Which has more side effects, terbinafine or fluconazole?

Terbinafine vs Fluconazole: Side Effect Profile Comparison

Fluconazole has a significantly higher rate of adverse events leading to treatment discontinuation compared to terbinafine, with 20-58% of patients discontinuing fluconazole (depending on dose) versus approximately 10.5% experiencing any adverse events with terbinafine. 1, 2

Direct Comparative Evidence

The most definitive head-to-head comparison demonstrates clear differences in tolerability:

• Terbinafine had a superior tolerability profile with adverse events occurring in only 10.5% of patients in post-marketing surveillance, with gastrointestinal complaints being most common 2
• Fluconazole showed adverse effects leading to treatment discontinuation in 20% of patients receiving 150 mg weekly, escalating dramatically to 58% at higher weekly doses (300-450 mg) 1
• In direct randomized controlled trials, terbinafine demonstrated a comparable or better tolerability profile than fluconazole 2

Common Side Effects by Agent

Terbinafine Side Effects 1, 3

• Gastrointestinal: Headache and gastrointestinal upset (most common)
• Dermatologic: Nausea and rashes in 8-15% of patients 1
• Taste disturbance: Occurs in approximately 1:400 patients (0.25%), can rarely be permanent 1, 4, 3
• Serious adverse events: Only 0.04% of patients experience serious reactions 4
• Rare but serious: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome, rhabdomyolysis, hepatotoxicity 5, 3

Fluconazole Side Effects 1, 6

• Common: Headache, skin rash, gastrointestinal complaints, insomnia 1
• Hepatotoxicity: Requires monitoring, particularly with high-dose or prolonged therapy 1
• Exfoliative skin reactions: Documented concern requiring wider clinical experience 6
• Overall burden: Higher discontinuation rates indicate greater symptomatic burden 1

Drug Interaction Profile: A Critical Safety Distinction

Terbinafine has minimal drug interactions, while fluconazole carries substantial interaction risks:

Terbinafine Interactions 4, 3, 7

• Primary interaction: Inhibits CYP2D6 only (affects tricyclic antidepressants, SSRIs, beta-blockers, class 1C antiarrhythmics) 3
• No contraindicated drug combinations 7
• Post-marketing surveillance of 25,884 patients (42.8% on concomitant medications) revealed no new drug-drug interactions 7

Fluconazole Interactions 1, 3

• Inhibits both CYP2C9 and CYP3A4 enzymes 3
• Weaker inhibitor than itraconazole but still clinically significant 1
• Can substantially increase systemic exposure of co-administered drugs 3
• Requires careful monitoring with multiple medication classes 1

Hepatotoxicity Risk Comparison

Both agents carry hepatotoxicity warnings, but the clinical significance differs:

• Terbinafine: Baseline liver function tests recommended in patients with history of hepatotoxicity; active or chronic liver disease is a contraindication 1, 5
• Fluconazole: Baseline liver function tests required; monitoring needed in high-dose or prolonged therapy 1
• Clinical context: The British Association of Dermatologists notes that fluconazole's use has been "relatively limited because of side-effects" 1

Practical Clinical Implications

For patients on multiple medications, terbinafine is the safer choice due to its minimal drug interaction profile, making it "the most rational choice of oral antifungal agent in patients receiving concomitant medications" 7. This is particularly important in elderly patients or those with polypharmacy.

For patients requiring higher doses or longer treatment duration, terbinafine maintains better tolerability, as fluconazole's discontinuation rate escalates dramatically with dose intensification (from 20% to 58%) 1.

Important Caveats

• Permanent taste/smell disturbance: While rare (1:400), patients must be counseled about this potentially permanent side effect of terbinafine before initiation 5, 4, 3
• Renal impairment: Terbinafine clearance is significantly decreased in severe kidney disease, making this a practical contraindication 5
• Pregnancy: Both agents should be avoided; onychomycosis treatment can be postponed until after pregnancy 3