Terbinafine

Introduction Overview

Generic Name

terbinafine

Brand Name

Lamisil

Dosage Form

oral tablet (250 mg); oral granules

Drug Class

Miscellaneous antifungals

Pharmacokinetics

Absorption: Terbinafine is well absorbed from the gastrointestinal tract following oral administration. Peak plasma concentrations are typically achieved within 1 to 2 hours after dosing. The oral bioavailability is approximately 40% due to first-pass metabolism in the liver. Food intake does not significantly affect the extent of absorption, facilitating flexible dosing with or without meals. The high lipophilicity of terbinafine facilitates its good oral absorption profile in humans. Distribution: Terbinafine displays extensive tissue distribution, especially accumulating in keratinous tissues such as skin, nails, and adipose tissue. It achieves significantly higher concentrations in nails and skin compared to plasma, which supports its efficacy in onychomycosis and dermatophytoses. Plasma protein binding is high, ranging from 99%, primarily to albumin. The drug also cross the blood-brain barrier minimally and is found in smaller concentrations in cerebrospinal fluid. Metabolism: Terbinafine undergoes extensive hepatic metabolism primarily via the cytochrome P450 enzyme system, particularly CYP2C9, CYP1A2, CYP3A4, and CYP2C8 isoenzymes. Its metabolism results in several inactive metabolites excreted renally. The pathways mainly include oxidation and conjugation reactions producing hydroxylated and conjugated derivatives. Hepatic function significantly influences terbinafine metabolism, and caution is warranted in patients with liver impairment. Elimination: The elimination half-life of terbinafine is biphasic; the initial phase is approximately 36 hours, whereas the terminal elimination phase extends up to 200 to 400 hours due to slow release from keratinized tissues. Approximately 70% of the administered dose is excreted in urine primarily as metabolites, while about 20% is eliminated via feces. The prolonged terminal phase supports once-daily dosing and accounts for persistent therapeutic levels in nail and skin tissues even after cessation of therapy.

Dosage Forms

Available Dosage Forms: Terbinafine is available as oral tablets and oral granules. The oral tablet form is specifically available as 250 mg tablets. The oral granules are intended for pediatric use and should be administered by sprinkling onto a spoonful of pudding or mashed potatoes, without mixing with applesauce, fruit juice, or other acidic foods, as that may affect stability. Dosages for Adults and Adolescents: The standard adult dose for onychomycosis (fungal nail infection) is 250 mg orally once daily for 6 weeks for fingernail infections and 12 weeks for toenail infections. For tinea capitis (scalp fungal infection) in children aged 4 years and older, terbinafine oral granules are used, with dosing adjusted based on weight and clinical judgment. Specific Patient Populations: In patients with hepatic impairment, terbinafine use requires caution due to metabolism predominantly occurring in the liver. No specific dosage forms or strengths are formulated for renal impairment, but dose adjustment may be needed in severe renal dysfunction. Terbinafine should not be used in patients with known liver disease. Pediatric formulations are available as oral granules for children 4 years and older for scalp infections. Pregnant or breastfeeding women should avoid terbinafine due to potential risk and lack of safety data. Hence, initiation of therapy during pregnancy is usually postponed until after delivery.

Mechanism Of Action

Terbinafine exerts its antifungal effects by inhibiting the enzyme squalene epoxidase, a critical catalyst in the fungal ergosterol biosynthesis pathway. Ergosterol is an essential component of fungal cell membranes, analogous to cholesterol in mammalian cells. By blocking squalene epoxidase, terbinafine prevents the conversion of squalene to lanosterol, leading to an accumulation of squalene within the fungal cell, which is toxic, and depletion of ergosterol, resulting in increased membrane permeability and impaired cell membrane function. This dual effect contributes to a fungicidal rather than merely fungistatic activity.

At the cellular level, the disruption of ergosterol synthesis compromises structural integrity and functionality of the fungal cell membrane, leading to leakage of intracellular contents and cell death. Terbinafine demonstrates selective toxicity due to higher affinity for the fungal squalene epoxidase compared to the mammalian enzyme, minimizing host toxicity at therapeutic doses.

Clinically, this mechanism underlies terbinafine’s efficacy against dermatophytes such as Trichophyton spp., Microsporum spp., and Epidermophyton spp., which cause onychomycosis, tinea capitis, and other cutaneous fungal infections. It is effective in both superficial and some invasive fungal infections where dermatophytes predominate.

Comparatively, terbinafine differs from azole antifungals, which inhibit lanosterol 14α-demethylase at a later step in ergosterol synthesis; terbinafine’s upstream inhibition results in rapid fungicidal activity. Research has demonstrated superior nail penetration and retention times for terbinafine compared to azoles, correlating with improved clinical outcomes in nail fungal infections. Numerous clinical studies confirm terbinafine’s efficacy and safety profile, establishing it as a first-line oral antifungal for onychomycosis.

Pharmacological Actions

Fungicidal activity against dermatophytes by inhibition of squalene epoxidase enzyme.
Disruption of fungal cell membrane synthesis leading to increased permeability and cell death.
Selective inhibition of fungal ergosterol biosynthesis resulting in accumulation of toxic squalene.
Effective penetration and retention in keratinized tissues such as skin, hair, and nails.
Treatment of fungal infections of the fingernails, toenails, and scalp.
Minimal mammalian toxicity due to selective enzyme inhibition.
Prolonged antifungal activity due to retention in nail and skin tissues after therapy cessation.
Metabolized by hepatic CYP450 enzymes with minimal direct drug-induced enzymatic inhibition.
Displays anti-dermatophytic and some activity against certain yeasts and molds.
Modulation of fungal cell growth and replication via biochemical pathway disruption.
Promotes clinical improvement in fungal infections by reducing fungal burden effectively.
Oral administration allows systemic treatment of deep and resistant fungal infections.
Useful in pediatric populations for scalp fungal infections via granule formulation.
Supports once-daily dosing regimen simplifying treatment adherence.
Demonstrated synergy with topical antifungals in combined therapy protocols.

Therapeutic Or Clinical Uses

Treatment of onychomycosis (fungal infections of toenails and fingernails) caused by dermatophytes.
Management of tinea capitis (fungal infection of scalp hair follicles) in pediatric patients 4 years and older.
Used in cutaneous dermatophytosis where oral therapy is indicated.
Treatment of fungal infections affecting keratinized tissues resistant to topical therapy.
Alternative therapy for chronic or recurrent fungal nail infections.
Effective in reducing fungal burden to improve nail appearance over months.
Adjunct in combined antifungal regimens in extensive or refractory cutaneous mycoses.
Off-label use in certain non-dermatophyte fungal infections as guided by susceptibility.
Prevention of recurrence in patients with recurrent onychomycosis.
Clinical use guided by mycological confirmation and susceptibility testing.
Reserved for infections where topical therapies are inadequate or impractical.
Pediatric use limited to tinea capitis due to formulation and safety considerations.
Used under specialist supervision for systemic fungal infections affecting skin/nails.
Management of severe or extensive athlete’s foot (tinea pedis) unresponsive to topical agents.
Treatment duration varies by infection site, typically 6 weeks for fingernails, 12 weeks for toenails.

Side Or Adverse Effects

Gastrointestinal disturbances including diarrhea, nausea, abdominal pain, and flatulence.
Cutaneous reactions such as rash, pruritus, and skin eruptions.
Headache and dizziness reported variably among patients.
Elevations in liver function tests indicating potential hepatocellular injury.
Rare but severe hepatotoxicity including liver failure necessitating transplantation or resulting in death.
Hypersensitivity reactions including urticaria, angioedema, and in rare cases anaphylaxis.
Possible taste and smell disturbances leading to loss or alteration of taste (dysgeusia).
Neuropsychiatric symptoms including depression, anxiety, insomnia, and irritability.
Hematologic abnormalities such as neutropenia, leukopenia, or thrombocytopenia.
Photosensitivity reactions causing increased risk of sunburn; specific skin rashes worsening in sunlight (e.g., butterfly rash).
Weight loss due to anorexia or altered taste perception.
Fatigue and malaise as nonspecific systemic symptoms.
Rare reports of blood in urine or stools indicating possible bleeding.
Swelling and rapid weight gain suggestive of fluid retention in severe cases.
Skin sores or worsening dermatologic conditions possibly linked to autoimmune reactions.

Precautions

Perform baseline and periodic liver function tests due to risk of hepatotoxicity.
Avoid use in patients with pre-existing liver disease.
Use cautiously in individuals with a history of lupus or autoimmune disorders.
Inform patients about the possibility of taste or smell disturbances and to report such symptoms.
Avoid concomitant use with other hepatotoxic drugs if possible.
Counsel patients to avoid excessive sun exposure and use sun protection measures.
Monitor for signs of hypersensitivity or severe skin reactions during treatment.
Use with caution in immunocompromised patients due to increased infection risks.
Not recommended during pregnancy; defer treatment until after delivery.
Contraindicated in breastfeeding due to potential neonatal exposure.
Monitor for neuropsychiatric symptoms and consider psychiatric evaluation if indicated.
Advise patients to complete entire prescribed course to prevent resistance and relapse.
Consider drug interactions with CYP450-metabolized medications that could alter terbinafine levels.
Dose adjustments or discontinuation should be considered in renal or hepatic impairment.
Be vigilant for signs of bleeding or unusual bruising as possible hematologic side effects.

Warnings

Severe liver damage, including cases requiring liver transplant or resulting in death, has been reported with terbinafine use.
Patients should be advised to discontinue therapy and seek immediate medical attention if symptoms of liver injury appear (e.g., nausea, upper abdominal pain, fatigue, jaundice).
Risk of serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, though rare.
Potential for severe allergic reactions necessitating emergency treatment.
Terbinafine can increase photosensitivity leading to increased risk of sunburn; protective measures must be taken.
Pregnancy use is not recommended due to unknown risk; therapy should be postponed until after pregnancy.
Risk of hematologic abnormalities warrants regular monitoring of blood counts in long-term use.
Caution in patients with lupus erythematosus since terbinafine may worsen disease activity.
Risk of taste disturbances which may be irreversible in some cases.
Avoid concurrent use of terbinafine with other hepatotoxic or CYP450-interacting drugs unless benefits outweigh risks.
Use in patients with immunosuppression requires close clinical supervision.
Discontinue if serious adverse effects or hypersensitivity reactions develop.
Not for use in patients allergic to terbinafine or related compounds.
Monitor for signs of serious drug reactions with systemic involvement (fever, rash, swollen lymph nodes).
Advise patients not to exceed recommended doses and to report any unexpected side effects promptly.

Contraindication

Known hypersensitivity or allergy to terbinafine or any component of the formulation.
Active or chronic liver disease or significant hepatic impairment.
Use during pregnancy due to potential risk to the fetus.
Breastfeeding women, as terbinafine is excreted in breast milk and may harm the nursing infant.
Concurrent use of other hepatotoxic drugs without close monitoring may be contraindicated.
Patients with history of severe cutaneous adverse reactions to terbinafine.
Severe renal impairment may contraindicate treatment due to altered elimination.
Caution or contraindication in patients with autoimmune diseases exacerbated by terbinafine.
Contraindicated in those with documented severe neurological or psychiatric disturbances triggered by terbinafine.
Avoid in patients with pre-existing blood dyscrasias or hematologic disorders without specialist consultation.
Children under 4 years of age (oral granule formulation indicated only from 4 years).
Not for treatment of non-dermatophyte fungal infections unless under specialist guidance.
Use cautiously or avoid in patients with immunodeficiency without risk/benefit assessment.
Contraindicated when combining with drugs causing QT prolongation without monitoring.
Not for prophylactic use in absence of confirmed fungal infection.

Drug Interactions

May interact with drugs metabolized by hepatic CYP450 enzymes, notably CYP2D6, leading to altered plasma levels.
Potential increased plasma concentrations of drugs metabolized by CYP2D6 such as selective serotonin reuptake inhibitors, beta-blockers, and tricyclic antidepressants.
Co-administration with other hepatotoxic drugs (e.g., methotrexate, isoniazid) may increase risk of liver injury.
Interaction with cimetidine can decrease terbinafine clearance, increasing risk of toxicity.
Rifampin reduces terbinafine plasma concentrations via enzyme induction, potentially decreasing efficacy.
Concomitant use with drugs that prolong QT interval requires caution due to additive cardiac risks.
Possible additive effects with other antifungal agents; combination therapies should be monitored carefully.
Interacts with warfarin and other anticoagulants potentially altering bleeding risk; close monitoring required.
Interactions with oral contraceptives may reduce hormonal contraceptive efficacy; backup contraception recommended.
Use caution with immunosuppressants due to potential overlapping toxicity profiles.
Hospitalized patients on multidrug regimens should be monitored closely for potential interactions.
Limited interaction with P-glycoprotein substrates but caution advised with narrow therapeutic index drugs.
Avoid grapefruit juice which may affect CYP3A4-mediated metabolism of terbinafine.
Reports of altered caffeine metabolism increasing sensitivity to caffeine’s side effects.
Monitoring therapeutic drug levels and clinical response is important when terbinafine is added to complex regimens.

Preparations Of The Drug

Terbinafine oral tablet: 250 mg film-coated tablets for systemic antifungal therapy.
Terbinafine oral granules: formulations intended for pediatric dosing in tinea capitis, administered by sprinkling on food.
Topical terbinafine formulations (not detailed here) available for cutaneous fungal infections.
Brand preparations include Lamisil (tablet and topical forms) and Terbinex (tablet).
Oral tablets distributed in blister packs or bottles with child-resistant caps.
Granule packets sealed individually to maintain stability until use.
Formulations comply with pharmacopeial standards for purity, dosage, and quality.
Storage recommendations advise keeping at room temperature, away from moisture, heat, and direct light.
Excipients chosen to enhance tablet durability and bioavailability.
Oral granules formulated for palatability with recommended administration instructions to prevent degradation.
Packaging includes detailed patient information leaflets on proper use and handling.
Manufactured under Good Manufacturing Practice (GMP) certified facilities.
Available as prescription-only medications due to systemic and safety considerations.
Various generics available after patent expiration offer equivalent effectiveness.
Specialty compounding is rarely required given availability of commercial formulations.