Side Effects of Ranolazine, Sotalol, and Mexiletine
Sotalol Side Effects
The most common side effects of sotalol include tiredness, slow heart rate, shortness of breath, and dizziness, with the most serious risk being life-threatening ventricular arrhythmias (torsades de pointes). 1
Cardiac Side Effects
- Proarrhythmia: Ventricular arrhythmias occurred in 0% to 5% of patients in clinical trials, with torsades de pointes being the most dangerous manifestation 2
- Bradycardia: Slow heart rate is a common beta-blocking effect 1
- Syncope and hypotension: Occur in approximately 6 in 1000 patients 3
- AV block/conduction disturbances: Approximately 2 in 1000 patients 3
- Increased mortality risk: In the SWORD trial, sotalol increased mortality in heart failure patients post-MI, though this may not apply in the current era of guideline-directed medical therapy 2
Non-Cardiac Side Effects
- Fatigue and exercise intolerance: Related to beta-blockade 1, 4
- Shortness of breath: Common beta-blocker effect, particularly problematic in patients with reactive airway disease 1
- Dizziness: Frequently reported 1
- Bronchospasm: Sotalol's beta-blocking properties can antagonize bronchodilators like albuterol, making it problematic in asthma/COPD patients 5
Discontinuation Rates
- Side effects prompted cessation or dose changes in 10% to 25% of patients treated with sotalol 2
- The drug is generally better tolerated than quinidine or disopyramide but has similar discontinuation rates to propafenone and flecainide 2
Important Monitoring Requirements
- Hospitalization required: Sotalol must be initiated in-hospital with continuous cardiac monitoring for the first 2 or more days to detect proarrhythmia and determine appropriate dosing 1
- QT interval monitoring: Regular ECGs are essential to detect QT prolongation that predisposes to torsades de pointes 2
- Renal function: Dose adjustment required in renal impairment as sotalol is entirely renally excreted 4
Mexiletine Side Effects
Mexiletine is poorly tolerated with intolerable side effects developing in 49% of patients, predominantly affecting the gastrointestinal and central nervous systems. 6
Gastrointestinal Side Effects (Most Common)
- Upper GI symptoms: Most frequent cause of discontinuation 2, 6
- Nausea and vomiting: Common dose-related effects 6
- Dyspepsia: Approximately 2 in 1000 patients 3
- Peptic ulcer: About 8 in 10,000 patients 3
- Upper GI bleeding: About 7 in 10,000 patients 3
- Esophageal ulceration: Rare (1 in 10,000) 3
Central Nervous System Side Effects
- Tremor: Common and dose-related 3, 6
- Dizziness and ataxia: Frequently reported 3, 6
- Short-term memory loss: About 9 in 1000 patients 3
- Paresthesias: Common neurologic complaint 3
- Hallucinations and psychological changes: Each about 3 in 1000 patients 3
- Psychosis and convulsions/seizures: Each about 2 in 1000 patients 3
- Loss of consciousness: About 6 in 10,000 patients 3
Cardiovascular Side Effects
- Syncope and hypotension: Each about 6 in 1000 patients 3
- Bradycardia: About 4 in 1000 patients 3
- Angina/angina-like pain: About 3 in 1000 patients 3
- Congestive heart failure exacerbation: Rare but reported in patients with preexisting compromised ventricular function 3
- Proarrhythmia: Less common than with other class I agents but still a concern 2
Unique Side Effects
- Heat intolerance: Occurs because mexiletine affects sodium channels involved in thermoregulation 7
- Hot flashes: Less than 1% of patients 3
- Diaphoresis: About 6 in 1000 patients 3
Hematologic Side Effects
- Thrombocytopenia: About 2 in 1000 patients 3
- Leukopenia (including neutropenia and agranulocytosis): About 1 in 1000 patients 3
- Myelofibrosis: About 2 in 10,000 patients 3
- Positive ANA: About 2 in 1000 patients 3
Hepatic Side Effects
- Abnormal liver function tests: About 5 in 1000 patients 3
- Severe hepatitis/acute hepatic necrosis: Rare but serious 3
Dermatologic Side Effects
- Exfoliative dermatitis and Stevens-Johnson syndrome: Rare but potentially life-threatening 3
Other Side Effects
- Altered taste: About 5 in 1000 patients 3
- Urinary hesitancy/retention: Each about 2 in 1000 patients 3
- Impotence/decreased libido: About 4 in 1000 patients 3
- Hair loss: About 4 in 1000 patients 3
- SLE syndrome: About 4 in 10,000 patients 3
- Pulmonary infiltration and fibrosis: Isolated reports, causal relationship not established 3
Discontinuation Rates
- 49% of patients receiving mexiletine alone developed intolerable side effects requiring discontinuation 6
- 57% of patients receiving mexiletine in combination with other antiarrhythmics developed intolerable side effects 6
- Side effects are dose-related and often transient 6
Clinical Context
- Mexiletine has not been extensively studied in heart failure patients, and class IB agents like mexiletine may be indicated for refractory ventricular arrhythmias only after consultation with electrophysiology specialists 2
- Given the lack of evidence and problematic side-effect profile in older adults, oral mexiletine is not favored as first-line therapy 2
Ranolazine Side Effects
Note: The provided evidence does not contain specific information about ranolazine side effects. The drug was mentioned in the question but no relevant guideline, drug label, or research evidence was provided regarding its adverse effect profile.
Combination Therapy Considerations
When combining sotalol with mexiletine, the antiarrhythmic efficacy increases substantially (79% reduction in ventricular ectopic beats versus 28% with sotalol alone), but side effects remain a significant concern. 8, 9
Sotalol + Mexiletine Combination
- Reduced ventricular ectopic beats by 79% compared to 28% with sotalol alone 8
- Suppressed complex ventricular arrhythmias by more than 80% 8
- Side effects necessitated discontinuation in 1 patient with sotalol/mexiletine combination 9
- This combination is more effective than either drug alone but requires careful monitoring 8, 9
Alternative Safer Combinations
- Low-dose mexiletine + metoprolol: Effectively reduced ventricular arrhythmias in 80% of patients with better tolerability than higher doses of single agents 10
- Amiodarone or dofetilide: These are the only antiarrhythmic agents with neutral effects on mortality in heart failure patients and may be preferred alternatives when sotalol or mexiletine are poorly tolerated 2