Terbinafine - Drug Monograph

Introduction

Terbinafine is a synthetic allylamine antifungal agent that represents a cornerstone in the treatment of fungal infections. First approved by the FDA in 1996, it has become one of the most widely prescribed oral antifungal medications worldwide. Terbinafine demonstrates potent activity against dermatophytes, the most common cause of fungal skin infections, and exhibits fungicidal rather than fungistatic properties, contributing to its clinical efficacy and shorter treatment durations compared to older antifungal agents.

Mechanism of Action

Terbinafine exerts its antifungal effect through selective inhibition of squalene epoxidase, a key enzyme in the ergosterol biosynthesis pathway. This enzyme inhibition leads to:

• Accumulation of squalene within fungal cells, causing membrane disruption and cell death
• Depletion of ergosterol, an essential component of fungal cell membranes
• Alteration of membrane permeability and function

The drug demonstrates greater affinity for fungal squalene epoxidase than the mammalian enzyme, contributing to its selective toxicity against fungal cells with minimal effects on human cells.

Indications

• Onychomycosis due to dermatophytes (tinea unguium)
• Tinea pedis (athlete's foot)
• Tinea corporis (ringworm)
• Tinea cruris (jock itch)
• Tinea versicolor (caused by Malassezia furfur)

• Cutaneous candidiasis
• Aspergillosis (in combination therapy)
• Chromoblastomycosis
• Prophylaxis in immunocompromised patients

Dosage and Administration

• Onychomycosis: 250 mg orally once daily for 6 weeks (fingernails) or 12 weeks (toenails)
• Tinea pedis/corporis/cruris: 250 mg orally once daily for 2-6 weeks
• Topical formulations: Apply once or twice daily to affected area for 1-4 weeks

• Renal impairment (CrCl <50 mL/min): Reduce dose by 50%
• Hepatic impairment (Child-Pugh A-B): Maximum 250 mg every other day
• Elderly: Consider dose reduction based on renal/hepatic function
• Pediatric: Safety not established for oral formulation in children under 4 years

Pharmacokinetics

Contraindications

• Hypersensitivity to terbinafine or any component of the formulation
• Chronic or active liver disease
• Severe renal impairment (CrCl <30 mL/min)
• Pregnancy (category B; use only if clearly needed)
• Breastfeeding (excreted in human milk)

Warnings and Precautions

• Cases of liver failure, some leading to death or liver transplant, have occurred

• Monitor for symptoms of hepatotoxicity (fatigue, anorexia, nausea, vomiting, abdominal pain, dark urine)
• Risk of taste disturbance (including permanent loss)
• Hematologic effects (neutropenia, thrombocytopenia)
• Serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Lupus erythematosus and psoriasis exacerbation
• Depression and anxiety reports

Drug Interactions

• CYP2D6 substrates (β-blockers, SSRIs, TCAs, antiarrhythmics): Increased concentrations
• Rifampin: Decreased terbinafine concentrations by 100%
• Cimetidine: Increased terbinafine concentrations by 33%
• Warfarin: Potential enhanced anticoagulant effect
• Oral contraceptives: Possible decreased efficacy
• Caffeine: Reduced clearance

Adverse Effects

• Headache (13%)
• Gastrointestinal disturbances (nausea, diarrhea, dyspepsia) (5-12%)
• Rash (6%)
• Taste disturbance (3%)

• Hepatotoxicity (elevated LFTs, hepatitis, liver failure)
• Severe cutaneous reactions
• Hematologic disorders
• Ocular changes
• Psychiatric symptoms

Monitoring Parameters

• Complete blood count with differential
• Liver function tests (ALT, AST, alkaline phosphatase, bilirubin)
• Renal function tests
• Symptom assessment

• LFTs at 4-6 week intervals during prolonged therapy
• CBC if symptoms suggest blood dyscrasia
• Periodic assessment of taste function
• Monitoring for skin reactions
• Assessment of psychiatric symptoms

• Clinical evaluation for treatment response
• Consider follow-up LFTs if prolonged therapy

Patient Education

• Complete full course of therapy even if symptoms improve
• Report any signs of liver problems (yellowing skin/eyes, dark urine, fatigue)
• Immediately report skin rash, mouth sores, or blistering
• Be aware of potential taste changes and report if persistent
• Avoid alcohol consumption during therapy
• Inform all healthcare providers about terbinafine use
• Use effective contraception during treatment
• For topical forms: Clean and dry area before application; wash hands after application

References

1. Gupta AK, Drummond-Main CD. Meta-analysis of randomized, controlled trials comparing particular doses of griseofulvin and terbinafine for the treatment of tinea capitis. Pediatr Dermatol. 2013;30(1):1-6. 2. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol. 1993;28(5 Pt 1):S28-S34. 3. Terbinafine [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 4. FDA Drug Safety Communication: FDA warns of risk of serious liver injury with use of the antifungal medicine Sporanox (itraconazole) and Lamisil (terbinafine hydrochloride). Silver Spring, MD: US Food and Drug Administration; 2013. 5. Kovacs MJ, Alshamma A, Guenther L, et al. Terbinafine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in superficial mycoses. Drugs. 1992;43(2):259-284. 6. Darkes MJ, Scott LJ, Goa KL. Terbinafine: a review of its use in onychomycosis in adults. Am J Clin Dermatol. 2003;4(1):39-65.