Summary

Dofetilide and trimethoprim have a significant drug interaction that can lead to dangerous cardiac arrhythmias. Trimethoprim inhibits the renal elimination of dofetilide, potentially causing toxic levels and life-threatening heart rhythm abnormalities. This combination is generally contraindicated and requires careful monitoring if unavoidable.

Introduction

Dofetilide is a Class III antiarrhythmic medication used to treat atrial fibrillation and atrial flutter by blocking potassium channels in the heart. Trimethoprim is an antibiotic commonly used alone or in combination with sulfamethoxazole to treat various bacterial infections, including urinary tract infections and pneumonia. Both medications require careful monitoring due to their potential for serious adverse effects, particularly when used together.

Mechanism of Interaction

The interaction between dofetilide and trimethoprim occurs through inhibition of renal tubular secretion. Trimethoprim blocks the organic cation transporter (OCT2) and multidrug and toxin extrusion proteins (MATE1/2-K) in the kidneys, which are responsible for the active secretion of dofetilide. This inhibition reduces dofetilide clearance by approximately 40-50%, leading to increased plasma concentrations and prolonged elimination half-life. The elevated dofetilide levels can result in excessive QT interval prolongation and increased risk of torsades de pointes.

Risks and Symptoms

The primary risk of this drug interaction is the development of life-threatening cardiac arrhythmias, particularly torsades de pointes, due to excessive QT interval prolongation. Increased dofetilide levels can cause severe bradycardia, heart block, and potentially fatal ventricular arrhythmias. Patients may experience symptoms such as dizziness, fainting, palpitations, or sudden cardiac arrest. The risk is particularly high in patients with pre-existing heart conditions, electrolyte imbalances, or renal impairment. This interaction is considered clinically significant and potentially life-threatening.

Management and Precautions

The concurrent use of dofetilide and trimethoprim is generally contraindicated. If trimethoprim therapy is absolutely necessary in a patient taking dofetilide, consider discontinuing dofetilide temporarily or switching to an alternative antibiotic. If the combination cannot be avoided, hospitalization for continuous cardiac monitoring is recommended, with frequent ECG monitoring to assess QT interval changes. Dofetilide dose reduction may be necessary, and serum electrolytes (particularly potassium and magnesium) should be monitored and corrected. Alternative antibiotics such as nitrofurantoin, fosfomycin, or fluoroquinolones (with caution) may be considered for urinary tract infections.

Dofetilide interactions with food and lifestyle

Dofetilide should be taken consistently with regard to meals - either always with food or always without food. Grapefruit juice should be avoided as it may increase dofetilide blood levels and risk of dangerous heart rhythm abnormalities. Alcohol should be used with caution as it may worsen heart rhythm problems. Patients should maintain consistent potassium and magnesium levels through diet, as low levels of these electrolytes can increase the risk of serious arrhythmias with dofetilide.

Trimethoprim interactions with food and lifestyle

Trimethoprim should be taken with adequate fluid intake to prevent kidney stone formation. Alcohol consumption should be limited as it may increase the risk of side effects and reduce the effectiveness of the antibiotic. Patients should maintain adequate folate intake through diet, as trimethoprim can interfere with folate metabolism, though routine folate supplementation is typically not required for short-term use.