What are the potential interactions between terbinafine, a CYP2D6 inhibitor, and venlafaxine in a patient with stable anxiety taking 75mg of venlafaxine?

Terbinafine as a CYP2D6 Inhibitor and Its Interaction with Venlafaxine

Yes, terbinafine is a potent CYP2D6 inhibitor, and when combined with venlafaxine 75mg in a patient with stable anxiety, it will cause a substantial 5-fold increase in venlafaxine levels while decreasing the active metabolite O-desmethylvenlafaxine (ODV) by 43%, requiring either dose reduction or consideration of alternative antifungal therapy. 1, 2

Mechanism of Interaction

Terbinafine's CYP2D6 Inhibition:

• Terbinafine is a competitive inhibitor of CYP2D6 with a Ki of 0.03 μM, making it one of the most potent CYP2D6 inhibitors among commonly prescribed medications 3
• The FDA drug label explicitly states that terbinafine inhibits the CYP450 2D6 isoenzyme and can convert extensive CYP2D6 metabolizers to poor metabolizer status 1
• This inhibition persists for at least 4 weeks after discontinuation of terbinafine, as demonstrated in studies showing a 2-fold increase in Cmax and 5-fold increase in AUC of desipramine that persisted at the last observation 4 weeks post-treatment 1

Impact on Venlafaxine Metabolism:

• Venlafaxine is metabolized to its active metabolite ODV primarily by CYP2D6 4, 5
• When terbinafine is coadministered, the AUC of venlafaxine increases to 490% (nearly 5-fold) of baseline, while ODV levels decrease to 57% of baseline 2
• The ODV-to-venlafaxine ratio decreases by 82%, fundamentally altering the pharmacokinetic profile 2

Clinical Significance and Risk Assessment

Cardiovascular and Serotonergic Risks:

• The combined active moiety (venlafaxine plus ODV) increases, raising concerns for dose-dependent adverse effects including hypertension, tachycardia, and serotonin syndrome 4, 5
• Venlafaxine can cause dose-dependent blood pressure elevation, particularly at doses above 225mg/day, though this is infrequently observed at lower doses 5
• At 75mg venlafaxine baseline, the 5-fold increase in parent compound could produce effective exposure equivalent to much higher doses 2

Serious Adverse Event Potential:

• The Mayo Clinic guidelines document a fatal case of a 34-year-old man with major depressive disorder taking venlafaxine who died from cardiac arrest due to high blood venlafaxine concentration (4.5 mg/kg) attributed to CYP2D6 poor metabolizer phenotype 6
• Terbinafine effectively converts patients to CYP2D6 poor metabolizer status, creating similar risk 1, 3

Management Algorithm

Option 1: Continue Current Therapy with Monitoring (Preferred for short-term antifungal courses)

• Reduce venlafaxine dose by 50-75% (to 18.75-37.5mg daily) when initiating terbinafine 1
• Monitor blood pressure and heart rate at baseline, 1 week, and 2 weeks after starting terbinafine 4
• Assess for serotonin syndrome symptoms: mental status changes, neuromuscular hyperactivity (tremor, hyperreflexia, clonus), autonomic instability (tachycardia, diaphoresis, hyperthermia) 7
• Monitor for increased anxiety, agitation, or behavioral activation in the first 2-4 weeks 8
• After completing terbinafine, maintain reduced venlafaxine dose for 4 additional weeks before gradually re-escalating 1

Option 2: Switch Antifungal Agent (Preferred for patients with cardiovascular risk factors)

• Consider itraconazole or fluconazole as alternatives for onychomycosis, though these have lower efficacy than terbinafine 6
• Fluconazole increases terbinafine exposure by 52-69% but does not significantly inhibit CYP2D6, making it safer with venlafaxine 1
• Voriconazole causes only a minor 31% increase in venlafaxine active moiety through CYP3A4 inhibition, representing a safer alternative 2

Option 3: Switch Antidepressant (For long-term antifungal therapy)

• Consider switching to an antidepressant not metabolized by CYP2D6, such as escitalopram, sertraline (at therapeutic doses), or mirtazapine 6
• Allow 4-5 half-lives washout of venlafaxine (approximately 1 week) before initiating alternative, accounting for terbinafine's ongoing CYP2D6 inhibition 4

Critical Pitfalls to Avoid

• Do not assume the interaction is clinically insignificant because the patient is on a "low" dose of venlafaxine—the 5-fold increase in exposure is substantial regardless of baseline dose 2
• Do not rely on patient-reported symptoms alone for monitoring—blood pressure and heart rate must be objectively measured as venlafaxine can cause asymptomatic hypertension 4, 5
• Do not discontinue terbinafine abruptly if toxicity develops—the CYP2D6 inhibition persists for 4 weeks after stopping, so venlafaxine dose reduction is still required during this period 1
• Do not combine with other serotonergic agents (tramadol, triptans, other antidepressants) during this interaction period, as this substantially increases serotonin syndrome risk 7, 4
• Avoid rapid venlafaxine dose adjustments which increase risk of behavioral activation and withdrawal symptoms 8, 4

Special Considerations for This Patient

For a patient with stable anxiety on 75mg venlafaxine:

• The anxiety disorder itself may worsen with venlafaxine dose reduction, requiring close psychiatric monitoring 6
• Behavioral activation and increased anxiety are recognized early adverse effects of dose changes in SNRIs 8
• The patient's CYP2D6 genotype, if known, would inform risk stratification—poor metabolizers are at highest risk, but terbinafine converts even extensive metabolizers to poor metabolizer phenotype 1, 3
• Consider whether the onychomycosis treatment is urgent or can be deferred until anxiety is better controlled with an alternative antidepressant not subject to this interaction 6