Can an overdose of flecainide worsen cardiac symptoms?

Can Excessive Flecainide Worsen Cardiac Symptoms?

Yes, excessive flecainide can significantly worsen cardiac symptoms and cause life-threatening proarrhythmias, conduction abnormalities, heart failure exacerbation, and cardiac arrest. 1, 2, 3

Mechanisms of Flecainide Toxicity

Flecainide overdose or accumulation causes dangerous cardiac effects through excessive sodium channel blockade, which manifests as:

• Severe QRS widening (the hallmark of toxicity), with marked prolongation of all conduction intervals including PR, QRS, and QT 4, 1, 3
• Proarrhythmic effects including polymorphous ventricular tachycardia, ventricular fibrillation, and unresuscitatable cardiac arrest 1, 3, 5
• Profound bradycardia with sinus pause, sinus arrest, or high-grade AV block 1, 2
• New or worsened heart failure occurring in 6.3% of patients with ventricular arrhythmias and 9.1% of those with sustained VT 1

Critical ECG Warning Signs of Toxicity

The European Society of Cardiology establishes that QRS widening ≥25% from baseline is the critical threshold signaling proarrhythmia risk and mandates immediate dose reduction or discontinuation 6, 4. Additional concerning findings include:

• QRS duration exceeding 150% of pretreatment baseline 4
• Development of new bundle branch block, particularly left bundle branch block 4
• Marked PR interval prolongation (though PR prolongation alone is expected and therapeutic) 4

Clinical Scenarios Leading to Toxicity

Acute Overdose

• Intentional or unintentional ingestion of excessive doses causes rapid toxicity with serum levels >1.5 mcg/mL (therapeutic range 0.2-1.0 mcg/mL) 2, 3
• A case report documented polymorphous ventricular tachycardia after a 3800 mg dose with serum levels five times the therapeutic range 3

Drug Accumulation

• Acute kidney injury is a high-risk scenario for missed diagnosis, as flecainide accumulates with reduced renal clearance 2
• CYP2D6 inhibitors (fluoxetine, quinidine, tricyclics) dramatically increase plasma concentrations, as 7-10% of the population genetically lacks this enzyme 7, 8
• Azole antifungals (fluconazole, itraconazole, ketoconazole) inhibit CYP2C9 and CYP3A4, potentially increasing flecainide to toxic ranges 8

Proarrhythmic Events

The FDA label documents that 80% of proarrhythmic events in sustained VT patients occurred within 14 days of therapy initiation, with 7% of patients developing new or exacerbated ventricular arrhythmias 1. The CAST trial demonstrated a 5.1% rate of death and non-fatal cardiac arrest in post-MI patients versus 2.3% with placebo 1.

High-Risk Patient Populations

Flecainide toxicity risk is substantially elevated in:

• Structural heart disease (coronary artery disease, heart failure, reduced LVEF) - absolute contraindication per ACC/AHA/ESC guidelines 6, 7
• Pre-existing conduction abnormalities including sick sinus syndrome, AV block, or bundle branch block 6, 4, 7
• Renal or hepatic impairment leading to drug accumulation 8, 9
• Concurrent QT-prolonging medications or other antiarrhythmics 7, 8

Management of Suspected Toxicity

When flecainide toxicity is suspected:

1. Immediately discontinue flecainide if QRS widening ≥25%, new ventricular arrhythmias, symptomatic bradycardia, or high-grade AV block develops 4
2. Obtain urgent ECG to measure QRS duration and compare to baseline 4, 2
3. Send flecainide level (though results may take days; do not delay treatment) 2, 3
4. Correct electrolyte abnormalities, particularly hypokalemia and hypomagnesemia 2
5. Consider sodium bicarbonate infusion to overcome sodium channel blockade 3
6. Beta-sympathomimetic agents may restore sinus rhythm in severe cases 3
7. Continuous cardiac monitoring for ventricular arrhythmias and conduction abnormalities 2, 10

Common Clinical Pitfall

The most dangerous pitfall is failing to recognize flecainide accumulation in patients with acute kidney injury or new drug interactions 2. Emergency physicians must maintain high suspicion for flecainide toxicity in any patient taking the drug who presents with wide complex tachycardia, altered mental status, or hemodynamic instability, as the diagnosis is easily missed and serum levels take days to result 2.

Another critical error is using flecainide in patients with structural heart disease, which the ACC/AHA/ESC guidelines list as an absolute contraindication due to increased mortality demonstrated in the CAST trial 6, 7, 1.