Terbinafine: An update

CLINICAL REVIEW

Terbinafine: An update

Aditya K. Gupta, MD, FRCPC, a and Neil H. Shear, MD, FRCPC b Toronto, Canada

Oral terbinafine was first introduced in the United Kingdom in February 1991 and was approved for the treatment of onychomycosis in the United States in May 1996. It is estimated that 4 million patients worldwide have been treated with oral terbinafine as of December 1996. The efficacy of terbinafine in the treatment of onychomycosis and other dermatomycoses is reviewed. The adverse-effects profile of oral terbinafine is evaluated. (J Am Acad Dermatol 1997;37:979-88.)

The allylamine class of drugs was discovered by chance in 1974 during a research program for the synthesis of new central nervous system com- pounds. 1 Naftifine is the first member of the allylamine series to be used in human beings and is active only topically. Terbinafine is the second in the series; the cream and oral tablet were approved in the United States in December 1992 and May 1996, respectively. Oral terbinafine was first approved for use by the United Kingdom in February 1991, by Denmark in October 1991, and by Canada in May 1993. It is estimated that, as of December 1996, there have been more than 4 million patient uses of oral terbinafine worldwide. The ratio of patients being treated for toenail/fingernail onychomycosis is approximately 4:1.

PHARMACODYNAMIC PROPERTIES

Terbinafine inhibits squalene epoxidase, a com- plex membrane-bound enzyme system that is not part of the cytochrome P-450 superfamily. 2 In fungi this results in ergosterol deficiency of the cell wall and intracellular squalene accumulation. The latter may be the mechanism most responsi- ble for the in vitro fungicidal action of terbinafine to most fungal pathogens, including dermatophytes and dimorphic and filamentous fungi) ,4 For dermatophytes the minimum inhibitory concentration (MIC) range is 0.001 to 0.01 mg/L. 5 Terbinafine is fungicidal in vitro against Candida parapsilosis but fungistatic against Candida albi-

From the Division of Dermatology, Department of Medicine, a and the Divisions of Dermatology and Clinical Pharmacology, Departments of Medicine and Pharmacology, b Sunnybrook Health Science Center and the University of Toronto.

Reprints not available from the authors. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 1g/1185755

cans. The initial targets of terbinafine action may be the outer and inner layers of the arthroconidial cell wall, followed by alteration to the cytosol and intracellular organelles. 6 This can produce an inhibitory effect on the morphologic transformation and invasiveness of dermatophytes.

PHARMACOKINETIC PROPERTIES

Orally administered terbinafine is well absorbed (>70%), and this is not significantly affected by food. 7 Terbinafine is highly lipophilic and keratophilic. It distributes extensively throughout adipose tissue, the dermis, epidermis, and nails. Terbinafine undergoes extensive bio- transformation, primarily through N-demethyla- tion and oxidation of the tertiary butyl group. 8 There are 15 known metabolites, none of them active. 9

The plasma concentration-time profile of terbinafine is triphasic. 1° In plasma the distribu- tion half-life of terbinafine is 1.1 hours. The elimination half-lives of terbinafine are 16 and 100 hours after a single oral dose of 250 mg. After 4 weeks of terbinafine 250 mg/day, the mean terminal half-life is 22 days in plasma. 9 In the dermis- epidermis, hair, and nails, the mean elimination half-life is 24 to 28 days.

A high concentration of terbinafine, well above the MIC for most dermatophytes, is reached in skin within hours of starting therapy. 11A2 With ongoing therapy, terbinafine is delivered to the stratum corneum primarily via the sebum and to a lesser extent through incorporation into the basal keratinocytes and diffusion through the dermis- epidermis. 13 In contrast, terbinafine in eccrine sweat is undetectable. Terbinafine remains in skin at concentrations above the MIC for most dermatophytes for 2 to 3 weeks after discontinuation

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Journal of the American Academy of Dermatology 980 Gupta and Shear December 1997

of long-term oral therapy.ll Terbinafine has been detected in the distal nail plate within 1 week of starting therapy. 14,15 After 6 and 12 weeks of oral therapy, terbinafine has been detected in the nail plate for 30 and 36 weeks, respectively, at a concentration of 0.19 to 0.28 gg/gm, which is well above the MIC for most dermatophytes and other fungi. 15

Because terbinafine is extensively metabolized in the liver, it is eliminated more slowly in patients with liver dysfunction and in this population dose adjustments may be necessary. 1° In patients with renal disease, the terminal elimination half-life can become prolonged although terbinafine is not excreted by the kidneys unchanged. 1° In renal insufficiency the decreased elimination of terbinafine may be explained by a change in the metabolism of the drug or a decrease in hepatic function secondary to renal insufficiency, or both. 1° It has been suggested that the dose of oral terbinafine should be approximately halved when the serum creatinine exceeds 300 ~tmol/L, or when the creatinine clearance is less than or equal to 50 ml/min (0.83 ml/sec). 16 No clinically relevant age-dependent changes in adults in the steady-state plasma concentration of terbinafine have been reported. 17

THERAPEUTIC USES

Oral terbinafine has been shown to be effective in the treatment of onychomycosis and other dermatomycoses. Terbinafine may also have a place in the management of some systemic mycoses (e.g., chromomycosis). 18 This aspect will not be covered in this review. There are an increasing number of reports in which terbinafine has been used effectively and safely in children, especially in the treatment of tinea capitis and onychomycosis. 19-27 Terbinafine is currently approved in 24 countries for the treatment of tinea capitis.

ONYCHOMYCOSIS

Oral terbinafine is approved for the treatment of dermatophyte onychomycosis as continuous therapy for 12 weeks. 1628 The product monographs in the United Kingdom 29 and Australia 3° suggest that when onychomycosis involves toenails other than the big toe and occurs in younger patients, a shorter duration of therapy may suffice. Furthermore, a subgroup of patients who may require a longer duration of therapy are those who

have poor nail outgrowth during the first few weeks of treatment. Some physicians treat toenail onychomycosis for 4 months rather than 3.

The efficacy of continuous therapy with terbinafine in onychomycosis has been confirmed in open, double-blind, and comparative studies. 16'31-49 The studies of the efficacy of terbinafine in toenail onychomycosis are of differ- ent durations: 3 months,* 4 to 6 months, t and 12 months. 32,34 The comparative studies have been placebo-controlled, 16,36,47 against griseofulvin 40,41,43 or itraconazole. 44,45,48,49 The efficacy

rates of terbinafine in the treatment of dermatophyte onychomycosis of the toenails have been obtained from eight studies~ with clinical cure, clinical response, and mycologic cure, meta-average (_+ standard error [SE]) of 64% _+ 8%, 76% ___ 6%, and 80% + 5%, respectively. The results have been combined with the method of DerSimonian and Laird 51 and modified for single-group analysis. 52 For fingernail dermatophyte onychomycosis the clinical cure, clinical response, and mycologic cure rates are meta-average (+ SE) 74% _ 13%, 80% _+ 10%, and 83% _+ 8%, respectively. Terbinafine has also been shown to be effective in the treatment of onychomycosis in kidney transplant recipients (n = 30; mycologic cure, 85%), 5° patients with Down syndrome (n = 32; mycologic cure, 94%), 46 somewhat effective in patients with AIDS (n = 10; mycologic cure, 30%), 53 with limited data in patients with diabetes. 54

Alternative protocols for treating onychomycosis have also been reported. Shuster and Munro 55 used a single dose of terbinafine 1000 mg given once (five patients), twice (two patients), or three times (four patients) with 2 weeks between doses. None of the patients given a single dose, but one of two patients given two doses and three of four patients administered three doses exhibited a clear response. Wong and Cho 56 treated fingernail onychomycosis with terbinafine 250 mg/day for 2 weeks (20 patients). The pathogens were Trichophyton rubrum or other dermatophytes (10 patients), C. albicans (two patients), C. parapsilosis (three patients), Aspergillus fumigatus (two patients), Cladosporium carrionii (two patients), and mixed infection (one patient). Patients were

*References 16, 36, 37, 42, 44, 45, 47, 49, 50. tReferences 31, 33, 35, 38, 39, 41, 43, 46, 48. *References 16, 36, 37, 42, 44, 45, 47, 49.

Journal of the American Academy of Dermatology Volume 37, Number 6 Gupta and Shear 981

then observed at monthly intervals and an addi- tional 2 weeks of therapy was administered 4 weeks later if there had been no response to the initial 2 weeks of therapy. Six months after treatment, 13 (65%) of the 20 patients exhibited com- plete cure, two (10%) had only mycologic cure, one (5%) had improvement, and four (20%) were considered as treatment failures. Of the 13 patients who were completely cured, nine received 2 weeks of therapy and the other four required an extra 2 weeks of terbinafine. When categorized by cause the response was dermatophyte (clinical cure [CC]: eight patients, mycolog- ical cure [MC]: one, failure [F]: one); C. albicans (F: two patients), C. parapsilopsis (CC: two, F: one); C. carrionii (CC: one, improvement [I]: one), A. fumigatus (CC: one, MC: one), and mixed infection (CC: 1). Terbinafine 500 mg/day administered for 1 week per month for 3 to 4 consecu- tive months ("pulse" therapy) has also been used in the treatment of onychomycosis. 48,57 Tosti et al. 4s compared the efficacy of terbinafine 250 rag/day x 4 months (n = 17 patients) with a regi- men of 250 mg twice daily for 1 week/month x 4 months (n = 20). Six months after therapy was discontinued, the MC in the two groups was 94.1% versus 80% (p = not signifcant). In another study, 57 the efficacy of terbinafine 250 mg/day x 3 months (n = 25) was compared with terbinafine 250 mg twice daily for 1 week/month x 3 months (n = 23). At follow-up, 48 weeks after starting therapy, the MC rates in the two groups were 79.2% and 73.9%, respectively (p = not significant). Oral terbinafine, 250 mg/day and 500 mg/day, both given as continuous dosing have been found to be equally effective in a 16-week course of therapy for toenail onychomycosis. 5s

In a U.S. study 16 patients were evaluated for at least 6 months after achieving CC and at least 1 year after completing terbinafine therapy, with a clinical relapse rate of approximately 15%. De Cuyper 59 treated toenail onychomycosis with terbinafine 250 mg/day for 16 weeks; the MC at 48 weeks and at more than 2 years was 84% (n = 19) and 82% (n = 17), respectively. The propor- tion of patients who exhibited CC or had minimal residual lesions at the two time points were 89% (n = 19) and 82% (n = 17), respectively.

In comparative trials terbinafine has been shown to be significantly more effective than griseofulvin in the treatment of toenail 4~,43 and

fingernail 4° onychomycosis. When terbinafine was compared with itraconazole continuous therapy for the treatment of toenail onychomycosis, terbinafine was the more effective agent in two studies, 45,49 with no significant difference between the antimycotics in two reports. 44'48 In the treatment of Candida nail infection, terbinafine may have to be given at a dose of 250 mg/day for 4 months, 6° rather than the 3 months, which is usually sufficient for toenail dermatophyte infection, or at the higher dose of 500 mg/day. 6~-63 More experience is required with the use of terbinafine in the treatment of nondermato- phyte molds. 63,64

TINEA PEDIS/CRURIS/CORPORIS

Oral terbinafine is not currently approved in the United States for the treatment of tinea pedis/cruris/corporis. In countries in which such approval exists, the recommended duration of therapy is 2 to 6 weeks for tinea pedis 65-7° and 2 to 4 weeks for tinea corporis/cruris. 71-74 Short- duration therapies lasting 2 weeks for tinea pedis 69,7° and 1 week for tinea corporis/cruris 74 may also be effective and lead to a higher compli- ance. :.

OTHER DERMATOMYCOSES

Oral terbinafine has also been effective in the treatment of tinea imbricata, 75 Majocchi's granuloma, 76 cutaneous sporotrichosis, 77 and black piedra. 78 Tinea capitis 19,21-25 has also been effec-

tively treated with terbinafine. A suggested dosage schedule is as follows: weight more than 40 kg, 250 mg/day; 20 to 40 kg, 125 mg/day; and less than 20 kg, 62.5 rag/day. Tinea capitis is generally treated for 4 to 6 weeks, with consideration given to treatment for a longer duration when the causative organism is, for example, Microsporum canis or Microsporum audouinii var. langeronii. 25 In a randomized, double-blind study, Haroon et al. 23 demonstrated that, 12 weeks after the start of therapy, the cure rates for three groups of children treated for 1 week (n = 53), 2 weeks (n = 51), and 4 weeks (n = 57) were 73.6%, 80.4%, and 85.9%, respectively, with no statistical difference in efficacy between the three groups.

ADVERSE EFFECTS

Since the approval of terbinafine in the United Kingdom in 1991 and in Austria, Germany, and


Table I. Adverse effects with terbinafine therapy for onychomycosis

Disorder

Postmarketing surveillance study 79

(S = 25,884)

U.S. Product monograph 16

Difference Canadian Product Terbinafine Placebo a .~ t r ibu tab le monograph 28

(N = 465) (N = 137) to terbinafine (N = 998)

Gastrointestinal 4.9% Diarrhea and/or cramps 0.8% Nausea and/or vomiting 1.3% Fullness NM Sickness NM Gastrointestinal irritation, 0.6%

dyspepsia, gastritis Abdominal pain 0.8% Flatulence NM

Disorders of the skin 2.3% Erythema or rash 0.9% Pruritus 0.3% Urticaria 0.3% Eczema 0.2%

Central nervous system 1.2% Headache NM Concentration NM

Liver enzyme abnormality 0.2% Disorders of special senses

Taste disturbance 0.7% Visual disturbance NM

Other Tiredness/fatigue NM Pain (back, knee, legs, feet, NM

kidney)

NM NM N/A 5.2% 5.6% 2.9% 2.7% 1.0% 2.6% 2.9% -0.3% 1.1% NM NM N/A 0.5% NM NM N/A 0.1% 4.3% 2.9% 1.4% 2.2%

2.4% 1.5% 0.9% NM 2.2% 2.2% 0% NM NM NM N/A 2.7% 5.6% 2.2% 3.4% 0.9% 2.8% 1.5% 1.3% 0.4% 1.1% 0 1.1% 0.5% NM NM N/A 0.1% NM NM N/A 1.2%

12.9% 9.5% 3.4% 0.9% NM NM N/A 0.2% 3.3% 1.4% 1.9% 0.1%

2.8% 0.7% 2.1% 0.1% 1.1% 1.5% -0.4% NM

NM NM N/A 0.3 % NM NM N/A 0.1%

N/A, Not applicable; NM, not mentioned.

The Netherlands in 1993, a prospective postmarketing surveillance study was performed over 4 years. 79 The objective was to document the safety profile of oral terbinafine in a large unselected population treated under normal medical condi- tions. A total of 25,884 patients were enrolled (with >10,000 patients each in the United Kingdom and Germany and >2500 patients each in Austria and The Netherlands). The study was completed by 1995 and the data were pooled and analyzed collectively. The adverse effects reported in the postmarketing surveillance study (N = 25,884) 79 and in the Canadian 28 (N = 998) and the U.S. 16 (n = 465) product monographs are given in Table I.

The organ system with the most adverse drug reactions (ADRs) appears to be the gastrointestinal system (Table I). 8°-82 In approximately half the patients the gastrointestinal ADRs occur during the first 2 weeks of starting therapy, s° The gas-

trointestinal ADRs are generally mild to moderate in severity and of a transient nature. In the U.S. product monograph (n = 465), 1.6% of patients discontinued the drug because of gastrointestinal symptoms. 16

Taste disturbance includes perversion of taste that may occur primarily during the first week of therapy. Taste loss can occur after 4 to 8 weeks of treatment. 79 In one report the modal time to onset of taste loss was 7 weeks. 8° Symptoms include metallic taste, an altered taste, foul taste, or com- plete taste loss. In rare instances the taste disturbance may be accompanied by parosmia and anosmia. Stricker et al.81 performed a case control study to determine the risk factors for the development of taste loss to terbinafine. The study population consisted of 87 cases with taste loss considered as "probably" being caused by terbinafine, and 362 controls who were users of terbinafine without taste loss. The relative risk of taste loss in

Journal of the Amer ican Academy of Dermatology Volume 37, Number 6 Gupta and Shear 983

patients older than 60 years of age compared with those younger than 30 years of age was 14.4 (95% confidence interval [CI] 2.2-601). 81 Patients with a body mass index (BMI) less than 21 had a 4.4- fold higher risk compared with those whose BMI was more than 27 (95% CI: 1.6-14.2). 81 Compared with controls, the affected patients had a lower zinc intake (p = 0.01) and gave a history of taste loss (p = 0.007). Therefore risk factors for taste loss include aging, low BMI, history of taste loss, and a low daily intake of zinc. 81 In another report more women than men reported symptoms (p = 0.016). 80 The taste loss has been generally reversible with a median time to recovery of 42 days (range, 2 to 186 days) in one report.

In general, in patients taking drugs the preva- lence of drug-induced liver damage is 0.1%. 82-86 Hepatobiliary dysfunction is a rare and labeled adverse event of terbinafine, and in the majority of such instances there is an asymptomatic reversible elevation of liver enzymes. The reporting rate of symptomatic liver injury, possibly related to terbinafine therapy, is about 1/45,000 to 1/54,000 exposed patients 28 (also personal communication, Sandoz Canada, Oct. 6, 1996). In general, hepatobiliary dysfunction may be classified as hepato- cellular, cholestatic, or mixed on the basis of liver function tests (LFTs). This classification can be based on the following ratio (R): alanine transaminase (ALT) value + alkaline phosphatase (ALP) value, with "value" being expressed as a multiple of the upper limit of the normal range. Hepatocelhilar injury is defined by an isolated elevation of transaminase or R ___5; a cholestatic injury is defined by the isolated elevation of alkaline phosphatase or R _<2; and mixed damage is defined by concomitant elevation of ALT and ALP with 2<R<5. 84 The rare reports of symptomatic liver injury associated with terbinafine are usually idiosyncratic and cholestatic. 87-9° This has usually manifested as jaundice and pruritus, although symptoms may include nausea, anorexia, and fatigue. Thus far, it has not been possible to dif- ferentiate between a metabolic pattern of idiosyn- crasy having a delay in onset of several weeks, which could be caused by an individual metabolic variant resulting in a toxic metabolite, or an immune allergic type. 88 In the latter, accompany- ing symptoms may include fever and an eruption. 91 In the postmarketing surveillance study (N = 25,884), five patients experienced symptomatic

cholestatic hepatic dysfunction. 79 In two of the five patients the symptoms were thought to be potentially related to terbinafine.

In general, there are several known factors that make an individual susceptible to drug-induced liver disease. The elderly have an increased incidence for all types of ADRs, 85,86 and age is an important risk factor for drug-induced liver disease. In the cases reported to the World Health Organization (WHO) concerning hepatic dysfunction in patients receiving terbinafine, 75% of those in whom jaundice developed were more than 50 years old and 41% were 65 years old or older. 92,* The duration between the start of terbinafine therapy and development of hepatobiliary dysfunction was 4.3 _+ 0.5 weeks (mean _ standard error). 92 In the data reported to the WHO, 65% of cases of hepatic dysfunction associated with terbinafine have occurred in men. 92 In general, for any drug, other risk factors for hepatic dysfunction include genetic factors, nutritional status, alcohol con- sumption, history of ADRs, preexisting hepatic disease, and concurrent therapy.

Eruptions associated with terbinafine have been reported in about 2% to 4% of patients. The majority are nonserious, occur in the first 2 weeks, and resolve within 2 to 3 weeks. 8° Rarely, the following have been reported in association with terbinafine therapy: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, 93-97 fixed drug eruption, 9s acute generalized exanthematous pustulosis, 99 exacerbation or induction of psoriasis de novo, 1°° erythema annulare centrifugum-like psoriatic drug eruption, 1°1 and alopecia. The average duration between starting terbinafine and onset of erythema multiforme or Stevens-Johnson syndrome or toxic epidermal necrolysis (n = 8) is 17 days (range, 3 to 35 days). 93-97 The WHO is aware of 38 cases of erythema multiforme and nine of Stevens-Johnson syndrome. 92,* McGregor and Rustin 95 stated that in the United Kingdom, erythema multiforme had been reported to the Committee on the Safety of Medicines, U.K., in 15 of approximately 110,000 total patient expo- sures to terbinafine (13.6 per 100,000). This was compared with estimates of erythema multiforme

*Information obtained from the WHO on Dec. 5, 1996. The information is not homogeneous, at least with respect to origin or like- lihood that the pharmaceutical product caused the adverse reaction. The information does not represent the opinion of the WHO.

Journal o f the Amer i can A c a d e m y of De rma to logy 984 Gupta and Shear December 1997

with other drugs: phenobarbital (20 per 100,000 patients exposure), nitrofurantoin (7 per 1000,000), trimethoprim-sulfamethoxazole (3 per 100,000), and ampicillin (3 per 100,000). 95'102

Visual disturbances are uncommon, occurring in 1.1% of patients in a U.S. study, compared with 1.5% with placebo. 16 Changes may occur in the lens or retina, 16 and patients may describe diffi- culty in focusing. There is a report of green vision, which was reversible, developing in association with terbinafine therapy. 1°3

In a postmarketing surveillance study (N = 10,361) conducted in the United Kingdom, the frequency of arthralgia and myalgia was 0.4% and 0.2%, respectively. 8° None of the cases was seri- ous and most occurred within the first 2 weeks of starting therapy. There was no evidence that terbinafine exacerbated preexisting musculoskele- tal symptoms. 8° A serum sickness-like reaction associated with terbinafine therapy may occur) °4 A hypersensitivity reaction to terbinafine in which there was multisystem involvement including hepatitis, pyrexia, lymphadenopathy, and a cutaneous eruption has been reported. 91

Rare cases of hematologic disorders, particu- larly neutropenia including agranulocytosis, may occur in association with terbinafine therapy.105,106 Other blood dyscrasias that can develop are leukopenia, lymphopenia, pancytopenia, gran- ulocytopenia, thrombocytopenia, and anemia. In the data available from the WHO, the duration between onset of terbinafine therapy and the development of the blood dyscrasia is 6.9 _+ 0.5 weeks.* This is an approximate figure because adverse effects reported to the WHO may not nec- essarily be definitely or probably linked with the drug. Worldwide, of the estimated 1.5 million patients treated with terbinafine as of September 1994, there have been eight isolated cases of blood dyscrasias reported, in particular, agranulocytosis, pancytopenia and thrombocytopenia, possibly or probably related to terbinafine (1:187,500 or 12 cases per million patients exposed). 28 If it is assumed that terbinafine is prescribed on average for 3 months, then the use in 1.5 million patients translates into 0.375 million patient-years. The incidence rate of blood dyscrasis becomes 32

*Information obtained from the WHO on Dec. 5, 1996. The information is not homogeneous, at least with respect to origin or like- lihood that the pharmaceutical product caused the adverse reaction. The information does not represent the opinion of the WHO.

cases per million patient-years. These include patients with agranulocytosis, pancytopenia, and thrombocytopenia possibly or probably related to terbinafine. For comparison, the incidence rate of agranulocytosis is estimated to be 9 per million per year in an age- and sex-standardized U.S. population in Minnesota, Michigan, and Florida. 107 In the Swedish normal population the estimated incidence rate of aplastic anemia or pancytopenia, thrombocytopenia (overall), and thrombocytopenia (drug-induced) is 24.6, 55.0, and 12.5 per million per year, respectively. 1°8

DRUG INTERACTIONS

Terbinafine acts as a substrate for a fraction of cytochrome P-450 by which it is rapidly metabolized. 1°9 Unlike the azoles, terbinafine demon- strates a weak substrate interaction with cytochrome P-450.11°,111 The metabolism of terbinafine has been reported not to involve the III A-4 and II 8-10 substrates. In contrast to ketoconazole, which shows a type II spectrum in binding to the microsomal system, terbinafine shows type I binding and is bound to less than 5% of cytochrome P-450 enzymes. Relevant competitive inhibition involving other substrates is probably clinically unlikely unless therapeutic plasma (and tissue) levels of terbinafine are vastly exceeded. 112 Drug interactions with terbinafine may include rifampin (increases terbinafine clearance by 100%), cimetidine (decreases terbinafine clearance by 33%), terfenadine (decreases terbinafine clearance by 16%), caffeine (decreases intra- venously administered caffeine clearance by 19%),113 and cyclosporine (terbinafine increases the clearance of cyclosporine by 15%). 16 Caffeine, like terbinafine, shows type I binding to the human microsomal system. It is therefore possible that elimination of drugs with type I binding may be inhibited by coadministration of terbinafine, whereas metabolism of drugs with type II binding may show little or no effect. For oral terbinafine, there is no information available from prospectively conducted drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thi- azide diuretics, beta blockers, and calcium chan- nel blockers. 16 In the U.K. postmarketing surveillance study there were no findings suggestive of a drug interaction between terbinafine and oral con-


traceptives, oral hypoglycemics, anticonvulsants, cimetidine, insulin, digoxin, and warfarin. 8°

PREGNANCY

Published data are limited on the use of terbinafine in pregnancy. In the U.K. postmarketing surveillance study (N = 10,361), the rate of menstrual disorders in women (21 to 40 years of age) taking an oral contraceptive pill was 4.5% (11 of 247) and the intermenstrual bleeding rate was 2.9% (7 of 246). 80 These rates may be within the range expected for patients taking an oral contraceptive. Terbinafine has a Food and Drug Administration pregnancy category B and is excreted in breast milk. 28

MONITORING

In the U.S. product monograph 16 it is recommended that hepatic function tests should be performed in patients taking terbinafine for longer than 6 weeks. In the Canadian and Australian product monographs 28,3° there are no such fixed guidelines and it is recommended that if the patient has signs or symptoms suggestive of hepatobiliary dysfunction, then the drug should be discontinued or appropriate laboratory testing done, or both.

With regard to monitoring for blood dyscrasias, there is no mandatory requirement for monitoring 28-3° in the monographs surveyed except in the United States where it is suggested that in patients with known or suspected immunodeficiency, consideration should be given to monitoring the com- plete blood cell count for treatment periods of more than 6 weeks) 6

Leeder et al. (personal communication, January 1996) suggest that regular monitoring for adverse events may be appropriate when the incidence of the ADR is more than or equal to 1/1000. In addi- tion, drugs such as dapsone, which have a much higher incidence of agranulocytosis, do not carry recommendations for routine monitoring for the blood dyscrasia. In keeping with the above, in a survey of Canadian dermatologists, we found that only 14% of prescribers perform regular prethera- py and follow-up blood tests when prescribing terbinafine. 114

Although there remain no firm monitoring guidelines when prescribing terbinafine in most countries worldwide (exception is the United States), patient education and counseling could

include discussion of the symptoms and signs that may indicate hepatobiliary dysfunction and blood dyscrasia, as well as the other side effects, guidelines on proper care of the feet and nails, especially those directed toward preventing reinfection.

PHARMACOECONOMIC EVALUATIONS

Although terbinafine has a higher acquisition cost than griseofulvin, the shorter duration of therapy, higher efficacy, and lower relapse rate make terbinafine the more cost-effective therapy. Similarly, oral terbinafine is a more cost-effective therapy for toenail onychomycosis than is ketoconazole.115-118 More recently, pharmacoeconomic analyses have compared terbinafine with itraconazole. In one study terbinafine appeared to be more cost-effective than itraconazole continuous therapy, 119 whereas the other analysis suggested that pulsed itraconazole and terbinafine had simi- lar cost-effectiveness ratios) 2°

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Terbinafine: An update

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