What are the side effects of mexiletine?

Side Effects of Mexiletine

Mexiletine commonly causes gastrointestinal and neurological side effects, with nausea, dizziness, and tremor being the most frequent adverse reactions that limit therapy in approximately 15-20% of patients. 1

Most Common Side Effects

Gastrointestinal Effects

• Nausea, vomiting, and heartburn occur in approximately 40% of patients, making these the most frequent adverse reactions 1
• Diarrhea affects approximately 5% of patients 1
• Constipation and abdominal pain/cramps occur in 1-4% of patients 1
• Rare but serious gastrointestinal effects include peptic ulcer, upper GI bleeding, esophageal ulceration, and pancreatitis 1

Central Nervous System Effects

• Dizziness and lightheadedness occur in approximately 19-26% of patients 1
• Tremor affects approximately 13% of patients 1
• Coordination difficulties occur in approximately 10% of patients 1
• Sleep disturbances affect approximately 7% of patients 1
• Nervousness (5%), fatigue (4%), and speech difficulties (3%) are also reported 1
• Less common neurological effects include confusion, paresthesias/numbness, short-term memory loss (9 in 1000), hallucinations, psychosis, and seizures 1

Cardiovascular Effects

• Palpitations occur in 4-7% of patients 1
• Mexiletine can exacerbate heart failure in susceptible patients and worsen arrhythmias 2
• Less common cardiac effects include syncope and hypotension (each 6 in 1000), bradycardia (4 in 1000), AV block/conduction disturbances (2 in 1000), and cardiogenic shock (1 in 1000) 1
• The American Heart Association notes that mexiletine may cause AV block or worsening of arrhythmias 2

Other Common Effects

• Blurred vision or visual disturbances occur in approximately 6-8% of patients 1
• Headache affects approximately 6% of patients 1
• Rash occurs in approximately 4% of patients 1
• Heat intolerance can occur because mexiletine affects sodium channels involved in thermoregulation 3

Serious but Less Common Side Effects

Hematologic Effects

• Blood dyscrasias including thrombocytopenia (2 in 1000), leukopenia, neutropenia, and agranulocytosis (1 in 1000) can occur 1
• Myelofibrosis has been reported (2 in 10,000 patients) 1
• The American College of Cardiology notes that blood dyscrasias have been associated with mexiletine use 2

Hepatic Effects

• Abnormal liver function tests occur in approximately 5 in 1000 patients 1
• Rare cases of severe hepatitis and acute hepatic necrosis have been reported 1

Dermatologic Effects

• Rare cases of exfoliative dermatitis and Stevens-Johnson syndrome have been reported 1

Pulmonary Effects

• Isolated reports of pulmonary infiltration and pulmonary fibrosis have occurred, though a causal relationship has not been definitively established 1

Other Rare Effects

• SLE syndrome (4 in 10,000 patients) 1
• Positive ANA (2 in 1000) 1
• Urinary hesitancy/retention, impotence/decreased libido, altered taste, and hair loss 1

Factors Affecting Toxicity Risk

Patient-Specific Factors

• Patients with severe liver disease may experience prolonged drug half-life (14-16 hours vs normal 10-14 hours) and require dosage adjustment 2
• Clearance is impaired in patients with hepatic dysfunction but not renal dysfunction 4
• Patients with heart failure, acute myocardial infarction, or hepatic insufficiency have longer elimination half-lives 5

Drug Interactions

• Combination with CYP1A2 inhibitors can cause significant hypotension and bradycardia 6
• Combination with amiodarone requires careful monitoring due to potential additive effects on cardiac conduction 2
• Concomitant use with QT-prolonging medications requires careful consideration 2

Clinical Implications

Approximately 15% of patients discontinue mexiletine therapy due to adverse reactions, usually gastrointestinal or nervous system effects 1. The American Heart Association recommends ECG monitoring during initiation of therapy, particularly when used with other antiarrhythmic agents 2. Despite the high incidence of adverse effects, mexiletine has minimal effects on hemodynamic variables and appears to have low proarrhythmic potential compared to other antiarrhythmics 7. Due to its poor side effect profile, it is recommended only as a second- or third-line treatment for neuropathic pain in patients refractory to other treatments 8.