Summary

The combination of doxepin (a tricyclic antidepressant) and fluvoxamine (an SSRI) represents a significant drug interaction that can lead to increased doxepin levels and enhanced side effects. This interaction occurs primarily through fluvoxamine's inhibition of cytochrome P450 enzymes responsible for doxepin metabolism.

Introduction

Doxepin is a tricyclic antidepressant (TCA) commonly prescribed for depression, anxiety disorders, and chronic insomnia. It works by blocking the reuptake of norepinephrine and serotonin neurotransmitters. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) primarily used to treat obsessive-compulsive disorder (OCD) and social anxiety disorder. It selectively inhibits serotonin reuptake and also has significant effects on cytochrome P450 enzymes, particularly CYP1A2 and CYP2D6, which are crucial for metabolizing many medications including tricyclic antidepressants.

Mechanism of Interaction

The interaction between doxepin and fluvoxamine occurs through pharmacokinetic mechanisms involving cytochrome P450 enzyme inhibition. Fluvoxamine is a potent inhibitor of CYP1A2 and a moderate inhibitor of CYP2D6, both of which are essential enzymes for doxepin metabolism. When fluvoxamine inhibits these enzymes, it significantly reduces the clearance of doxepin from the body, leading to elevated plasma concentrations. This can result in a 2-5 fold increase in doxepin levels, prolonging its half-life and intensifying both therapeutic and adverse effects. Additionally, both medications affect serotonin levels, which may contribute to an increased risk of serotonin-related side effects.

Risks and Symptoms

The primary clinical risks of combining doxepin and fluvoxamine include significantly increased anticholinergic effects such as dry mouth, constipation, urinary retention, and confusion, particularly in elderly patients. Cardiovascular risks are elevated, including prolonged QT interval, arrhythmias, and orthostatic hypotension. Central nervous system effects may be intensified, leading to excessive sedation, cognitive impairment, and increased fall risk. There is also a potential for serotonin syndrome, though this is less common with this specific combination. The interaction is considered clinically significant and may require dose adjustments or alternative therapy selection to ensure patient safety.

Management and Precautions

Doxepin interactions with food and lifestyle

Alcohol: Avoid alcohol while taking doxepin as it can increase drowsiness, dizziness, and impair thinking and motor skills. The combination may also increase the risk of respiratory depression. Grapefruit: Grapefruit and grapefruit juice may increase doxepin levels in the blood by inhibiting CYP3A4 metabolism, potentially leading to increased side effects. Driving and Operating Machinery: Doxepin may cause drowsiness, dizziness, and blurred vision. Patients should avoid driving or operating heavy machinery until they know how the medication affects them. Sun Exposure: Doxepin may increase sensitivity to sunlight (photosensitivity). Use sunscreen and protective clothing when outdoors to prevent sunburn and skin reactions.

Fluvoxamine interactions with food and lifestyle

Fluvoxamine should not be taken with alcohol as it may increase drowsiness and impair cognitive function. Caffeine intake should be limited or avoided as fluvoxamine significantly inhibits caffeine metabolism, potentially leading to caffeine toxicity with symptoms including jitteriness, rapid heartbeat, and insomnia. Smoking cessation may be necessary as tobacco use can reduce fluvoxamine effectiveness by increasing its metabolism. Patients should maintain consistent timing of doses with regard to meals, as food can affect absorption, though fluvoxamine can be taken with or without food.