Terbinafine and CYP2D6
Yes, terbinafine is a potent inhibitor of cytochrome P450 2D6 (CYP2D6) and significantly affects the metabolism of drugs processed by this enzyme. This interaction is clinically important and requires careful monitoring when terbinafine is co-administered with CYP2D6 substrates 1.
Mechanism and Clinical Significance
Terbinafine inhibits CYP2D6 with sufficient potency to convert extensive metabolizers into phenotypic poor metabolizers. Research demonstrates that terbinafine increases the dextromethorphan/dextrorphan metabolite ratio by 16- to 97-fold on average, effectively converting approximately 93% of the population (extensive metabolizers) into poor metabolizer status 2. This is not a trivial interaction—it represents one of the most clinically significant drug interactions with terbinafine 3.
Duration of Inhibition
A critical and often underappreciated aspect is that this CYP2D6 inhibition persists for weeks to months after terbinafine discontinuation. The FDA label explicitly states that effects on desipramine metabolism persisted at 4 weeks after stopping terbinafine 1. Clinical case reports document interactions lasting up to 6 months after terbinafine cessation 4. This prolonged effect occurs because terbinafine has a long terminal half-life and persists in tissues.
Affected Drug Classes
The following drug classes are predominantly metabolized by CYP2D6 and require careful monitoring or dose reduction when co-administered with terbinafine 1:
Tricyclic antidepressants (e.g., desipramine, amitriptyline): Terbinafine causes a 2-fold increase in Cmax and 5-fold increase in AUC for desipramine 5. A case report documented extreme anticholinergic effects with amitriptyline that persisted for 6 months 4.
Selective serotonin reuptake inhibitors (SSRIs): Paroxetine concentrations increased 1.9-fold (Cmax) and 2.5-fold (AUC) with terbinafine 6.
Beta-blockers: Require monitoring and potential dose reduction.
Class 1C antiarrhythmics (flecainide, propafenone): These narrow therapeutic index drugs are particularly concerning.
MAO-B inhibitors: Require careful monitoring.
Atypical antipsychotics: Risperidone metabolism is significantly affected, with documented clinical deterioration 7. Aripiprazole concentrations increased 18-59% 8.
Opioid analgesics: Tramadol's conversion to its active metabolite (M1) is reduced by 64%, potentially decreasing analgesic efficacy while increasing monoaminergic side effects 9.
Clinical Management Algorithm
When prescribing terbinafine:
Review all current medications for CYP2D6 substrates, particularly those with narrow therapeutic indices (tricyclic antidepressants, Class 1C antiarrhythmics).
For drugs with narrow therapeutic indices: Consider alternative antifungal therapy (e.g., itraconazole for appropriate indications, though it has its own CYP3A4 interactions).
If terbinafine must be used with CYP2D6 substrates:
- Reduce the dose of the CYP2D6 substrate preemptively (typically by 25-50% for drugs like tricyclic antidepressants)
- Monitor closely for increased drug effects and toxicity
- Consider therapeutic drug monitoring where available
After terbinafine discontinuation: Continue monitoring for at least 4-8 weeks, as inhibition persists. Do not rapidly increase doses of CYP2D6 substrates immediately after stopping terbinafine.
Important Caveats
While terbinafine is a potent CYP2D6 inhibitor, it does not significantly inhibit other major CYP enzymes. In vitro and in vivo studies confirm it does not meaningfully affect CYP1A2, 2C9, 2C19, or 3A4 metabolism of most substrates 1. However, terbinafine itself is primarily metabolized by CYP2C9 and CYP3A4 (not CYP2D6), so its own metabolism can be affected by inhibitors of these enzymes 10.
The British Association of Dermatologists guidelines explicitly state that CYP2D6 substrate interactions represent "the only potentially significant drug interaction with terbinafine" 3. This underscores both the importance of this interaction and the relative safety of terbinafine regarding other metabolic pathways.