What are the risks and considerations when prescribing dofetilide and triamterene (hydrochlorothiazide) together?

Dofetilide and Triamterene-Hydrochlorothiazide: Contraindicated Combination

The concomitant use of dofetilide and hydrochlorothiazide (including combinations such as triamterene-hydrochlorothiazide) is absolutely contraindicated due to significant risk of QT interval prolongation and potentially fatal arrhythmias. 1

Mechanism of Interaction and Risks

The interaction between dofetilide and hydrochlorothiazide poses several serious risks:

1. QT Interval Prolongation:

   • Hydrochlorothiazide significantly increases dofetilide plasma concentrations, leading to QT interval prolongation 1
   • This increases the risk of torsades de pointes, a potentially fatal ventricular arrhythmia

2. Pharmacokinetic Interaction:

   • Hydrochlorothiazide interferes with the renal cation transport system that eliminates dofetilide
   • This leads to increased dofetilide levels in the bloodstream, even when the prescribed dose remains unchanged

FDA Labeling and Guideline Recommendations

The FDA label for dofetilide (Tikosyn) explicitly states:

• "The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with TIKOSYN is contraindicated" 1

The ACC/AHA/HRS guidelines for supraventricular tachycardia management also note this contraindication in their prescribing information for dofetilide, listing "concomitant use of hydrochlorothiazide, cimetidine, dolutegravir, itraconazole, ketoconazole, megestrol, trimethoprim, prochlorperazine trimethoprim/sulfamethoxazole or verapamil" as contraindicated 2

Alternative Management Options

For patients requiring both rhythm control for atrial arrhythmias and diuretic therapy:

1. Alternative Antiarrhythmic Options:

   • Sotalol may be considered for patients with preserved renal function who need both rhythm control and diuretic effects 2
   • Amiodarone may be considered as a third-line option for rhythm control in patients who cannot take other agents 2

2. Alternative Diuretic Options:

   • Loop diuretics (furosemide, bumetanide, torsemide) can be used instead of thiazides 2
   • For potassium-sparing effects, consider spironolactone or eplerenone instead of triamterene 2

3. Monitoring Requirements:

   • If switching from thiazide to loop diuretics, monitor electrolytes closely, especially potassium levels
   • For patients on dofetilide, regular ECG monitoring is essential to assess QTc interval

Special Considerations

• Renal Function: Dofetilide is already contraindicated in severe renal impairment (CrCl <20 mL/min) 1
• Elderly Patients: Older adults are at higher risk for drug interactions and electrolyte disturbances with both medications 2, 3
• QT Monitoring: Dofetilide requires baseline and follow-up QT interval monitoring; adding hydrochlorothiazide further increases this risk 2

Common Pitfalls to Avoid

1. Overlooking combination products: Remember that many fixed-dose combination products contain hydrochlorothiazide (like Maxzide, Dyazide) 4

2. Assuming potassium-sparing component negates risk: Even though triamterene is potassium-sparing, the combination with hydrochlorothiazide still poses a significant risk with dofetilide 5

3. Inadequate monitoring: If transitioning between these medications, ensure proper washout periods and close monitoring of QT interval and electrolytes

4. Underestimating the severity: This is not a minor interaction that can be managed with dose adjustments or monitoring - it is an absolute contraindication that requires alternative therapy selection

The evidence is clear and consistent across all sources that this combination should never be used together due to the significant risk of life-threatening arrhythmias.