Is it safe to take trazodone 100 mg nightly with propafenone 150 mg three times a day (tid)?

Drug Interaction Safety: Trazodone with Propafenone

Trazodone 100 mg nightly can be taken with propafenone 150 mg three times daily, but requires caution due to a specific cardiac interaction risk—both drugs can prolong the QT interval, and propafenone is specifically contraindicated with certain cardiac medications in the same class as trazodone when used for other purposes.

Critical Drug Interaction Concern

The primary safety issue is additive QT prolongation risk:

• Trazodone is noted to require caution in patients with premature ventricular contractions and has documented cardiac effects 1
• Propafenone itself causes QT interval prolongation and requires ECG monitoring, with discontinuation recommended if QT interval exceeds 500 ms 1
• The combination is not explicitly contraindicated in major guidelines, but the 2001 U.S. Public Health Service guidelines specifically list propafenone alongside other antiarrhythmics as requiring caution with drugs that affect cardiac conduction 1

When This Combination Is Acceptable

This combination can proceed if:

• The patient has no structural heart disease (propafenone is contraindicated in coronary artery disease, reduced left ventricular ejection fraction, or heart failure) 1, 2, 3
• Baseline ECG shows QTc <450 ms and no conduction abnormalities 1
• The patient has no history of ventricular arrhythmias beyond isolated premature ventricular contractions 1
• No other QT-prolonging medications are being used concurrently 1

Required Monitoring Protocol

Obtain a baseline ECG before starting trazodone if the patient is already on propafenone, specifically checking:

• QTc interval (must be <450 ms to proceed safely) 1
• QRS duration (propafenone causes QRS widening; >25% increase above baseline requires propafenone dose reduction) 1, 3
• PR interval (both drugs can affect AV conduction) 1

Repeat ECG at 1-2 weeks after initiating trazodone to assess for:

• QTc prolongation >500 ms (requires discontinuation of one or both drugs) 1
• New conduction abnormalities 1

Dosing Considerations

The doses mentioned are within safe ranges:

• Trazodone 100 mg nightly is a conservative dose well below the maximum of 400 mg/day, and nighttime dosing minimizes daytime side effects 4, 5, 6
• Propafenone 150 mg TID (450 mg/day total) is in the mid-range of the 450-900 mg/day therapeutic window 1, 2

Alternative Approach If Concerned

If cardiac risk factors are present or ECG monitoring is not feasible:

• Consider alternative sleep agents with no cardiac effects: ramelteon, suvorexant, or low-dose doxepin (3-6 mg) 1
• Avoid benzodiazepines in elderly patients due to cognitive impairment risk 1
• Do not substitute with other antidepressants that are strong CYP2D6 inhibitors (fluoxetine, paroxetine) as these significantly increase propafenone levels and beta-blocking effects 2

Absolute Contraindications to This Combination

Do not use trazodone with propafenone if:

• Patient has structural heart disease, ischemic heart disease, or reduced ejection fraction (propafenone itself is contraindicated) 1, 2, 3
• Baseline QTc >450 ms 1
• Patient is on other QT-prolonging drugs (antipsychotics, macrolide antibiotics, azole antifungals) 1
• Sinus node dysfunction or AV block without a pacemaker (propafenone contraindication) 1, 2
• Brugada syndrome (propafenone absolutely contraindicated) 2

Common Pitfall to Avoid

Do not confuse trazodone's cardiac caution with the absolute contraindications listed for lopinavir/ritonavir with propafenone—that specific interaction involves dangerous inhibition of propafenone metabolism leading to toxic levels and life-threatening arrhythmias 1. Trazodone does not inhibit propafenone metabolism but adds QT risk through a different mechanism.