Terbinafine

Pronunciation

(TER bin a feen)

U.S. Brand Names

Lamisil®; Lamisil® AT™ [OTC]

Synonyms

Terbinafine Hydrochloride

Generic Available

No

Canadian Brand Names

Apo-Terbinafine®; Gen-Terbinafine; Lamisil®; Novo-Terbinafine; PMS-Terbinafine

Use

Active against most strains of Trichophyton mentagrophytes, Trichophyton rubrum; may be effective for infections of Microsporum gypseum and M. nanum, Trichophyton verrucosum, Epidermophyton floccosum, Candida albicans, and Scopulariopsis brevicaulis

Oral: Onychomycosis of the toenail or fingernail due to susceptible dermatophytes

Topical: Antifungal for the treatment of tinea pedis (athlete's foot), tinea cruris (jock itch), and tinea corporis (ringworm) [OTC/prescription formulations]; tinea versicolor [prescription formulations]

Pregnancy Risk Factor

B

Pregnancy Implications

Avoid use in pregnancy since treatment of onychomycosis is postponable.

Lactation

Enters breast milk/not recommended

Contraindications

Hypersensitivity to terbinafine, naftifine, or any component of the formulation

Warnings/Precautions

While rare, the following complications have been reported and may require discontinuation of therapy: Changes in the ocular lens and retina, pancytopenia, neutropenia, Stevens-Johnson syndrome, toxic epidermal necrolysis. Rare cases of hepatic failure (including fatal cases) have been reported following oral treatment of onychomycosis. Not recommended for use in patients with active or chronic liver disease. Discontinue if symptoms or signs of hepatobiliary dysfunction or cholestatic hepatitis develop. If irritation/sensitivity develop with topical use, discontinue therapy. Oral products are not recommended for use with pre-existing liver or renal disease (50 mL/minute GFR). Use caution in writing and/or filling prescription/orders. Confusion between Lamictal® (lamotrigine) and Lamisil® (terbinafine) has occurred.

Adverse Reactions

Oral:

1% to 10%:

Central nervous system: Headache, dizziness, vertigo

Dermatologic: Rash, pruritus, urticaria

Gastrointestinal: Diarrhea, dyspepsia, abdominal pain, appetite decrease, taste disturbance

Hematologic: Lymphocytopenia

Hepatic: Liver enzymes increased

Ocular: Visual disturbance

<1%, postmarketing and/or case reports: Angioedema, agranulocytosis, allergic reactions, alopecia, anaphylaxis, arthralgia, changes in ocular lens and retina, fatigue, hepatic failure, malaise, myalgia, neutropenia, precipitation/exacerbation of cutaneous and systemic lupus erythematosus, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, vomiting

Topical: 1% to 10%:

Dermatologic: Pruritus, contact dermatitis, irritation, burning, dryness

Local: Irritation, stinging

Drug Interactions

Substrate (minor) of 1A2, 2C8/9, 2C19, 3A4; Inhibits CYP2D6 (strong); Induces CYP3A4 (weak)

Effects of drugs metabolized by CYP2D6 (including beta-blockers, SSRIs, MAO inhibitors, tricyclic antidepressants) may be increased; warfarin effects may be increased

CYP2D6 substrates: Terbinafine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Terbinafine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

Rifampin: Rifampin increases terbinafine clearance (100%).

Stability

Cream: Store at 5°C to 30°C (41°F to 86°F).

Solution: Store at 5°C to 25°C (41°F to 77°F); do not refrigerate

Tablet: Store below 25°C (77°F); protect from light

Mechanism of Action

Synthetic alkylamine derivative which inhibits squalene epoxidase, a key enzyme in sterol biosynthesis in fungi. This results in a deficiency in ergosterol within the fungal cell wall and results in fungal cell death.

Pharmacodynamics/Kinetics

Absorption: Topical: Limited (<5%); Oral: >70%

Distribution: Vd: 2000 L; distributed to sebum and skin predominantly

Protein binding, plasma: >99%

Metabolism: Hepatic; no active metabolites; first-pass effect; little effect on CYP

Bioavailability: Oral: 40%

Half-life elimination:

Topical: 22-26 hours

Oral: Terminal half-life: 200-400 hours; very slow release of drug from skin and adipose tissues occurs; effective half-life: ~36 hours

Time to peak, plasma: 1-2 hours

Excretion: Urine (70% to 75%)

Dosage

Children 12 years and Adults:

Topical cream, solution:

Athlete's foot (tinea pedis): Apply to affected area twice daily for at least 1 week, not to exceed 4 weeks [OTC/prescription formulations]

Ringworm (tinea corporis) and jock itch (tinea cruris): Apply cream to affected area once or twice daily for at least 1 week, not to exceed 4 weeks; apply solution once daily for 7 days [OTC formulations]

Adults:

Oral:

Superficial mycoses: Fingernail: 250 mg/day for up to 6 weeks; toenail: 250 mg/day for 12 weeks; doses may be given in two divided doses

Systemic mycosis: 250-500 mg/day for up to 16 months

Topical solution: Tinea versicolor: Apply to affected area twice daily for 1 week [prescription formulation]

Dosing adjustment in renal impairment: GFR <50 mL/minute: Oral administration is not recommended.

Dosing adjustment in hepatic impairment: Clearance is decreased by ~50% with hepatic cirrhosis; use is not recommended.

Monitoring Parameters

CBC and LFTs at baseline and repeated if use is for >6 weeks

Patient Education

Topical: Avoid contact with eyes, nose, or mouth. Advise physician if eyes or skin becomes yellow or if irritation, itching, or burning develops. Do not use occlusive dressings concurrent with therapy. Full clinical effect may require several months due to the time required for a new nail to grow. Breast-feeding precaution: Breast-feeding is not recommended. Should not be used on breast tissue.

Additional Information

Due to potential toxicity, the manufacturer recommends confirmation of diagnosis testing of nail specimens prior to treatment of onychomycosis. Patients should not be considered therapeutic failures until they have been symptom-free for 2-4 weeks off following a course of treatment; GI complaints usually subside with continued administration.

A meta-analysis of efficacy studies for toenail infections revealed that weighted average mycological cure rates for continuous therapy were 36.7% (griseofulvin), 54.7% (itraconazole), and 77% (terbinafine). Cure rate for 4-month pulse therapy for itraconazole and terbinafine were 73.3% and 80%. Additionally, the final outcome measure of final costs per cured infections for continuous therapy was significantly lower for terbinafine.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

Cream, as hydrochloride (Lamisil® AT™): 1% (15 g, 30 g)

Solution, as hydrochloride [topical spray] (Lamisil®, Lamisil® AT™): 1% (30 mL)

Tablet (Lamisil®): 250 mg

References for Terbinafine

Abdel-Rahman SM and Nahata MC, "Oral Terbinafine: A New Antifungal Agent,"Ann Pharmacother, 1997, 31(4):445-56.

Amichai B and Grunwald MH, "Adverse Drug Reactions of the New Oral Antifungal Agents - Terbinafine, Fluconazole, and Itraconazole,"Int J Dermatol, 1998, 37(6):410-5.

Angello JT, Voytovich RM, and Jan SA, "A Cost/Efficacy Analysis of Oral Antifungals Indicated for the Treatment of Onychomycosis: Griseofulvin, Itraconazole, and Terbinafine,"Am J Manag Care, 1997, 3(3):443-50.

De Backer M, De Vroey C, Lesaffre E, et al, "Twelve Weeks of Continuous Oral Therapy for Toenail Onychomycosis Caused by Dermatophytes: A Double-Blind Comparative Trial of Terbinafine 250 mg/day Versus Itraconazole 200 mg/day,"J Am Acad Dermatol, 1998, 38(5 Pt 3):S57-63.

Dwyer CM, White MI, and Sinclair TS, "Cholestatic Jaundice Due to Terbinafine,"Br J Dermatol, 1997, 136(6):976-7.

Gupta AK and Shear NH, "Terbinafine: An Update,"J Am Acad Dermatol, 1997, 37(6):979-88.

Gupta AK, Sibbald RG, Knowles SR, et al, "Terbinafine Therapy May Be Associated With the Development of Psoriasis De Novo or Its Exacerbation: Four Case Reports and a Review of Drug Induced Psoriasis,"J Am Acad Dermatol, 1997, 36(5 Part 2):858-62.

Jones TC, "Overview of the Use of Terbinafine in Children,"Br J Dermatol, 1995, 132(5):683-9.

Trepanier EF and Amsden GW, "Current Issues in Onychomycosis,"Ann Pharmacother, 1998, 32(2):204-14.

International Brand Names

Apo-Terbinafine® (CA); Atifan® (SI); Brinaf® (CZ); Cloridrato de Terbinafina® (BR); Daskil® (AT, IT); Daskyl® (PT); Exifin® (RU); Finex® (BR, EC); Gen-Terbinafine (CA); Lamisil® (AR, AT, AU, BD, BE, BG, BR, CA, CH, CL, CO, CR, CZ, DE, DK, DO, EC, ES, FI, FR, GB, GT, HK, HN, HR, HU, ID, IE, IL, IN, IT, LU, MT, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SE, SG, SI, SV, TH, TR, YU, ZA); Lamisilatt® (PL); Lamisildermgel® (FR); Lamisil DermGel® (SE); Lamisil Oral® (CL); Micoter® (BR); Novo-Terbinafine (CA); Onychon® (CZ); PMS-Terbinafine (CA); Tenasil® (PL); Terbinafine-Teva® (IL); Terbisil® (CZ, HU, PL, TR); Terbix® (DO); Terekol® (AR); Terfex® (CL); Termisil® (ID)