Terbinafine (DB00857): A Comprehensive Pharmacological and Clinical Monograph

1.0 Executive Summary

Terbinafine is a synthetic allylamine antifungal agent that represents a significant therapeutic advance in the management of superficial dermatophyte infections. As a small molecule drug, it is distinguished by its primarily fungicidal mechanism of action, which contrasts with the fungistatic properties of many older antifungal classes. The primary therapeutic target of Terbinafine is the fungal enzyme squalene epoxidase, a critical component of the ergosterol biosynthesis pathway. Inhibition of this enzyme leads to a dual-pronged assault on the fungal cell: depletion of the essential membrane component ergosterol and the toxic intracellular accumulation of squalene, resulting in cell death. This mechanism is highly selective for the fungal enzyme, affording the drug a wide therapeutic index with respect to human cholesterol synthesis.

Pharmacokinetically, Terbinafine is characterized by its high lipophilicity and keratophilicity. Following oral administration, it is well-absorbed but undergoes significant first-pass metabolism, resulting in approximately 40% bioavailability. Its defining feature is its extensive distribution and accumulation in deep tissue compartments, including the skin, adipose tissue, and, most critically, the nail plate. This sequestration leads to a complex, multiphasic elimination profile with a long terminal half-life of 200-400 hours. This property creates a persistent drug reservoir in target tissues, allowing for high cure rates and low relapse rates in onychomycosis, even after therapy is discontinued.

Clinically, oral Terbinafine is a first-line treatment for dermatophyte onychomycosis and tinea capitis, demonstrating superior efficacy compared to agents such as griseofulvin and itraconazole in numerous trials. It is available as oral tablets and granules, as well as various topical formulations for cutaneous infections. While generally well-tolerated, with common adverse effects being mild gastrointestinal upset and headache, its use is associated with several important safety considerations. The most significant of these is a rare but potentially severe idiosyncratic hepatotoxicity, which can lead to acute liver failure. Consequently, the drug is contraindicated in patients with active or chronic liver disease, and baseline liver function testing is recommended for all patients. Other notable adverse effects include sensory disturbances, such as loss of taste and smell, which can be prolonged or permanent, and rare but serious hematologic and dermatologic reactions like Stevens-Johnson syndrome.

A critical aspect of Terbinafine's clinical profile is its potent inhibition of the cytochrome P450 2D6 (CYP2D6) isoenzyme. This creates a high potential for clinically significant drug-drug interactions, necessitating a thorough review of concomitant medications. Of particular concern is its ability to reduce the efficacy of drugs requiring CYP2D6 for activation, such as the analgesic codeine and the breast cancer therapeutic tamoxifen. Therefore, the risk-benefit assessment for Terbinafine requires judicious patient selection, comprehensive pre-treatment screening, and robust patient education on potential risks and warning signs.

2.0 Introduction: Profile of an Allylamine Antifungal

Historical Context and Development

Terbinafine (DrugBank ID: DB00857) is a synthetic, second-generation antifungal agent belonging to the allylamine class of compounds.[1] The allylamines represent a unique chemical and pharmacological class, distinct from the more prevalent azole antifungals (e.g., ketoconazole, fluconazole) and older agents like griseofulvin.[2] The development of this class marked a significant evolution in antifungal therapy, moving toward agents with more specific molecular targets and primarily fungicidal, rather than fungistatic, activity.[2]

Discovered in 1991, Terbinafine was first introduced for clinical use in Europe that same year.[4] The drug was developed and originally marketed by Novartis under the brand name Lamisil.[1] Its emergence in the early 1990s was part of a broader shift in drug discovery toward mechanism-based, rational design. Unlike older antifungals with less specific modes of action, Terbinafine was developed to selectively inhibit a key enzyme in the fungal sterol biosynthesis pathway, squalene epoxidase.[1] This targeted approach not only conferred high potency but also a favorable selectivity profile, as the mammalian counterpart of the enzyme is significantly less sensitive to the drug's effects.[6] This specificity and potent fungicidal action translated into superior clinical outcomes, particularly compared to the fungistatic agent griseofulvin, allowing for shorter treatment durations and lower rates of relapse in dermatophyte infections.[2]

Regulatory Milestones

Following its European debut, Terbinafine charted a course for global use, gaining approval in the United States in 1996.[4] The U.S. Food and Drug Administration (FDA) granted initial approval for the 250 mg oral tablet formulation on May 10, 1996.[8] The therapeutic armamentarium was later expanded with the approval of oral granules (125 mg and 187.5 mg) on September 28, 2007, specifically for the treatment of tinea capitis in children aged four and older.[4]

A pivotal moment in the drug's lifecycle occurred on June 30, 2007, with the expiration of its primary patent protection.[4] This event paved the way for the approval of generic versions of Terbinafine hydrochloride tablets. Mylan Pharmaceuticals received final FDA approval for its Abbreviated New Drug Application (ANDA) for the 250 mg tablet on July 2, 2007, at which time the brand-name product had annual U.S. sales of approximately $685 million.[9] The introduction of generic formulations dramatically reduced the cost of therapy, from over $500 for a 12-week course in 1999 to as low as $10 by 2015, thereby increasing its accessibility for a broader patient population.[4]

Therapeutic Significance

The clinical importance of Terbinafine is underscored by its inclusion on the World Health Organization's List of Essential Medicines, which identifies medications considered to be most effective and safe to meet the most important needs in a health system.[4] Its widespread clinical use is reflected in prescription statistics; in 2022, it was the 255th most commonly prescribed medication in the United States, with over one million prescriptions filled.[4]

Terbinafine's primary therapeutic advantage is its potent, fungicidal activity against dermatophytes, the causative organisms of most superficial fungal infections of the skin, hair, and nails.[2] This is a key differentiator from fungistatic agents, which only inhibit fungal growth and rely on the host's immune system and natural turnover of infected tissue to achieve a cure. By actively killing fungal cells, Terbinafine allows for shorter courses of therapy and achieves higher cure rates with less frequent relapse, particularly in the treatment of onychomycosis.[2] Its high lipophilicity and tendency to accumulate in keratinized tissues further enhance its efficacy in these difficult-to-treat infections.[1]

3.0 Physicochemical Characteristics and Formulations

Chemical Identification

Terbinafine is classified as a small molecule drug.[1] Chemically, it is a tertiary amine and a member of the naphthalenes, characterized by a naphthalene ring system fused to an allylamine side chain.[10] Its formal IUPAC (International Union of Pure and Applied Chemistry) name is (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine.[1] The molecular formula is

C21​H25​N, corresponding to a molecular weight of approximately 291.43 g/mol.[2] For clinical and commercial use, it is typically formulated as a hydrochloride salt, Terbinafine HCl (CAS Number: 78628-80-5), which has a molecular formula of

C21​H26​ClN and a molecular weight of approximately 327.90 g/mol.[11] The free base form is identified by the CAS Number 91161-71-6.[1]

Table 3.1: Key Identifiers and Physicochemical Properties of Terbinafine

Property/Identifier	Value	Source(s)
DrugBank ID	DB00857	1
Type	Small Molecule	1
CAS Number (Free Base)	91161-71-6	1
CAS Number (HCl Salt)	78628-80-5	11
IUPAC Name	(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine	1
Molecular Formula	C21​H25​N	14
Molecular Weight	291.43 g/mol	10
Physical Description	White to off-white crystalline powder	4
Melting Point	~205 °C	1
Boiling Point	417.9 °C	1
Water Solubility (HCl Salt)	Slightly soluble; 0.63%	4
pKa (Basic)	~7.10	10
LogP	5.9 (experimental); 5.51 (predicted)	10

Physical Properties

As a hydrochloride salt, Terbinafine is a white or off-white crystalline powder.[4] Its solubility profile is dictated by its predominantly nonpolar structure. It is freely soluble in organic solvents such as methanol and dichloromethane, soluble in ethanol, but only slightly soluble in water.[4] This poor aqueous solubility is a key consideration for its formulation and pharmacokinetic behavior. The experimental melting point of the hydrochloride salt is approximately 205 °C, and its basic pKa is around 7.1, indicating it is a weak base that will be partially ionized at physiological pH.[2]

Structural Features and Lipophilicity

The molecular structure of Terbinafine is fundamental to its pharmacological activity and disposition in the body. It consists of two primary functional regions: a bulky, planar naphthalene ring system and a flexible (E)-allylamine side chain containing an enyne moiety and a terminal tert-butyl group.[1] This combination of a large aromatic system and a long hydrocarbon chain confers a highly lipophilic (fat-loving) and keratophilic (keratin-loving) character upon the molecule.[1]

This high lipophilicity is quantitatively described by its octanol-water partition coefficient (LogP), which has an experimentally determined value of approximately 5.9.[10] A LogP value of this magnitude indicates a strong preference for lipid environments over aqueous ones. This physicochemical property is the primary driver of its pharmacokinetic profile, governing its tendency to accumulate in lipid-rich tissues such as the stratum corneum, sebum, adipose tissue, and the nail plate.[1]

Available Formulations

Terbinafine is available in a variety of formulations designed for both systemic and topical administration, allowing for tailored treatment based on the site and severity of the fungal infection.[4]

• Systemic Formulations:
• Oral Tablets: The most common formulation for systemic therapy, typically available as 250 mg tablets of Terbinafine hydrochloride.[19] These are used for treating onychomycosis and severe or extensive cutaneous fungal infections.[4]
• Oral Granules: To facilitate administration in pediatric populations, Terbinafine is available in single-dose packets of oral granules, in strengths of 125 mg and 187.5 mg.[8] These are specifically approved for the treatment of tinea capitis (scalp ringworm) in children and are designed to be sprinkled on non-acidic foods.[22]
• Topical Formulations:
• Creams, Gels, and Sprays: For localized cutaneous infections, 1% Terbinafine hydrochloride is available as a cream, gel, or spray.[4] These are commonly sold over-the-counter under brand names such as Lamisil AT and are used for conditions like tinea pedis, tinea cruris, and tinea corporis.[23]
• Single-Use Solution: A unique topical formulation is a single-application film-forming solution (e.g., Lamisil Once) designed for the treatment of tinea pedis.[18] After application to the feet, the solvent evaporates, leaving a concentrated film of Terbinafine that provides a sustained release of the drug into the stratum corneum.[18]

4.0 Comprehensive Pharmacological Profile

4.1 Mechanism of Action and Pharmacodynamics

The antifungal efficacy of Terbinafine stems from its highly specific and potent interaction with a key enzyme in the fungal cell membrane synthesis pathway. Its mechanism is distinct from that of the azole antifungals, which act further downstream in the same pathway by inhibiting lanosterol 14-alpha-demethylase.

Primary Target: Squalene Epoxidase

Terbinafine exerts its antifungal effect through the non-competitive inhibition of the enzyme squalene epoxidase, also known as squalene monooxygenase (EC 1.14.13.132).[1] This enzyme is a crucial component of the fungal sterol biosynthesis pathway, responsible for catalyzing one of its earliest steps: the epoxidation of squalene to form 2,3-oxydosqualene (also called squalene epoxide).[1] This product serves as the precursor for lanosterol, which is subsequently converted through a series of enzymatic steps into ergosterol.[4] Ergosterol is the principal sterol in the fungal cell membrane, where it plays a role analogous to that of cholesterol in mammalian cells, regulating membrane fluidity, integrity, and the function of membrane-bound proteins.[1]

Dual Fungicidal Effect

The inhibition of squalene epoxidase by Terbinafine results in a dual-pronged, primarily fungicidal assault on the fungal cell.[2]

1. Ergosterol Deficiency: The blockade of 2,3-oxydosqualene formation leads to a downstream deficiency in ergosterol synthesis.[1] The resulting ergosterol-depleted cell membrane becomes structurally dysfunctional, with altered fluidity and permeability.[6] This disruption of membrane integrity contributes a fungistatic component to the drug's action, impairing fungal growth and replication.[2]
2. Squalene Accumulation: The primary fungicidal effect is attributed to the toxic intracellular accumulation of the enzyme's substrate, squalene.[1] As the pathway is blocked, squalene builds up to high concentrations within the fungal cytoplasm, often sequestered in lipid vesicles.[1] Squalene is a highly lipophilic and insoluble substance, and its excessive accumulation is cytotoxic.[6] This is thought to fatally disrupt the fungal cell membrane's structure and function and may leach other essential lipids away from the membrane, further weakening it and ultimately leading to cell lysis and death.[1]

Selectivity and Safety Margin

A critical pharmacodynamic feature of Terbinafine is its high degree of selectivity for the fungal enzyme over its mammalian homologue. In humans, squalene epoxidase is part of the cholesterol biosynthesis pathway.[4] However, due to evolutionary divergence between fungi and animals, there are sufficient structural differences in the enzyme to allow for preferential binding of Terbinafine to the fungal target.[4] The mammalian squalene epoxidase is reported to be at least 1,000 to 10,000 times less sensitive to inhibition by Terbinafine.[6] This substantial difference in affinity is the pharmacological basis for the drug's wide therapeutic index. It allows Terbinafine to be administered at concentrations that are lethal to fungi without significantly affecting human cholesterol synthesis, contributing to its overall safety profile.[4]

4.2 Pharmacokinetics: A Profile of Tissue Accumulation and Persistence

The clinical utility and safety profile of Terbinafine are intrinsically linked to its unique pharmacokinetic properties, which are dominated by its high lipophilicity and extensive tissue distribution.

Absorption and Bioavailability

Following oral administration, Terbinafine is well-absorbed from the gastrointestinal tract, with over 70% of the dose being absorbed.[1] However, it undergoes substantial first-pass metabolism in the liver, a process where a significant fraction of the absorbed drug is metabolized before it reaches systemic circulation. This reduces its absolute systemic bioavailability to approximately 40%.[1] Peak plasma concentrations (

Cmax​) of about 1 µg/mL are typically reached within 2 hours of a standard 250 mg dose.[1] The absorption and bioavailability of Terbinafine are not significantly affected by the presence of food, allowing it to be taken with or without meals.[18]

Distribution: The Role of Lipophilicity

Once in the systemic circulation, Terbinafine's disposition is governed by its physicochemical properties. It is highly bound to plasma proteins (>99%), primarily to serum albumin, as well as to high- and low-density lipoproteins.[1] Its most defining pharmacokinetic characteristic, however, is its extensive distribution into tissues, driven by its highly lipophilic and keratophilic nature.[1]

The drug rapidly leaves the plasma compartment and accumulates in deep tissue compartments, particularly those rich in lipids and keratin. These include the dermis, epidermis, adipose tissue, sebum, hair follicles, and, most importantly for its primary indication, the nail plate and nail bed.[1] Physiologically based pharmacokinetic (PB-PK) modeling has quantified this distribution, demonstrating that adipose tissue and skin account for the vast majority of the drug's total apparent volume of distribution (

Vss​), at approximately 52% and 41%, respectively.[17] This extensive tissue sequestration results in a very large apparent volume of distribution, reported to be in the range of 780 to 2,000 liters in humans, indicating that the majority of the drug in the body resides outside of the plasma.[17]

Metabolism

Terbinafine is extensively biotransformed in the liver into inactive metabolites, meaning the parent drug is the sole active moiety.[17] This metabolism is complex and involves multiple cytochrome P450 (CYP) isoenzymes. The primary metabolic pathways include N-demethylation and oxidation of the side chain.[17] A multitude of CYP enzymes contribute to its clearance, including CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19.[1] The involvement of several parallel metabolic pathways may contribute to a lower susceptibility to clinically significant drug interactions when Terbinafine is the object drug (i.e., the drug being acted upon).[28]

Elimination and Complex Half-Life

The elimination of Terbinafine metabolites occurs primarily via the kidneys, with approximately 80% of an administered dose excreted in the urine.[1] The remaining 20% is eliminated in the feces.[1] Importantly, no unmetabolized parent drug is found in the urine, underscoring the completeness of its hepatic metabolism.[1]

The elimination profile of Terbinafine from the plasma is multiphasic and cannot be described by a single half-life. This complexity is a direct consequence of its extensive tissue distribution. An effective half-life of approximately 36 hours is often cited, which describes the initial, relatively rapid decline in plasma concentrations as the drug is distributed into tissues and undergoes metabolism.[1] However, this is followed by a much slower, prolonged elimination phase. This phase is characterized by a very long

terminal elimination half-life, ranging from 200 to 400 hours.[1]

This dual half-life phenomenon is central to understanding both the efficacy and the potential for prolonged adverse effects of Terbinafine. The initial distribution phase rapidly removes the drug from the plasma and delivers it to deep tissue compartments. The slow terminal elimination phase is not governed by the rate of metabolism or excretion, but rather by the slow, rate-limiting process of the drug redistributing from these deep tissue reservoirs (like adipose tissue and the nail plate) back into the systemic circulation to be cleared. This creates a double-edged sword. On one hand, this slow release from tissues like the nail plate maintains therapeutic, fungicidal concentrations for weeks to months even after the cessation of therapy, which is crucial for the high cure rates seen in onychomycosis.[4] On the other hand, this same persistence means that if a patient experiences an adverse drug reaction, such as taste disturbance or a severe skin reaction, the offending agent is cleared from the body very slowly. This can lead to a prolonged duration of the adverse effect, with some sensory disturbances having been reported as permanent.[4]

5.0 Clinical Efficacy and Therapeutic Applications

5.1 Approved Indications and Spectrum of Antimycotic Activity

Terbinafine is a cornerstone in the treatment of superficial fungal infections caused by dermatophytes, with specific approvals for both systemic and topical use.

FDA-Approved Uses

The U.S. Food and Drug Administration (FDA) has approved oral Terbinafine for two primary indications [21]:

1. Onychomycosis: Treatment of fungal infections of the toenail or fingernail (tinea unguium) confirmed to be caused by dermatophyte organisms.[19] Oral Terbinafine is considered the most effective therapy for the mycological cure of toenail dermatophyte infections.[21]
2. Tinea Capitis: Treatment of scalp ringworm in pediatric patients aged four years and older.[19]

Topical formulations of Terbinafine are FDA-approved for the treatment of common cutaneous mycoses, including [4]:

• Tinea pedis (athlete's foot)
• Tinea cruris (jock itch)
• Tinea corporis (ringworm of the body)

Spectrum of Activity

Terbinafine's spectrum of activity is primarily focused on dermatophytes, where it exhibits potent fungicidal action.[2] The key susceptible organisms include [1]:

• Trichophyton species: such as T. rubrum, T. mentagrophytes, T. verrucosum, and T. tonsurans. T. rubrum is the most common cause of dermatophytosis worldwide.[30]
• Microsporum species: such as M. canis.
• Epidermophyton floccosum.

While Terbinafine is often the treatment of choice for tinea capitis caused by Trichophyton spp. (the most common cause in North America), griseofulvin has demonstrated greater efficacy against infections caused by Microsporum spp..[21]

Terbinafine also has activity against certain yeasts, though its effect can be variable. It is used to treat skin infections caused by Candida species (e.g., C. albicans) and Malassezia furfur (the causative agent of pityriasis versicolor, also known as tinea versicolor).[1] Against yeasts, its activity may be fungicidal or fungistatic, depending on the specific species.[12]

5.2 Off-Label and Investigational Uses

Given its high efficacy against dermatophytes, oral Terbinafine is frequently used in clinical practice for indications beyond its formal FDA approval.

Common Off-Label Uses

Oral Terbinafine is widely considered a first-line option for extensive, chronic, or recalcitrant cutaneous dermatophyte infections that are unlikely to respond to or have failed topical therapy. These common off-label uses include [20]:

• Tinea corporis and Tinea cruris: When lesions are widespread or severe.
• Tinea pedis: Particularly for the chronic hyperkeratotic (moccasin-type) presentation, which is notoriously difficult to treat with topical agents alone.
• Tinea manuum: Fungal infection of the hands.
• Tinea faciei and Tinea barbae: Infections of the face and beard area.

Other Infections

The use of oral Terbinafine has also been reported for less common fungal infections, including [11]:

• Majocchi's granuloma: A deep, follicular dermatophyte infection.
• Sporotrichosis: Both cutaneous and lymphocutaneous forms of this infection, caused by the dimorphic fungus Sporothrix schenckii.

5.3 Dosing Regimens and Administration Guidelines

The dosing and duration of Terbinafine therapy are highly dependent on the indication, the formulation used, and the patient population. It is critical that the full course of treatment is completed to prevent relapse, as fungal infections can be very slow to clear.[19]

Table 5.1: Recommended Dosing Regimens for Terbinafine by Indication and Patient Population

Indication	Patient Population	Formulation	Dose	Frequency	Duration	Source(s)
Toenail Onychomycosis	Adults	Tablet	250 mg	Once daily	12 weeks	19
Fingernail Onychomycosis	Adults	Tablet	250 mg	Once daily	6 weeks	19
Tinea Capitis (Scalp Ringworm)	Children ≥4 years, >35 kg	Tablet/Granules	250 mg	Once daily	6 weeks	19
	Children ≥4 years, 25-35 kg	Granules	187.5 mg	Once daily	6 weeks	19
	Children ≥4 years, <25 kg	Granules	125 mg	Once daily	6 weeks	19
Tinea Pedis (Athlete's Foot)	Adults & Teenagers (Oral, Off-label)	Tablet	250 mg	Once daily	2 to 6 weeks	18
	Adults & Teenagers (Topical)	Cream/Gel/Spray	Apply to affected area	1-2 times/day	1 to 2 weeks	18
Tinea Corporis/Tinea Cruris	Adults & Teenagers (Oral, Off-label)	Tablet	250 mg	Once daily	2 to 4 weeks	18
	Adults & Teenagers (Topical)	Cream/Gel/Spray	Apply to affected area	1-2 times/day	1 to 2 weeks	18
Pulse Dosing (Onychomycosis, Off-label)	Adults	Tablet	500 mg (250 mg twice daily)	Once daily	1 week per month for 4 months	32

Administration Guidelines

• Oral Tablets: Tablets should be swallowed whole with water and can be taken with or without food.[18]
• Oral Granules: The contents of a packet should be sprinkled onto a spoonful of soft, non-acidic food such as pudding or mashed potatoes and swallowed entirely without chewing. Administration with fruit-based or acidic foods should be avoided.[22]
• Topical Preparations: The affected skin should be cleaned and dried thoroughly before applying a thin layer of cream, gel, or spray. For the single-use solution, it should be applied to both feet, covering all surfaces, and allowed to dry for 1-2 minutes before putting on footwear. The feet should not be washed for 24 hours after application.[18]

Pulse Dosing

An alternative, off-label dosing strategy for onychomycosis is "pulse" therapy. One such regimen involves administering a higher dose (500 mg/day) for one week, followed by three weeks off, with the cycle repeated for 3-4 months.[32] A retrospective analysis comparing this pulse regimen to the standard continuous 250 mg/day regimen found that the pulsed approach was at least as effective, and in some measures superior, for toenail onychomycosis. This offers potential advantages in terms of reduced total drug exposure, lower cost, and improved patient convenience.[32]

6.0 Safety, Tolerability, and Toxicology

While Terbinafine is an effective antifungal, its use, particularly systemically, requires careful consideration of its safety profile, which includes a range of adverse effects from common and mild to rare and life-threatening.

6.1 Profile of Adverse Drug Reactions

Common and Mild Effects

The majority of adverse events associated with oral Terbinafine are mild, transient, and self-limited.[4] The most frequently reported side effects include [4]:

• Headache: This is the most common adverse event, reported by approximately 1 in 8 patients in clinical trials.[4]
• Gastrointestinal Disturbances: These are also very common and include diarrhea, dyspepsia (indigestion), nausea, flatulence, and abdominal pain.[4]
• Dermatologic Reactions: Non-serious skin rashes and pruritus (itching) are frequently reported.[4]

Sensory Disturbances

A notable and clinically important category of side effects involves sensory perception.

• Taste Disturbance: Changes in taste (dysgeusia), a complete loss of taste (ageusia), or a distorted metallic taste are well-documented side effects.[4] These disturbances can be severe enough to cause decreased appetite, significant weight loss, and associated depressive symptoms.[21]
• Smell Disturbance: Similarly, a change or loss of the sense of smell (anosmia or hyposmia) has been reported.[22]

While these sensory changes often resolve within weeks to months after discontinuing the drug, there are rare reports of prolonged or even permanent loss.[4] Patients experiencing any change in taste or smell should be advised to contact their physician, and discontinuation of therapy is recommended.[22]

Other Effects

A variety of other adverse effects have been reported, including musculoskeletal pain (myalgia, arthralgia), visual disturbances (blurred vision, changes in the ocular lens), fatigue, and photosensitivity, which can increase the risk of sunburn.[4]

Table 6.1: Adverse Reactions Associated with Oral Terbinafine, Stratified by Incidence and System Organ Class

System Organ Class	Adverse Reaction	Incidence/Frequency	Source(s)
Nervous System	Headache	Very Common (>10%)	4
	Dizziness, Vertigo	Common (1-10%)	4
	Taste disturbance (dysgeusia, ageusia)	Common (1-10%)	4
	Smell disturbance (anosmia, hyposmia)	Postmarketing (Rare)	22
Gastrointestinal	Diarrhea, Nausea, Abdominal pain, Dyspepsia, Flatulence	Common (>2%)	4
	Vomiting	Common (1-10%)	33
	Pancreatitis	Postmarketing (Very Rare)	36
Hepatobiliary	Liver enzyme abnormalities (transient)	Common (>2%)	4
	Drug-Induced Liver Injury (DILI), Hepatitis, Cholestasis, Liver Failure	Rare (1:50,000-1:120,000)	4
Dermatologic	Rash, Urticaria, Pruritus	Common (>2%)	4
	Photosensitivity	Postmarketing (Rare)	19
	Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), DRESS Syndrome	Postmarketing (Very Rare)	4
Hematologic	Neutropenia, Agranulocytosis, Thrombocytopenia, Pancytopenia	Postmarketing (Very Rare)	4
Immune System	Precipitation/exacerbation of Lupus Erythematosus (Cutaneous or Systemic)	Postmarketing (Rare)	4
Psychiatric	Depression, Anxiety	Postmarketing (Rare)	4
Musculoskeletal	Arthralgia (joint pain), Myalgia (muscle pain)	Common (1-10%)	4

6.2 Hepatotoxicity: A Critical Safety Concern

The most serious risk associated with oral Terbinafine is idiosyncratic drug-induced liver injury (DILI).

Incidence and Onset

While mild, transient, and asymptomatic elevations in serum aminotransferases (ALT, AST) can occur in less than 1% of patients and often resolve without intervention, clinically apparent hepatotoxicity is a rare but well-documented event.[38] The estimated incidence is between 1 in 50,000 and 1 in 120,000 prescriptions.[38] The onset of liver injury typically occurs within the first 6 weeks of initiating therapy, with an average onset of around 30 days.[38]

Clinical Presentation and Patterns

The clinical presentation of Terbinafine-induced DILI can vary. The pattern of enzyme elevation can be hepatocellular (predominantly elevated ALT), cholestatic (predominantly elevated alkaline phosphatase), or mixed.[38] However, the injury often evolves into a cholestatic pattern, which can be prolonged.[38] Patients must be educated to immediately report any signs or symptoms suggestive of liver dysfunction, including persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice (yellowing of the skin or eyes), dark urine, or pale stools.[12]

Mechanism and Toxicology

Terbinafine hepatotoxicity is considered an idiosyncratic reaction, meaning it is unpredictable, not related to the dose, and occurs in susceptible individuals.[21] The underlying mechanism appears to be multifactorial, involving metabolic, genetic, and immunological components. The prevailing hypothesis for this toxicity involves the metabolic bioactivation of Terbinafine in the liver. One of its metabolites, a reactive aldehyde named 6,6-dimethyl-2-hepten-4-ynal (TBF-A), has been identified as a potential culprit.[28] This reactive metabolite can covalently bind to cellular proteins, forming neoantigens. In genetically susceptible individuals, these neoantigens may be presented by the immune system, triggering an inflammatory or autoimmune-like attack on the liver cells and bile ducts. This immunological basis is strongly supported by genome-wide association studies that have identified a significant link between Terbinafine-induced cholestatic hepatotoxicity and the presence of the human leukocyte antigen (HLA) allele HLA-A*33:01.[38] This genetic predisposition helps explain the rare and unpredictable nature of the reaction.

Severity and Outcomes

The severity of DILI can range from mild enzyme elevations to fulminant hepatic failure. Severe cases leading to liver transplantation or death have been reported, even in patients without pre-existing liver disease.[4] Prolonged cholestasis can, in some instances, progress to a chronic condition known as vanishing bile duct syndrome, characterized by the progressive destruction of intrahepatic bile ducts.[38] A severe outcome is more likely if the drug is continued after the onset of symptoms.[38]

Monitoring and Management

Due to the risk of hepatotoxicity, specific precautions are mandatory.

• Contraindication: Terbinafine is contraindicated in patients with chronic or active liver disease.[12]
• Screening: A pre-treatment assessment for underlying liver disease should be performed for all patients. The FDA recommends obtaining baseline serum transaminase (ALT and AST) tests before initiating therapy.[21]
• Monitoring: While periodic monitoring of liver function tests (e.g., after 4-6 weeks of treatment) is advised by some guidelines, evidence suggests that most cases of severe DILI are identified based on patient-reported symptoms rather than routine laboratory screening.[39] Therefore, robust patient education is paramount.
• Management: If clinical or biochemical evidence of liver injury develops, Terbinafine must be discontinued immediately.[12] Management is supportive, and in cases of acute liver failure, urgent referral to a specialist center for consideration of liver transplantation may be necessary.[21]

6.3 Rare but Severe Systemic Reactions

In addition to hepatotoxicity, Terbinafine is associated with other rare but potentially life-threatening systemic reactions.

Dermatologic Reactions

Severe cutaneous adverse reactions (SCARs) have been reported. These include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome.[4] These are medical emergencies characterized by widespread blistering, mucosal erosions, and systemic symptoms. The appearance of any progressive skin rash should prompt immediate discontinuation of the drug.[12]

Hematologic Effects

Severe hematologic disorders, although very rare, have been associated with Terbinafine use. These include severe neutropenia (a low count of neutrophils, a type of white blood cell), agranulocytosis (a near-complete absence of neutrophils), thrombocytopenia (low platelet count), and pancytopenia (a deficiency of all three blood cell types).[4] Patients who develop signs of infection (e.g., fever, sore throat) while on therapy should have a complete blood count performed. If the neutrophil count is found to be below 1,000 cells/mm³, Terbinafine should be discontinued.[22]

Lupus Erythematosus

There have been postmarketing reports of Terbinafine precipitating new cases of cutaneous and systemic lupus erythematosus (SLE) or exacerbating pre-existing disease.[4] The drug should be used with caution in patients with a history of lupus and should be stopped if clinical signs and symptoms suggestive of lupus (e.g., malar rash, joint pain, photosensitivity) develop.[19]

6.4 Contraindications, Warnings, and Overdose Management

Contraindications

The primary absolute contraindications for the use of oral Terbinafine are [12]:

• A history of allergic reaction or hypersensitivity to Terbinafine.
• Chronic or active liver disease.

It is also not recommended for use in patients with significant renal impairment (Creatinine Clearance, CrCl <50 mL/min) as its clearance may be reduced.[20]

Pregnancy and Lactation

Terbinafine is classified as FDA Pregnancy Category B. However, because onychomycosis is not a life-threatening condition and data on use in pregnancy are limited, its use is generally not recommended during pregnancy.[21] The drug is known to be excreted in breast milk; therefore, breastfeeding is not recommended during treatment.[10]

Overdose

Overdose with Terbinafine is rare, reflecting its wide therapeutic index.[1] A few cases involving doses up to 5 grams have been reported.[12] Symptoms are generally consistent with its known side effect profile and may include nausea, vomiting, epigastric or abdominal pain, dizziness, rash, frequent urination, and headache.[1] Management of an overdose is symptomatic and supportive. Administration of activated charcoal to limit further absorption may be considered.[1]

7.0 Clinically Significant Drug Interactions

The drug interaction profile of Terbinafine is a critical component of its safe clinical use. While it is metabolized by multiple CYP enzymes, its most significant impact on other drugs arises from its potent inhibitory effect on a single key enzyme, CYP2D6.

7.1 The Central Role of CYP2D6 Inhibition

Mechanism

Terbinafine is a potent inhibitor of the hepatic cytochrome P450 2D6 (CYP2D6) isoenzyme.[20] This enzyme is responsible for the metabolism of a large number of commonly prescribed drugs, accounting for up to 25% of all medications in clinical use. By inhibiting this enzyme, Terbinafine can significantly decrease the clearance of co-administered drugs that are CYP2D6 substrates, leading to increased plasma concentrations and a heightened risk of toxicity.

Clinical Consequences

The clinical implications of this interaction are broad and necessitate a proactive management strategy that goes beyond simple awareness. A clinician prescribing Terbinafine must actively screen a patient's medication list for CYP2D6 substrates and consider the potential consequences.

• Increased Toxicity of Co-administered Drugs: Terbinafine can elevate the levels of several classes of drugs, increasing the risk of their associated side effects. Dose reduction and/or closer monitoring may be required. Examples include:
• Tricyclic Antidepressants (TCAs): e.g., amitriptyline, nortriptyline, desipramine.[20]
• Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., paroxetine, fluoxetine.[21]
• Beta-blockers: Primarily those metabolized by CYP2D6, such as metoprolol and propranolol.[21]
• Class IC Antiarrhythmics: e.g., flecainide, propafenone.[24]
• Antipsychotics: e.g., risperidone, aripiprazole.[20]
• Loss of Efficacy of Co-administered Drugs (Prodrugs): For medications that are prodrugs requiring metabolic activation by CYP2D6, co-administration with Terbinafine can lead to therapeutic failure.
• Codeine: This opioid analgesic is metabolized by CYP2D6 to its active form, morphine. Terbinafine can block this conversion, rendering codeine ineffective for pain relief.[21] Patients may report inadequate analgesia, which could be mistakenly interpreted as drug-seeking behavior or disease progression if the interaction is not recognized.
• Tamoxifen: This interaction is of paramount importance. Tamoxifen is a selective estrogen receptor modulator used in the treatment and prevention of breast cancer. It requires activation by CYP2D6 to its most potent active metabolite, endoxifen. By inhibiting this step, Terbinafine can substantially reduce endoxifen levels, potentially compromising the efficacy of the anticancer therapy.[46] This interaction is so significant that the combination of Terbinafine and tamoxifen should be avoided whenever possible.[46] An alternative antifungal agent should be considered for patients on tamoxifen.

This necessitates a higher order of clinical reasoning from the prescriber, who must actively decide whether to adjust doses, switch to an alternative antifungal, or change the co-administered medication to avoid a potentially harmful interaction.

7.2 Other Pharmacokinetic and Pharmacodynamic Interactions

While CYP2D6 inhibition is the primary concern, other interactions can also occur.

Inhibitors of Terbinafine Metabolism

Drugs that inhibit the CYP enzymes responsible for Terbinafine's own metabolism can increase its plasma concentrations, potentially increasing the risk of toxicity. Examples include:

• Cimetidine: A non-specific CYP inhibitor.[21]
• Fluconazole: An inhibitor of CYP2C9 and CYP3A4.[21]

Inducers of Terbinafine Metabolism

Conversely, potent inducers of hepatic CYP enzymes can accelerate the metabolism of Terbinafine, leading to lower plasma concentrations and a potential reduction in its antifungal efficacy.

• Rifampin: A potent inducer of multiple CYP enzymes, including CYP3A4 and CYP2C9.[21]

Caffeine

Terbinafine can decrease the clearance of caffeine, which is metabolized by CYP1A2. While Terbinafine is not a potent inhibitor of this enzyme, the effect can be clinically noticeable. Patients should be advised that their sensitivity to caffeine (from coffee, tea, cola, etc.) may increase, potentially leading to nervousness, shakiness, or tachycardia.[19]

Table 7.1: Major Drug-Drug Interactions with Terbinafine: Mechanisms and Clinical Recommendations

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Tamoxifen	Terbinafine (potent CYP2D6 inhibitor) blocks metabolic activation to active endoxifen.	Reduced efficacy of tamoxifen; potential for breast cancer treatment failure.	Avoid combination. Consider alternative antifungal therapy.	46
Codeine	Terbinafine (potent CYP2D6 inhibitor) blocks metabolic activation to active morphine.	Loss of analgesic effect.	Avoid combination. Use an alternative analgesic not dependent on CYP2D6 activation.	21
Tricyclic Antidepressants, certain SSRIs, Beta-blockers, Class IC Antiarrhythmics	Terbinafine inhibits CYP2D6-mediated metabolism of these drugs.	Increased plasma concentrations and risk of toxicity (e.g., cardiotoxicity, CNS effects).	Monitor closely. Consider dose reduction of the CYP2D6 substrate or use alternative antifungal.	20
Rifampin	Rifampin (potent enzyme inducer) increases the metabolic clearance of Terbinafine.	Decreased plasma concentrations of Terbinafine; potential for therapeutic failure.	Monitor for reduced efficacy. Dose increase of Terbinafine may be needed.	21
Cimetidine, Fluconazole	These drugs (enzyme inhibitors) decrease the metabolic clearance of Terbinafine.	Increased plasma concentrations of Terbinafine; increased risk of adverse effects.	Use with caution. Monitor for signs of Terbinafine toxicity.	21
Caffeine	Terbinafine decreases the clearance of caffeine.	Increased effects of caffeine (e.g., nervousness, tachycardia).	Advise patient to limit caffeine intake.	19

8.0 Synthesis and Concluding Remarks

Terbinafine has firmly established its role as a first-line, highly effective fungicidal agent for the treatment of dermatophyte infections, particularly onychomycosis and tinea capitis. Its targeted mechanism of action, which confers high selectivity and potency, results in superior mycological and clinical cure rates and shorter treatment durations compared to many older and alternative therapies.[2] The drug's unique pharmacokinetic profile, characterized by extensive accumulation in keratinized tissues, is fundamental to this success, creating a persistent reservoir of antifungal activity that minimizes the risk of relapse.[4]

However, this therapeutic efficacy must be carefully balanced against a complex and significant safety profile. While the majority of patients tolerate Terbinafine well, with common side effects being mild and manageable, the potential for rare but severe adverse events necessitates a vigilant and informed approach to its prescription. The primary concern is idiosyncratic hepatotoxicity, an unpredictable reaction that can, in very rare instances, progress to acute liver failure.[21] This risk mandates strict adherence to its contraindication in patients with pre-existing liver disease and underscores the importance of pre-treatment liver function screening for all patients.

Furthermore, the potent inhibition of the CYP2D6 enzyme by Terbinafine represents a major source of clinically significant drug-drug interactions.[21] This property can lead to either toxicity or therapeutic failure of co-administered medications, requiring a proactive and knowledgeable management strategy from the prescribing clinician. The interaction with tamoxifen, in particular, highlights the need for a thorough medication review and consideration of therapeutic alternatives in certain patient populations.[46]

In conclusion, Terbinafine remains an invaluable tool in the dermatologic armamentarium. Its successful and safe use hinges on a comprehensive understanding of its pharmacological and toxicological properties. The following principles are recommended to optimize its risk-benefit profile:

1. Judicious Patient Selection: Therapy should be reserved for patients with confirmed dermatophyte infections who are most likely to benefit, avoiding its use in individuals with active or chronic liver disease, significant renal impairment, or those taking critical CYP2D6-metabolized drugs (like tamoxifen) for which safe alternatives are not available.
2. Thorough Pre-treatment Screening: A comprehensive patient history, a complete medication reconciliation to identify potential drug interactions, and baseline liver function tests (serum transaminases) should be performed before initiating oral Terbinafine.
3. Comprehensive Patient Education: Patients must be thoroughly counseled on the signs and symptoms of liver injury (jaundice, persistent nausea, dark urine), severe skin reactions (progressive rash, blistering), and hematologic disorders (signs of infection). Empowering patients to recognize and report these warning signs promptly is arguably the most effective strategy for mitigating the risk of severe outcomes.

Future research and development may continue to focus on novel topical formulations, such as those employing penetration enhancers or new delivery systems, with the goal of achieving the high efficacy of systemic therapy for onychomycosis while circumventing the risks associated with systemic exposure.[13] Until such alternatives are widely available, oral Terbinafine will remain a critical, albeit complex, therapeutic agent.

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