Summary

Fluoxetine significantly inhibits the metabolism of flecainide through CYP2D6 enzyme inhibition, potentially leading to increased flecainide plasma concentrations and enhanced risk of cardiac toxicity. This interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Flecainide is a Class IC antiarrhythmic medication primarily used to treat and prevent certain types of irregular heartbeats, including atrial fibrillation, atrial flutter, and ventricular arrhythmias. It works by blocking sodium channels in cardiac tissue to stabilize heart rhythm. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant commonly prescribed for depression, anxiety disorders, obsessive-compulsive disorder, and other psychiatric conditions. Beyond its primary therapeutic effects, fluoxetine is a potent inhibitor of the cytochrome P450 2D6 (CYP2D6) enzyme system, which metabolizes many medications including flecainide.

Mechanism of Interaction

The interaction between flecainide and fluoxetine occurs through competitive inhibition of the CYP2D6 enzyme pathway. Flecainide is primarily metabolized by CYP2D6, with this enzyme responsible for converting flecainide to its inactive metabolites. Fluoxetine and its active metabolite norfluoxetine are potent CYP2D6 inhibitors with long half-lives, leading to sustained enzyme inhibition. When fluoxetine blocks CYP2D6 activity, flecainide clearance is significantly reduced, resulting in elevated plasma concentrations that can persist for weeks due to fluoxetine's extended elimination period. This pharmacokinetic interaction can increase flecainide levels by 50-100% or more, depending on individual patient factors and CYP2D6 genetic polymorphisms.

Risks and Symptoms

The primary clinical risk of this interaction is flecainide toxicity due to elevated plasma concentrations. Increased flecainide levels can lead to serious cardiac complications including proarrhythmic effects, where the medication intended to treat arrhythmias actually causes new or worsened irregular heart rhythms. Patients may experience bradycardia (slow heart rate), heart block, ventricular tachycardia, or other life-threatening arrhythmias. Additional risks include negative inotropic effects leading to reduced cardiac contractility and potential heart failure exacerbation. Non-cardiac symptoms of flecainide toxicity may include dizziness, blurred vision, nausea, and neurological effects. The interaction is particularly concerning because both the onset and resolution can be delayed due to fluoxetine's long half-life, making management challenging.

Management and Precautions

Flecainide interactions with food and lifestyle

Flecainide should be taken consistently with regard to meals - either always with food or always on an empty stomach - as food can affect absorption and blood levels. Patients should avoid excessive caffeine intake as it may worsen arrhythmias. Alcohol should be used with caution as it can increase the risk of cardiac side effects and may interfere with the drug's effectiveness in controlling heart rhythm. Smoking cessation is recommended as smoking can affect flecainide metabolism and reduce its effectiveness.

Fluoxetine interactions with food and lifestyle

Alcohol: Fluoxetine may increase the sedative effects of alcohol and impair cognitive and motor performance. Patients should avoid or limit alcohol consumption while taking fluoxetine. Grapefruit juice: May increase fluoxetine blood levels, though this interaction is generally considered minor. St. John's Wort: Should be avoided as it may increase the risk of serotonin syndrome when combined with fluoxetine.