second- and Third-Degree AV Block

Patients with pre-existing second- or third-degree atrioventricular (AV) block should not take mexiletine unless a functioning artificial pacemaker is present. Mexiletine can slow the heart's conduction system, and in these patients, it could lead to dangerously slow heart rates or asystole (cardiac arrest). For this reason, hospitalization is often required for continuous monitoring when starting therapy.

Cardiogenic Shock

This is a state of severe heart failure where the heart is unable to pump enough blood to meet the body's needs. Mexiletine is contraindicated in the presence of cardiogenic shock, as it could further aggravate this life-threatening condition.

Recent Myocardial Infarction

A boxed warning accompanies antiarrhythmic drugs like mexiletine following the results of the Cardiac Arrhythmia Suppression Trial (CAST). This study found an increased risk of death or non-fatal cardiac arrest in patients with asymptomatic, non-life-threatening ventricular arrhythmias who had suffered a myocardial infarction (heart attack) within the preceding two years. Therefore, mexiletine is generally not recommended for patients who have experienced a heart attack within the last two years.

Liver and Renal Impairment

Mexiletine is extensively metabolized by the liver, and its elimination can be impaired in patients with compromised liver function.

Hepatic Impairment: Patients with liver disease should be monitored carefully while taking mexiletine. The drug's half-life can be prolonged in those with liver impairment, increasing the risk of toxicity. Liver function tests should be conducted regularly, and the dose may need to be lowered. Rare instances of severe liver injury, including hepatic necrosis, have also been reported.
Renal Dysfunction: While the kidneys excrete only a small amount of unchanged mexiletine, caution is advised for patients with significant renal impairment. Clinical monitoring of cardiac and renal function is recommended.

Allergic and Hypersensitivity Reactions

Patients with known hypersensitivity to mexiletine or other similar medications, such as lidocaine, should not take this drug. Serious allergic and hypersensitivity reactions, though rare, can occur.

DRESS Syndrome: A severe reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with mexiletine. This syndrome can present with symptoms like fever, rash, and organ involvement (hepatitis, nephritis). If DRESS is suspected, mexiletine should be immediately discontinued.

Neurological and Other Precautions

While mexiletine has been studied for epilepsy, seizures have been reported in patients taking the drug, including those with no prior history.

Seizure Disorders: Caution should be exercised when prescribing mexiletine to patients with a known seizure disorder.
Pregnancy and Breastfeeding: The safety of mexiletine during pregnancy has not been established. It also passes into breast milk in concentrations similar to those in plasma, so an alternative feeding method should be considered if the drug is essential for the mother.

Key Drug Interactions to Avoid

Mexiletine is metabolized by the CYP2D6 and CYP1A2 enzymes, and numerous drugs can interfere with its metabolism, affecting plasma concentrations and effectiveness.

Dofetilide: This antiarrhythmic drug has a severe interaction with mexiletine.
CYP Inducers: Drugs that increase metabolism, such as phenytoin, rifampin, and phenobarbital, can decrease mexiletine plasma levels and reduce its effectiveness.
Theophylline: Concurrent use can lead to significantly increased plasma levels of theophylline. Theophylline levels must be monitored closely.

Comparative Risks in Different Patient Populations

This table summarizes the risks of taking mexiletine in various patient populations based on their underlying health conditions.


Patient Population	Risk Level	Reason for Risk
Untreated 2nd/3rd-degree AV Block	High (Contraindicated)	Can cause severe bradycardia or asystole.
Cardiogenic Shock	High (Contraindicated)	May worsen severe heart failure.
Recent Myocardial Infarction	High (Precautionary Warning)	Increased risk of mortality based on CAST trial.
Severe Liver Disease	Moderate to High (Caution)	Reduced clearance and increased risk of toxicity; potential for severe liver injury.
Severe Congestive Heart Failure	Moderate (Caution)	Can aggravate existing heart failure.
Seizure Disorders	Moderate (Caution)	Seizures have been reported with mexiletine use.
Pregnancy / Breastfeeding	Moderate (Caution)	Safety not established; drug passes into breast milk.

Conclusion

While mexiletine is an effective treatment for certain life-threatening ventricular arrhythmias, its use is associated with several serious contraindications and precautions. Patients with specific cardiac conduction problems like untreated second- or third-degree AV block, cardiogenic shock, and a recent history of heart attack face significant risks. The potential for severe hypersensitivity reactions, liver toxicity, and drug interactions also requires careful medical supervision and patient awareness. Any patient considering or currently taking mexiletine must have a complete medical evaluation and ongoing monitoring by their healthcare provider to ensure safety and therapeutic effectiveness. For more information regarding drug interactions, resources like DrugBank provide comprehensive details.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult your healthcare provider regarding any health concerns or before starting or stopping any medication.

Frequently Asked Questions

No, mexiletine is contraindicated in patients with second- or third-degree AV heart block unless a functional pacemaker is in place.

According to the CAST trial, there is an increased risk of mortality or cardiac arrest in patients who had a heart attack within the previous two years and took antiarrhythmic drugs like mexiletine. Its use in such cases is generally not recommended.

Patients with liver disease require careful monitoring of cardiac function via ECG and liver function tests. A dosage adjustment might be necessary.

DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) is a rare but severe hypersensitivity reaction that has been reported in patients taking mexiletine. It presents with fever, rash, and organ involvement.

Yes, mexiletine can interact with many medications. Serious interactions exist with dofetilide and certain antidepressants. Other drugs, like phenytoin and rifampin, can lower mexiletine's effectiveness.

The safety of mexiletine during pregnancy has not been established. It is present in breast milk, so alternative feeding options should be considered for infants if the mother requires the medication.

Yes, although rarely, convulsions have been reported in patients on mexiletine. It should be used with caution in individuals with known seizure disorders.