Nu-Terbinafine Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations, terbinafine is fungicidal against dermatophytes, molds and certain dimorphic fungi. The activity against yeasts is fungicidal or fungistatic, depending on the species.

Terbinafine interferes specifically with fungal sterol biosynthesis by inhibition of squalene epoxidase in the fungal cell membrane. The enzyme squalene epoxidase is not a cytochrome

P450 enzyme. Its inhibition leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. When given orally, the drug concentrates rapidly in skin, hair and nails at levels associated with fungicidal activity.

Pharmacokinetics

A single oral dose of 250 mg terbinafine results in peak plasma concentrations of 0.97 µg/mL within 2 hours after administration. Seventy percent of the dose is absorbed by the gastrointestinal tract. The absorption half-life is 0.8 hours and the distribution half-life is 4.6 hours. The peak plasma concentration and bioavailability (AUC) roughly double when steady state is reached at 10-14 days. The bioavailability of terbinafine is moderately increased (20%)

by food, but not sufficiently to require dosing adjustments.

Terbinafine binds strongly to plasma proteins (99%) and is lipophilic. Terbinafine is widely distributed in the body including adipose tissue. It rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum. Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and in sebum-rich skin. There is evidence that terbinafine is distributed into the nail plate within the first few weeks of commencing therapy.

Terbinafine is excreted mainly in urine (80%) and in feces (20%). Following absorption terbinafine is metabolised rapidly and extensively by the liver. At least seven cytochrome P450 isoenzymes are involved in its metabolism with major contributions from CYP 2C9, CYP 1A2,

CYP 3A4, CYP 2C8 and CYP 2C19. Terbinafine inhibits, but is not metabolized by CYP 2D6.

Biotransformation is nearly complete and results in at least 15 identified metabolites all of which are excreted in the urine and lack antifungal activity. The plasma elimination half-life is 17 hours and the terminal half-life in stratum corneum, nail, hair, dermis and epidermis ranges from 22 to

28 days. Higher plasma concentrations were noted in older adults and in hypertensives and lower concentrations were noted in smokers.

Following a single 250 mg dose in 12 hepatically impaired cirrhotic (alcoholic) patients;

elimination of terbinafine was reduced by about 40%. Despite this difference in the mean clearance of terbinafine between cirrhotic patients and healthy subjects, the ranges of estimated clearances overlapped. Wide intra and intersubject variation was noted in normal volunteers.

The AUC was two-fold compared to the normal volunteers, but Cmax and Tmax were unchanged.

In a sample of 12 renally impaired patients (median creatinine clearance of 17.6 mL/sec), terbinafine clearance following a single 250 mg dose was halved resulting in the doubling or more of peak plasma concentrations or AUC. Patients at the highest and lowest ends of the renal impairment spectrum were not represented. There was no direct correlation between creatinine clearance and terbinafine clearance in renally impaired patients, the metabolism of the drug having been impaired in these patients due to competition between metabolite and parent drug.

Comparative Bioavailability

A comparative bioavailability study was performed using healthy human volunteers. The rate and extent of absorption of terbinafine was measured and compared following a single oral 250 mg dose of NU-TERBINAFINE (terbinafine hydrochloride) or Lamisil 250 mg tablets. The results from measured data are summarized as follows:

INDICATIONS AND CLINICAL USE

NU-TERBINAFINE (terbinafine hydrochloride) is indicated in the treatment of fungal infections of the skin and nails caused by dermatophytes such as Trichophyton (e.g. T. rubrum, T.

mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum.

Oral NU-TERBINAFINE is indicated in the treatment of onychomycosis (fungal infection of the nail) caused by dermatophyte fungi.

Where oral therapy is considered appropriate owing to the site, severity or extent of the infection,

NU-TERBINAFINE tablets may also be indicated in the treatment of tineal skin infections (tinea corporis, tinea cruris and tinea pedis).

Note: Oral terbinafine is not effective in pityriasis versicolor.

CONTRAINDICATIONS

NU-TERBINAFINE (terbinafine hydrochloride) tablets are contraindicated in patients with a hypersensitivity to terbinafine or any of the excipients (see Composition).

WARNINGS

Rare cases of symptomatic hepatobiliary dysfunction including cholestatic hepatitis and very rarely liver failure have been reported.

If a patient presents with signs or symptoms of liver dysfunction such as unexplained persistent nausea, anorexia, tiredness, abdominal pain, jaundice, pale stools or dark urine, treatment should immediately be discontinued and hepatic origin verified (See PRECAUTIONS, ADVERSE

REACTIONS).

There have been isolated reports of anaphylactoid and serious skin reactions (e.g. Stevens

Johnson Syndrome and Toxic Epidermal Necrolysis and Erythema Multiforme). If progressive skin rash occurs, treatment with terbinafine should be discontinued.

Isolated cases of blood dyscrasias have been reported in patients treated with terbinafine.

PRECAUTIONS

General

Indications of liver dysfunction ranging from asymptomatic liver enzyme increases to symptomatic cholestatic and hepatocytic injury have been reported with oral NU-TERBINAFINE (terbinafine hydrochloride). These have been observed at various times after treatment initiation, but on average, peak between 3 and 8 weeks. Though not always predictive, the monitoring of liver enzymes may be useful.

NU-TERBINAFINE should be kept out of the reach of children.

Use in Patients with Hepatic or Renal Impairment

There is very limited experience on the use of NU-TERBINAFINE in patients with liver disease or renal impairment. Plasma clearance appears to be reduced in some of these patients (see

Pharmacokinetics).

Caution should be exercised in patients at higher risk of developing hepatic dysfunction (e.g.

those receiving potentially hepatotoxic drugs; those with a history of alcoholism or suspicion of liver disorder). If the benefits of treatment are judged to outweigh potential risks in these patients liver function tests conducted at baseline and periodically during NU-TERBINAFINE treatment should be considered.

Use in Pregnancy and Lactation

Though fetal toxicity and fertility studies have shown no adverse effects in animals, there is only very limited clinical experience with NU-TERBINAFINE (terbinafine hydrochloride) in pregnant women; therefore, unless the potential benefits outweigh any potential risks, NU-TERBINAFINE should not be used during pregnancy.

Terbinafine is excreted in breast milk; therefore mothers receiving oral treatment with NU-

TERBINAFINE should not breast-feed.

Use in the Elderly

Plasma concentrations and drug half-life appear to be slightly higher in elderly patients than in the general population. In addition, the incidence of all adverse events in a Post Marketing

Surveillance study appeared to be slightly higher at normal adult doses; however, the overall rate of adverse events possibly or probably related to terbinafine did not appear to be different compared to the general population. When prescribing tablets for patients in this age group, the possibility of pre-existing impairment of liver or kidney function should be considered (see

Pharmacokinetics).

Use in Pediatrics

There is limited experience with terbinafine in children.

Drug Interactions

Many categories of drugs are known to inhibit or induce drug metabolism by cytochrome P450

(CYP) enzymes located in the liver and intestine. Coadministration of such drugs may impact metabolic elimination of drugs, and in some cases, bioavailability may be either increased or decreased and possibly necessitate dosage adjustments.

Results from in vitro experiments and in vivo studies in healthy volunteers suggest that, in general, there is a low potential for terbinafine inhibition or induction of the elimination of drugs metabolised by various CYP isoenzymes (e.g. coumarin (warfarin), ethinyl estradiol, cyclosporine, terfenadine, triazolam, and tolbutamide). Some cases of menstrual irregularities and pregnancies have been reported in patients taking NU-TERBINAFINE concomitantly with oral contraceptives; however, the rate of occurrence appears to be within the background incidence for patients taking oral contraceptives alone.

In vitro and clinical studies, however, have shown that terbinafine is a potent inhibitor of the ethnically polymorphic CYP 2D6 isoenzyme, which is responsible for the metabolism of a wide variety of drugs. Caution should be exercised in patients receiving concomitant therapy with drugs metabolized by CYP 2D6, especially those with a narrow therapeutic window. This includes, but is not limited to, tricyclic and serotonin-reuptake inhibitor antidepressants (e.g.

desipramine, fluvoxamine), antihypertensives such as $₁-adrenergic blocking agents (e.g.

metoprolol, propranolol), certain antiarrhythmic agents (e.g. flecainide, propafenone), monoamine oxidase inhibitors Type B (e.g. selegiline) and antipsychotics (e.g. chlopromazine, haloperidol).

For such drugs, which are metabolized by CYP 2D6, and where therapeutic activity is dependent upon the parent compound, an increased effect (or toxicity) may be produced. In contrast, for compounds such as codeine, where a metabolite is primarily responsible for drug action, a decrease in therapeutic effect may be realized.

Because multiple CYP enzyme pathways are involved in the metabolism of terbinafine, alternate pathways are available if one is inhibited by a competing substrate. Therefore, it is expected that few interactions will occur that result in significant increases in terbinafine plasma concentrations.

However, the plasma clearance of oral terbinafine has been shown to be increased by inducers of CYP enzyme metabolism (CL increased 100% by rifampin) and decreased by inhibitors (CL decreased 33% by cimetidine; and 42% by fluconazole). Where co-administration of such drugs is necessary NU-TERBINAFINE dosage may need to be adjusted accordingly.

Terbinafine co-administration has been reported to reduce plasma clearance of caffeine by 19% and of theophylline by 14%.

Carcinogenesis

An increase in liver tumours was observed in male rats at the highest dose level (69 mg/kg)

during the life-time (123 weeks) carcinogenicity study. The changes included increased enzyme activity, peroxisome proliferation and altered triglyceride metabolism. The changes have been shown to be species specific since they were not seen in mice or monkeys.

ADVERSE REACTIONS

Frequency estimate: very common $ 10%, common $ 1% to < 10%, uncommon $ 0.1% to < 1%, rare $ 0.01% to < 0.1%, very rare < 0.01%.

Terbinafine Hydrochloride Tablets

In general, terbinafine is well tolerated. Side effects are mild to moderate in severity, and transient.

In clinical trials adverse events occurred in 10.4% of patients receiving the recommended oral dose. Of these, 5% were mild to moderate gastrointestinal events (feeling of fullness, loss of appetite, dyspepsia, nausea, mild abdominal pain, diarrhea), 3% were non-serious forms of skin reactions (rash, urticaria) and the remainder were for musculoskeletal reactions (arthralgia, myalgia) and miscellaneous non-specific events such as malaise or tiredness. The following table lists adverse events observed in clinical trials with oral terbinafine, by organ system.

OTHER (overall) 11 1.1

Tiredness, fatigue 3 0.3

Adverse events not frequently observed include the following:

Uncommon: Taste disturbances, including taste loss, which usually recover within several weeks after discontinuation of the drug were reported.

Rare: Hepatobiliary dysfunction (2/3 primarily cholestatic in nature and the remainder involving hepatocytic damage or both) has been reported in association with terbinafine treatment, including very rare cases of liver failure. Unspecific prodromal symptoms (nausea, anorexia, fatigue, general malaise) have been reported. Liver enzyme increases have been noted in asymptomatic patients as well as in patients with more specific symptoms of hepatic dysfunction jaundice, upper abdominal right quadrant pain, pruritus, pale stools, dark urine).

The frequency of reported apparent hepatic dysfunctions has varied. An analysis of 7 key placebo-controlled trials (262 placebo vs 1624 terbinafine patients) suggested increases of 1.4% vs 3.4% in liver function test indicators (APase, SGPT (AST), SGOT (ALT), g-GT, bilirubin >2x above upper normal). In a European post-marketing study in 25 884 patients, asymptomatic liver enzyme increases were reported in 0.17% of patients treated. The reporting frequency for symptomatic liver disorder possibly related to terbinafine was 1:13 000. The relative risk of acute liver injury in this group was considered to be 4.2 times the background incidence. In the less controlled circumstances of spontaneous worldwide reporting, the development of clinically significant signs and symptoms of hepatobiliary dysfunction for which no other cause was apparent, and in which terbinafine was considered the possible causative agent was calculated to be approximately 1:37 000 treated patients. The reporting frequency overall for hepatobiliary events including elevations in liver enzymes was 1:15 000. Very rare cases of liver failure, some fatal, have been associated with terbinafine treatment and the incidence rate is about 1:1 000 000 exposed patients.

Oral terbinafine has been rarely associated with systemic allergic reactions including urticaria, angioedema, arthralgia, arthritis and serum sickness like reactions.

Very rare: Serious skin reactions (e.g. Stevens Johnson Syndrome, Toxic Epidermal Necrolysis and Erythema Multiforme) and anaphylactoid reactions have been reported.

Hair loss has been reported, however, a causal relationship has not been established.

Haematological disorders such as neutropenia, agranulocytosis, pancytopenia and thrombocytopenia have been reported. Very rare cases of thrombotic thrombocytopenic purpura

(TTP) have been reported. The mechanism of TPP induction and the role of terbinafine have not been elucidated.

Isolated cases of photosensitivity have been reported in association with terbinafine.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

A few cases of overdosage with terbinafine of (up to 5 g) have been reported, giving rise to headache, nausea, epigastric pain and dizziness. The recommended treatment of overdosage consists of eliminating the drug primarily by the administration of activated charcoal and giving, symptomatic supportive therapy, if needed.

DOSAGE AND ADMINISTRATION

NU-TERBINAFINE (terbinafine hydrochloride) Tablets

Adult Dosage: 250 mg once daily.

The duration of treatment varies according to the indication and the severity of infection:

* In patients with fingernail infections or toenail infections other than the big toe, or in younger patients, treatment periods of less than 3 months may be adequate. In patients with infections of the big toenail, treatment for 3 months is usually sufficient, although some patients may require treatment for 6 months or longer. Poor nail outgrowth during the first weeks of treatment may enable identification of those patients in whom longer therapy is required.

In onychomycosis the optimal clinical effect is seen some months after mycological cure and cessation of treatment. This is related to the period required for outgrowth of healthy nail tissue.

** Complete resolution of the signs and symptoms may not occur until several weeks after mycological cure.

Patients with Hepatic or Renal Impairment

There is very limited experience on the use of NU-TERBINAFINE in patients with liver disease or renal impairment. ln patients with pre-existing stable chronic liver dysfunction baseline liver function tests should be established and close follow-up is required (see Pharmacokinetics-

PRECAUTIONS, ADVERSE REACTIONS).

H₂C

N

CH₂

CH₃

C

H

C

H

C

C

C

CH₃

CH₃ H₃C

HCl PHARMACEUTICAL INFORMATION

Drug Substance

Proper/Common Name: terbinafine hydrochloride

Chemical Name: (E)–N–(6,6–dimethyl–2–hepten–4–inyl)–N–methyl–1–naphthaline–methanamine hydrochloride

Structural Formula:

Molecular Formula: C₂₁H₂₅N ! HCl

Molecular Weight: 327.90

Description: Terbinafine hydrochloride is a white to off-white finely crystalline powder with a melting point of ~205EC. The pKa (I) value is 7.10 and the pH of a solution (0.5%) in methanol/water 4:6 (v/v) is ~4.7 at 25EC. The solubility of terbinafine hydrochloride is 0.63%

(w/v) in water and >2% (w/v) in chloroform.

Composition

In addition to terbinafine hydrochloride, each tablet contains the non-medicinal ingredients methylcellulose, croscarmellose sodium, magnesium stearate, and colloidal silicon dioxide.

Stability and Storage Recommendations

Store at temperatures between 15E and 30EC. Protect from light.

AVAILABILITY OF DOSAGE FORMS

NU–TERBINAFINE 250 mg: Each round, white, biconvex, beveled-edged tablet, engraved ‘APO’ on one side, and scored and engraved ‘TER’ over ‘250’ on the other contains terbinafine hydrochloride equivalent to 250 mg terbinafine. Available in bottles of 100.

INFORMATION FOR THE PATIENT

NU-TERBINAFINE (ORAL) Patient Information Leaflet

Take once daily, preferably at the same time each day.

ABOUT YOUR MEDICINE

NU-TERBINAFINE is used to treat fungal infections of the skin, fingernails and toenails. The treatment should only be taken as prescribed by your doctor. Some evidence of infection may still be present at the end of treatment. This will gradually diminish.

If any of the information in this leaflet causes you special concern or if you want additional information about your medicine and its use, contact your doctor or pharmacist. Remember, keep this and all other medicines out of the reach of children and never share your medicines with others.

BEFORE USING THIS MEDICINE

Discuss with your doctor the possible side effects that may be caused by this medicine.

Tell your doctor if you:

• are allergic to any medicines, either prescription or nonprescription (OTC), or foods;
• are pregnant or intend to become pregnant while using this medicine;
• are breast-feeding; terbinafine is excreted in breast milk;
• are taking any other medicine, prescription or nonprescription (OTC), especially cimetidine or rifampicin;
• have a history of other medical problems, especially liver diseases such as jaundice

(yellowness to skin and/or eyes), kidney disease, alcohol abuse, serious skin reactions, or blood diseases such as anemia.

PROPER USE OF THIS MEDICINE

To help clear up your infection completely, it is very important that you keep taking this medicine for the prescribed treatment period, even if your symptoms begin to clear up or you begin to feel better after a few days. Since fungal infections may be very slow to clear up, stopping your medication too soon can cause the symptoms and the fungal infection to flare up again. Try not to miss any doses. If you do miss a dose, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular schedule. Do not double the doses and never make dose changes on your own. Take as prescribed by your doctor.

• Keep your regular appointments with your doctor.
• If you think you have taken an overdose of this medicine, check with your doctor.
• Store at temperatures between 15EC and 30EC. Protect tablets from light.

PRECAUTIONS WHILE USING NU-TERBINAFINE

Some individuals may be either very sensitive to terbinafine or may have had some liver disease in the past. These individuals are at risk of developing abnormal liver function. Stop taking NU-

TERBINAFINE and consult your doctor immediately should you develop jaundice (yellowness to skin and/or eyes).

Very occasionally some patients have developed blood abnormalities while being treated with

NU-TERBINAFINE. These reactions usually resolve on their own after stopping NU-

TERBINAFINE treatment.

If you have any questions about this, check with your doctor.

Always remember to follow your doctor’s instructions and have any medical tests done that your doctor may request. Keep your appointments for follow-up visits.

POSSIBLE SIDE EFFECTS OF NU-TERBINAFINE

TELL your doctor if you notice any of these possible side effects:

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor.

ASK your doctor if you do not understand these instructions or want more information.

MICROBIOLOGY

In vitro

The minimum inhibitory concentrations (MICs) of terbinafine were determined by serial dilution tests against yeasts, molds, dermatophytes, the mycelial form of Candida albicans, Pityrosporum spp., and Sporothrix schenkil. The spectrum and MIC values obtained for the various species and strains of fungi at different research laboratories (summarized as a range of activity in the following table) demonstrate that terbinafine possesses a high activity against dermatophytes, aspergilli, and dimorphous or dermatiaceous fungi. The susceptibility of blastospores of various species and strains of yeasts to terbinafine is much lower with MIC’s ranging from 0.1 to >128

:g/mL. The efficacy of terbinafine against 2 clinically important yeasts was confirmed by an evaluation of the susceptibility of 78 clinical isolates of Candida albicans and 20 of Candida parapsilosis. Blastophores of the Candida parapsilosis were more sensitive than those of

Candida albicans, but the mycelial growth form of the Candida albicans (considered the pathogenic form) was the most sensitive form (MIC₅₀ = 0.195 :g/mL).

Summary of results published on in vitro activities of terbinafine against pathogenic and opportunistic fungi

IV. Pathogenic Yeasts

Candida albicans (yeast form) Candida albicans (mycelial form) Candida parapsilosis

Candida tropicalis

6.25 0.098 0.1 10.0

-

-

-

-

>128.0 0.78 3.13 128.0

* Exophiala jeanselmei, Wangiella dermatitidies, Cladosporium bantianum

* * Fonseceas pedrosoi, Phialophora spp.

Terbinafine was primarily fungicidal against T. mentagrophytes, M. canis, A. fumigatus, Sc.

brevicaulis, S. schenkii, and C. parapsilosis, and fungistatic against C. albicans.

PHARMACOLOGY

The mechanism of action of terbinafine involves specific inhibition of fungal ergosterol biosynthesis at the point of squalene epoxidation, leading to a deficiency of an essential component of the fungal cell membranes (i.e. ergosterol) and to intracellular accumulation of the precursor squalene. The latter effect appears to be responsible for the primary fungicidal activity, its consequent disruption of cell membranes and cell wall synthesis having been noted in ultrastructural studies of terbinafine treated fungi. This mechanism distinguishes terbinafine from the azole antimycotics, which affect a later step in ergosterol biosynthesis by inhibiting 14 "-demethylase, a cytochrome P-450 enzyme, upon which terbinafine has no effect. In contrast to many azoles, terbinafine does not bind to cytochromes P-450 in mammalian steroidogenic tissues.

The pharmacokinetics of orally administered terbinafine in plasma can best be described by a

2–compartment model. More than 80% of the dose is absorbed, clearance of the drug is high, it is extensively metabolized in the liver, and it is extensively distributed in the tissues. The peak plasma concentration is proportional to the dose, and the time to peak is ~2 hours, independent of the dose. Terbinafine has an elimination half-life of 17 hours.

Mean concentrations of terbinafine (in µg/g) measured in the stratum corneum, dermis/ epidermis, hair, sweat, and sebum during and after 12 days of 250 mg terbinafine per day in 10 healthy volunteers were as follows before (day 0), during (days 2, 6, 12) and after treatment

(days 13 and 16).

The pattern of tissue distribution suggests a rapid diffusion of drug through the dermis/lower epidermis into the stratum corneum, where maximal concentrations were achieved at day 12, and the t_1/2 was 3-4 days (this implies that the concentrations of terbinafine would remain above the

MIC for most dermatophytes for 3 weeks). Another route of terbinafine distribution likely to be important for the treatment of dermatomycosis would be secretion into sebum, in which drug levels were high and persisted for several days after cessation of treatment.

In a study evaluating the efficacy of terbinafine in the treatment of onychomycosis, plasma levels were measured monthly in 9 patients, half of whom received 250 mg terbinafine q.d. in the evening and the other half 125 mg b.i.d. A pharmacokinetic steady state was attained at or before 4 weeks, the first analysis time point available. The steady-state plasma concentrations were 0.22 - 0.56 and 0.15 - 0.35 µg/mL for the b.i.d. and q.d. doses, respectively, and did not increase over time.

TOXICOLOGY

Acute Toxicity

M, F M, F

1% cream orally 1% solution orally

25 mg/kg (no mortalities)

>200 mg/kg

Long Term Toxicity

Reproduction Studies

Rabbits

Mutagenicity

In vitro and in vivo mutagenicity testing revealed no specific mutagenic or genotoxic properties of terbinafine. In vitro tests of cell transformation to malignancy were negative.

Carcinogenicity

Additional Studies

The following additional chronic toxicity and genotoxicity studies were performed to investigate the findings of the life-time rat study and their relevance to man.

4-week oral toxicity study in rats with special emphasis on hepatic alterations

Effects of 13-week treatment on selected toxicological variables in rats

4-week oral toxicity study in mice

Preliminary toxicity study in monkeys

32-week oral toxicity study in monkeys

Test for tumour-initiating activity in the rat liver foci bioassay

After partial hepatectomy, rats were treated with a single oral dose of 1 g/kg terbinafine (controls were treated with N-nitrosomorpholine [NNM]) followed by an 8-week treatment with phenobarbital (for promotion of growth of putative preneoplastic foci). A significant increase in foci/cm was seen only in NNM–treated animals in comparison with the respective control groups.

No differences were observed between control animals (treated only with phenobarbital) and those treated with terbinafine plus phenobarbital. It was concluded that terbinafine did not have tumor-initiating potential even in combination with a tumor promoting agent.

Autoradiographic determination of the induction of DNA repair/synthesis and cell replication in rat hepatocyte primary cultures after in vivo treatment

No evidence was found for any induction of either DNA repair or DNA replication in the hepatocytes from terbinafine treated rats, and the frequency of replicating nuclei were in the control range.

Mutagenicity test using Salmonella typhimurium

Liver fractions from male rats treated for 13 weeks with 69 mg/kg/day of terbinafine and non-treated control rats were used to evaluate terbinafine for genetic activity. There was no evidence that repeated treatment of rats with terbinafine induces enzymes capable of producing mutagenic intermediates of terbinafine.

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