Terbinafine

Abstract

Terbinafine is an allylamine with fungicidal activity, first approved for the treatment of onychomycosis in the United Kingdom in the early 1990s, and in the US in 1996. Terbinafine is the most frequently prescribed oral antifungal agent in the US and Canada for onychomycosis. Its efficacy and safety in dermatophyte toenail onychomycosis in adults has been established in many studies. In fact, 18 randomized controlled trials have shown terbinafine to be highly effective, with a meta-average for mycological cure of 76% [+ or -] 3% (mean [+ or -] standard error). In large surveillance studies, terbinafine exhibited excellent safety profiles consistent with results obtained in pivotal studies. Additionally, terbinafine has been reported to be superior to both itraconazole and fluconazole in comparative studies in the treatment of dermatophyte toenail onychomycosis. Recent studies have reported terbinafine to be more cost effective than griseofulvin, fluconazole, or itraconazole. Terbinafine has also been used to treat onychomycosis effectively and safely in special patient populations, such as children, the elderly, immunocompromised patients, diabetics, and those with Down syndrome. Terbinafine should therefore be considered for the management of onychomycosis in adults based on its effectiveness, broad spectrum, fungicidal nature, established safety profile, and very low occurrence of drug interactions. Furthermore, the data support the use of terbinafine to treat dermatophyte onychomycosis in children and the elderly.

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Introduction

Onychomycosis is a common fungal infection of the nail that can be caused by dermatophytes, non-dermatophyte moulds, and yeasts. Predisposing factors of this disease include presence of tinea pedis, positive family history of onychomycosis, increasing age, the male gender, trauma to the nail, diabetes, immunosuppression (eg, HIV positive), poor peripheral (arterial) circulation, smoking, and possibly psoriasis. (1,2)

The management of onychomycosis has greatly improved with the introduction of oral antifungals, in particular, terbinafine and itraconazole, as well as topical ciclopirox and amorolfine nail lacquers. Terbinafine was first approved for the management of onychomycosis in the United Kingdom in 1991 and in the United States in May 1996. It is the most frequently prescribed antifungal agent in the US and Canada for onychomycosis. This broad-spectrum allylamine is fungicidal in vitro whereas the azoles (ketoconazole, itraconazole, and fluconazole) are primarily fungistatic; this may partially account for the superior efficacy of terbinafine. (3)

Numerous studies have shown the high incidence of onychomycosis in diabetics. The infection may lead to secondary bacterial infections, ulceration, and osteomyelitis and can possibly lead to gangrene and lower limb amputation.

In the immunocompromised patient, fungal infections such as onychomycosis are often difficult to treat; as a result, oral antifungal agents may be indicated in these populations. (4) However, the treatment of immunocompromised individuals with oral antifungals can be problematic due to the increased potential of drug-drug interactions. (5) These individuals require a more definitive therapy because their underlying illness makes them more susceptible to complications from untreated superficial fungal infections. (5) Terbinafine would be an attractive therapeutic option for the immunocompromised patient considering its potent fungicidal activity and the low incidence of drug-drug interactions. (5)

The purpose of this article is to review the use of terbinafine in the treatment of onychomycosis in adults and special patient populations, with particular emphasis on diabetics, immunocompromised patients, Down syndrome patients, children, and the elderly.

Methods

We searched MEDLINE (1966 to June 2004) for relevant clinical studies evaluating the efficacy of oral terbinafine to treat onychomycosis. The key words used in conjunction with terbinafine included onychomycosis, clinical trial, tinea capitis, HIV, transplant patients, diabetes, children, and elderly.

Efficacy

Several randomized controlled studies (RCTs) have confirmed the efficacy and safety of terbinafine in successfully treating dermatophyte toenail onychomycosis in healthy adults, with a meta-analytic average for mycological cure (negative microscopy and negative culture) of 76 [+ or -] 3%, mean [+ or -] S.E. (6) The meta-analytic average for clinical response (nail visibly clear of infection or marked improvement) among 15 trials reporting this variable was 66 [+ or -] 5% (mean [+ or -] S.E.). (6)

In a 60-week study, Havu et al (7) compared terbinafine with fluconazole in patients with toenail onychomycosis and found the allylamine was significantly superior to the azole in achieving mycological cure (P < .001) and clinical cure (P < .0001). In a 72-week study (the L.I.ON study), significantly superior efficacy was demonstrated in mycological cure, clinical response, clinical cure, and complete cure with continuous terbinafine when compared with intermittent itraconazole in the treatment of toenail onychomycosis (P < .0001). (3) The L.I.ON extension studies followed Finnish (8) and Icelandic (9) participants for 4 and 5 years, respectively, and found that fewer terbinafine-treat ed patients experienced a mycological or clinical relapse compared with itraconazole-treated patients (P < .01). (9)

Safety

The most commonly reported adverse events associated with terbinafine include gastrointestinal (GI) symptoms (eg, diarrhea, dyspepsia, and abdominal pain), liver test abnormalities, rashes, urticaria, pruritus, and taste disturbances. (10) These events were generally mild to moderate in severity, and usually did not lead to discontinuation of treatment.

Four open, prospective, uncontrolled, post-marketing surveillance studies were conducted in 4 countries to broaden the safety database for oral terbinafine. (11) Of the 25,884 patients who entered these studies, 72.2% were being treated for onychomycosis. This study showed that of nearly 26,000 patients, 89.5% of all patients did not suffer any adverse event. Approximately 38.5% of these patients had concomitant medication with many being elderly.

Adverse events were reported in 2,717 patients. The majority were GI (4.9%) or skin related (2.3%), with 76.9% and 62.4%, respectively, probably or possibly related to terbinafine therapy. (11) Other reported events were central nervous system (1.2%), respiratory (1.0%), perversion of taste (0.4%), loss of taste (0.3%), and hepatobiliary events (0.2%). (11)

Other rare adverse events reported included idiosyncratic and symptomatic hepatic injury, liver failure (leading to death or liver transplant), serious skin reactions, severe neutropenia, thrombocytopenia, and allergic reactions. (10) With respect to reported liver cases, the majority of patients had serious underlying systemic conditions and an uncertain causal association with terbinafine. (10) A cohort study in the UK evaluated the risk of acute liver injury among users of antifungal agents in 69,830 patients (20-79 years of age). (12) The incidence rates of acute liver injury per 100,000 persons/month were as follows: ketoconazole 134.1, itraconazole 10.4, and terbinafine 2.5. The highest relative risk was associated with ketoconazole (228), followed by itraconazole and terbinafine with relative risks of 17.7 and 4.2, respectively.

Terbinafine is not recommended for patients with chronic or active liver disease, or renal impairment. (10) Serum transaminase tests should be performed prior to prescribing terbinafine to assess for pre-existing hepatic disease. Transient decreases in absolute lymphocyte counts have also been observed and hence blood counts should be monitored in patients with known or suspected immunodeficiency. (10)

Drug Interactions

There are no drugs contraindicated with terbinafine. (10) Metabolism of this allylamine differs from the azole antifungals, and involves at least 7 different pathways in the CYP 450 system (1A2, 2B6, 2C8, 2C9, 2C19, 3A4, and 3A5). As access to multiple pathways reduces the likelihood of drug-drug interactions, terbinafine tablets can be used safely with many drugs metabolized by the CYP 450 system. Terbinafine has been shown to inhibit the CYP 450 isoform 2D6 in vivo, (13) which may be of clinical relevance for compounds metabolized predominantly by this enzyme (eg, tricyclic antidepressants, [beta]-blockers, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors). Terbinafine decreases the clearance of caffeine by 19% and increases cyclosporine clearance by 15%. (10) The clearance of terbinafine is increased 100% by rifampin and decreased 33% by cimetidine. (10)

Special Patient Populations

Children

Onychomycosis is observed less frequently in children than in adults. In a North American study, the prevalence of onychomycosis in children was 0.16% (N = 2,500). (14) Although the safety and efficacy of terbinafine in pediatric patients is not yet established by large-scale RCTs, (10) preliminary data suggest the allylamine may be a consideration for use in this population. (15-19) In a retrospective study of 14 pediatric patients treated with terbinafine (mean dose 4 mg [kg.sup.-1] [day.sup.-1] for 2-5 months), Heikkila and Stubb (15) reported mycological and clinical cure rates of 77% and 69%, respectively, 1 to 9 years after treatment. Goulden and Goodfield (19) reported clinical and mycological success in the treatment of 3 cases of childhood onychomycosis with terbinafine 250 mg/day for 3 or 6 months. Similar results have been reported by other authors. (17)

Terbinafine may also be a consideration for the treatment of onychomycosis in pediatric patients with Down syndrome. In an open study, 32 Down syndrome patients diagnosed with onychomycosis were treated with terbinafine 250 mg daily for 16 weeks. (20) At week 40, mycological cure (negative culture and microscopy) was achieved in 94% of patients and clinical cure (no clinical signs of dermatophyte infection) in 78%. (20) Adverse events reported included abdominal cramps (N = 1), abdominal pain (N = 1), constipation (N = 1), and eczematous eruptions (N = 2); all were treatable. The authors of this study suggested that the decreased cellular immunity found in Down syndrome had no effect on the therapeutic effect of terbinafine. (20)

Elderly

The prevalence of onychomycosis increases with age and is higher in patients over 60 years of age. The management of this fungal infection with terbinafine has been reported to be safe and effective in this population. Smith et al, (21) in an open-label study, evaluated the efficacy and safety of terbinafine in patients 60 years or older with onychomycosis. At week 24, 93.3% (N = 15) of patients were mycologically cured and the cure rate between week 24 and 72 was greater than or equal to 92.9%. (21) A negative mycologic culture was used as the basis for efficacy. At week 72, 46.7% (N = 15) achieved a complete cure. Adverse events were mild to moderate in severity and transient in nature. Of the 30 patients evaluated for safety, investigators attributed a possible, probable, or definite causal relationship between an event and terbinafine in 13 patients. Smith et al (21) also found that no drug interactions occurred in patients taking terbinafine with drugs metabolized by cytochrome P-450 2D6 enzymes (eg, [beta]-blockers, tricyclic antidepressants, antiarrhythmic agents, antimicrobials, opioid analgesics, muscle relaxants, or cough/cold preparations).

In a single-blind, randomized, controlled study, patients greater than 60 years of age (mean age of 68 years) with toenail onychomycosis were treated with either terbinafine (250 mg/day for 12 weeks) or itraconazole pulse (200 mg twice daily given for 1 week each month for 3 pulses). (22) At month 18, mycological cure (negative culture and microscopy) was achieved in 64% (N = 50) and 62.7% (N = 51) in the terbinafine and itraconazole pulse groups, respectively. (22) Adverse events were reported in 5 terbinafine patients (GI and cutaneous) and 7 itraconazole pulse patients (GI, cutaneous, elevation of liver function tests, and drowsiness). (22)

Transplant Patients

In an open study, Lee et al (23) assessed the efficacy of terbinafine (250 mg/day for 6 or 12 weeks) in the treatment of finger and toenail onychomycosis in renal transplant patients. Mycological cure (negative microscopy and culture) was achieved in 85.7% of patients at the end of follow-up (12 weeks after end of treatment). (24) No significant changes in laboratory tests, including hematological, hepatic, renal blood test, and urinalysis, were noted at the end of treatment or at the end of follow-up. (23)

HIV Patients

The prevalence of onychomycosis in HIV-positive individuals was found to be 23.2% (N = 500) (24) compared to 6.9% (N = 2001) (25) in immunocompetent individuals. Patients with human immunodeficiency virus (HIV) infection may be more prone to develop certain cutaneous dermatoses than immunocompetent individuals. (24) The appearance of many fungal diseases in HIV-positive patients is directly correlated with the patient's CD4 count. For instance, onychomycosis is correlated with a CD4 count of 450 cells/mm. (26) It is also interesting to note that proximal subungual onychomycosis, a rare presentation among immunocompetent individuals, is considered an early clinical marker of HIV infection. (27, 28)

Terbinafine is not contraindicated for use in patients with AIDS or who are HIV positive. Terbinafine has good in vitro activity against the most common dermatophytes associated with onychomycosis. Arzeni et al (29) tested terbinafine against 20 clinical isolates of dermatophytes belonging to 7 species (Microsporum canis, M. gypseum, Trichophyton rubrum, T. mentagrophytes, T. tonsurans, T. verrucosum and Epidermophyton floccosum). Terbinafine was fungicidal at concentrations of less than or equal to 1.0 [micro]g/mL for 19 of these isolates. (29) In this study, 5 strains isolated from AIDS patients were equally as susceptible to terbinafine as those from HIV-negative individuals, (29) suggesting that terbinafine would be of benefit in treating onychomycosis in HIV-positive patients. Villars and Jones (30) evaluated the use of oral terbinafine in 2,500 patients over a 5-year period, focusing on patients with serious infections often associated with local or generalized immunological defects. The authors report that oral terbinafine was effective in 9 out of 13 immunologically deficient patients, moderately effective in 2 and ineffective in 2 as opposed to amphotericin-B, which was ineffective in 10 cases.

In addition, in an open, non-comparative study, 21 HIV-positive patients (mean age 37 years, range 27 to 50) with dermatophyte onychomycosis and advanced immunosuppression (mean CD4 count of 163 cells/[micro]L) were treated with terbinafine 250 mg/day. (31) After 16 weeks of treatment, 8 of 16 evaluable patients were clinically cured. At this time point, 7 of 16 patients achieved mycological cure (negative culture) although it is not clear if these are the same patients that were reported as clinically cured. At follow-up (month 10), 13 patients were clinically and mycologically cured. (31) It is important to note that no drug interactions or serious adverse effects were reported; one patient developed moderate gastric pain, but did not discontinue treatment. (31) In another study, 30% of HIV-positive patients with onychomycosis achieved mycological cure (negative microscopy and culture) (N = 10) after being treated with terbinafine 250 mg/day for 12 weeks. (32) Three patients with-drew due to terbinafine-induced rash (N = 1) and HIV-related illness (unrelated to terbinafine, N = 2). (32)

Diabetics

Diabetes is a common condition in North America and can result in peripheral and autonomic neuropathy, altered peripheral circulation, impaired immunology, foot ulceration, and impaired wound healing. (33,34) Onychomycosis is a common condition among diabetics that can result in adjacent and undetected skin injury, which provides a reservoir for pathogens, increasing the risk of secondary infections. (34) In a multicenter survey, the prevalence of toenail onychomycosis in diabetic subjects was 2.77 times greater than in normal individuals. (35) In addition, because onychomycosis is often associated with tinea pedis, fissures can develop and potentially serve as portals of entry for bacteria, resulting in systemic infection, such as cellulitis or osteomyelitis, and in severe cases, lower-limb amputation. (36,37) Hence, it is imperative to treat onychomycosis to avoid such complications that may compromise the limb. (38)

Managing onychomycosis in diabetics may require an antifungal agent, mechanical/physical therapies (eg, debridement), and patient education regarding proper foot care. (36) Antifungal therapy, in particular itraconazole and terbinafine, may reduce the need for limb amputation in diabetic patients with severe complications of onychomycosis. (38) When treating diabetics with an oral antifungal agent it is important to consider the patient's current regimen of pharmacotherapy. For instance, it is known that itraconazole can interact with drugs metabolized by the P-450 (CYP) 3A4 isoenzyme, while this enzyme does not substantially metabolize terbinafine.

In a multicenter study, Farkas et al (39) treated insulin-dependent diabetes mellitus (IDDM) patients and non-insulin-dependent diabetes mellitus (NIDDM) patients with distal-lateral toenail onychomycosis with terbinafine (250 mg/day for 12 weeks). Of the 89 diabetic patients studied, 37 had IDDM and 52 NIDDM. At week 48, mycological cure (negative microscopy and culture) was achieved in 73% of patients, clinical cure (100% clearing) in 57.3%, and complete cure (mycological cure plus clinical cure) in 48.3%. (39) There was no statistically significant difference between IDDM and NIDDM with respect to cure rates (P > .05). (39) Terbinafine resulted in a good tolerability profile, and blood glucose levels in 83% of patients remained the same as that observed at baseline. (39) In a post-marketing surveillance study of 25,884 patients, (11) 869 patients had diabetes mellitus. Of this group, 714 (82.2%) were taking one or more antidiabetic agents. The incidence of adverse events in diabetic patients remained low and comparable to that observed in clinical trials that excluded patients with diabetes mellitus and/or were taking oral hypoglycemics. No evidence of clinically apparent drug-drug interactions was found.

Cost Effectiveness

Studies have shown that terbinafine is a cost-effective agent for treating onychomycosis. (40,41) An analysis based on results from the L.I.ON study (3) found continuous terbinafine to be less costly and more effective than intermittent itraconazole. (41) Pharmacoeconomic evaluations have shown terbinafine to be more cost-effective than fluconazole and griseofulvin.

Conclusion

Terbinafine is an antifungal used to treat a variety of dermatological diseases, including onychomycosis. This agent has been safely and effectively used in the treatment of onychomycosis in both healthy patients and in a variety of special patient populations and is of particular interest in those who are immunocompromised. The limited data that are available suggest that terbinafine should be considered for the treatment of dermatophyte onychomycosis in children, Down syndrome patients, the elderly, diabetics, and immunocompromised patients (eg, HIV-positive). This allylamine should be considered for the management of onychomycosis based on its effectiveness, broad spectrum, fungicidal nature, safety profile, very low occurrence of drug interactions, and pharmacoeconomic considerations.

Disclosure: This manuscript was supported in part by funding from Novartis Pharmaceuticals Corporation.

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Aditya K. Gupta MD PhD FRCP(C), (a,b) Jennifer E. Ryder HBSc, (b) Lindsay E. Lynch HBSc (b) Amir Tavakkol PhD Dip Bact (c)

a. Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Sciences Center (Sunnybrook site) and the University of Toronto, Toronto, Canada

b. Mediprobe Research, Inc., London, Ontario, Canada

c. US Clinical Development and Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, NJ

Address for Correspondence

Dr. Aditya K. Gupta

645 Windermere Road

London, Ontario N5X 2P1, Canada

Phone: 519 657 4222

Fax: 519 657 4233

e-mail: agupta@execulink.com

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