Summary

Rifampin significantly reduces doxepin plasma concentrations through CYP450 enzyme induction, potentially leading to decreased antidepressant effectiveness. This interaction requires careful monitoring and possible dose adjustments to maintain therapeutic efficacy.

Introduction

Doxepin is a tricyclic antidepressant (TCA) primarily used to treat depression, anxiety disorders, and chronic insomnia. It works by inhibiting the reuptake of norepinephrine and serotonin neurotransmitters. Rifampin is a potent antibiotic belonging to the rifamycin class, commonly prescribed for tuberculosis, atypical mycobacterial infections, and certain staphylococcal infections. It is also used for meningococcal prophylaxis and has anti-inflammatory properties.

Mechanism of Interaction

Rifampin is a potent inducer of hepatic cytochrome P450 enzymes, particularly CYP3A4, CYP2C9, and CYP2C19. Doxepin is primarily metabolized by CYP2D6 and CYP2C19 enzymes in the liver to its active metabolite, nordoxepin. When rifampin is co-administered, it significantly increases the activity of these metabolic enzymes, leading to enhanced metabolism and clearance of doxepin. This results in substantially reduced plasma concentrations of both doxepin and its active metabolite, potentially compromising the antidepressant's therapeutic effectiveness.

Risks and Symptoms

The primary clinical risk of this interaction is the potential loss of antidepressant efficacy due to subtherapeutic doxepin levels. Patients may experience a return of depressive symptoms, increased anxiety, or sleep disturbances. The interaction can occur within days of starting rifampin and may persist for several weeks after rifampin discontinuation due to the time required for enzyme activity to normalize. This interaction is considered clinically significant and may require intervention to maintain therapeutic outcomes. Patients with severe depression or those at risk for suicidal ideation require particularly careful monitoring.

Management and Precautions

Close monitoring of patient response and depressive symptoms is essential when these medications are used concurrently. Consider increasing the doxepin dose by 50-100% or more to compensate for increased clearance, with careful titration based on clinical response and tolerability. Monitor for signs of treatment failure, including worsening depression, anxiety, or sleep disturbances. Therapeutic drug monitoring of doxepin levels may be helpful if available. When rifampin is discontinued, gradually reduce the doxepin dose to prevent toxicity as enzyme activity returns to baseline over 2-4 weeks. Consider alternative antibiotics with less enzyme induction potential if clinically appropriate, or alternative antidepressants less affected by CYP450 induction.

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.

Rifampin interactions with food and lifestyle

Rifampin should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food can significantly reduce its absorption and effectiveness. Alcohol consumption should be avoided or limited while taking rifampin, as both rifampin and alcohol can cause liver toxicity, and the combination may increase the risk of hepatotoxicity. Patients should be counseled to take rifampin consistently either with or without food (preferably without) to maintain consistent blood levels.