Auro-Terbinafine (Auro Pharma, 125 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

AURO-TERBINAFINE (terbinafine hydrochloride tablets) 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, Epidermophyton floccosum and yeasts of the genus Candida (eg. C.albicans), as well as Malassezia furfur.

Terbinafine is indicated in the treatment of onychomycosis (fungal infection of the nail) caused by dermatophyte fungi.

Prior to initiating treatment with terbinafine tablets, appropriate nail or skin specimens should be obtained for laboratory testing (KOH preparation, fungal culture, or nail biopsy) in order to confirm the diagnosis of onychomyocosis or dermatomycosis.

Terbinafine may be considered for the treatment of severe tineal skin infections (tinea corporis, tinea cruris and tinea pedis), which have been unresponsive to topical treatment.

Note: Terbinafine is not effective in pityriasis versicolor.

CONTRAINDICATIONS

Terbinafine is contraindicated in patients with a known hypersensitivity to terbinafine or to any of the excipients of terbinafine. (see DOSAGE FORMS, COMPOSITION and PACKAGING)

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of terbinafine tablets for the treatment of onychomycosis and dermatomycosis in individuals with and without pre-existing liver disease.

In the majority of liver cases reported in association with terbinafine use, the patients had serious underlying systemic conditions and an uncertain causal association with terbinafine. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease. Treatment with terbinafine tablets should be discontinued if biochemical or clinical evidence of liver injury develops.

Hepatic

Terbinafine tablets are not recommended for patients with chronic or active liver disease. Before prescribing terbinafine tablets, pre-existing liver disease should be assessed. Hepatotoxicity may occur in patients with and without pre-existing liver disease. Pre-treatment serum transaminase (ALT and AST) tests are advised for all patients before taking terbinafine tablets. Patients prescribed terbinafine tablets should be warned to report immediately to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale stools. Patients with these symptoms should discontinue taking oral terbinafine, and the patient's liver function should be immediately evaluated.

Renal

The pharmacokinetics of terbinafine have been investigated in patients with renal impairment (creatinine clearance ≤ 50 mL/ min); based on this study the use of terbinafine in renally impaired patients is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Metabolism

In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6 metabolism. Therefore, patients receiving concomitant treatment with drugs predominantly metabolised by this enzyme, e.g. certain members of the following drug classes, tricyclic antidepressants (TCAs), β blockers, selective serotonine reuptake inhibitors (SSRIs), antiarrhythmics class 1A, 1B and 1C and monoamine oxidase inhibitors (MAO-Is) Type B, should be followed up, if the co-administered drug has a narrow therapeutic window (see DRUG INTERACTIONS).

Skin

Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) have been very rarely reported in patients taking terbinafine tablets. If progressive skin rash occurs, treatment with terbinafine tablets should be discontinued.

Ophthalmologic

Changes in the ocular lens and retina have been reported following the use of terbinafine tablets in controlled trials. The changes noted were non-specific and the significance of these changes is unknown.

Immune

Transient decreases in absolute lymphocyte counts (ALC) have been observed in controlled clinical trials. The clinical significance of this observation is unknown. However, in patients with known or suspected immunodeficiency, physicians should consider monitoring complete blood counts in individuals using terbinafine therapy for greater than six weeks.

Lupus erythematosus:

During post-marketing experience, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported infrequently in patients taking terbinafine. Terbinafine therapy should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus.

Hematologic

Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with terbinafine tablets. Aetiology of any blood dyscrasias that occur in patients treated with terbinafine tablets should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with terbinafine tablets.

Carcinogenesis and Mutagenesis

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

General:

Special Populations

Pregnant Women: Animal fetal toxicity and fertility studies did not reveal any teratogenic or embryofetotoxic potential of terbinafine. However, there is only very limited clinical experience with terbinafine in pregnant women; therefore, unless the potential benefits outweigh any potential risks, terbinafine should not be used during pregnancy.

Nursing Women: Terbinafine is excreted in breast milk; therefore mothers receiving treatment with terbinafine should not breast feed.

Geriatrics: 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 in the elderly 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).

Pediatrics: The safety and efficacy of terbinafine have not been established in pediatric patients. Terbinafine should be kept out of the reach of children.

Occupational Hazards

Effects on ability to drive and use machines

No studies on the effects of terbinafine tablets treatment on the ability to drive and use machines have been performed. Patients who experience dizziness as an undesirable effect should avoid driving vehicles or using machines.

ADVERSE REACTIONS

The following table of adverse events illustrates some of these results:

Less Common Clinical Trial Adverse Drug Reactions (<1%)

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. Isolated cases of prolonged taste disturbances have been reported. A decrease of food intake leading to significant weight loss was observed in very few severe cases.

Rare: Idiosyncratic and symptomatic hepatobiliary reactions (2/3 primarily cholestatic in nature and the remainder involving hepatocytic damage or both) have been reported in

association with terbinafine treatment, including very rare cases of serious liver failure (some leading to liver transplant or death). 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) (see WARNINGS AND PRECAUTIONS).

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 1:37000 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.

Hepatobiliary dysfunction (primarily cholestatic in nature), very rare cases of serious liver failure (some with a fatal outcome, or requiring liver transplant). In the majority of liver failure cases the patients had serious underlying systemic conditions and a causal association with the intake of terbinafine was uncertain.

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), acute generalized exanthematous pustulosis psoriasiform eruptions or exacerbation of psoriasis (if progressive skin rash occurs, terbinafine treatment should be discontinued). Anaphylactic reactions (including angioedema) have been reported. Precipitation or exacerbation of cutaneous and systemic lupus erythematosus have been reported.

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

Hematologic disorders such as neutropenia, agranulocytosis, pancytopenia and thrombocytopenia have been reported (very rare). 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.

Post-Market Adverse Drug Reactions

During post-marketing experience with terbinafine tablets, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported infrequently in patients taking terbinafine. Terbinafine therapy should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus.

The following adverse events were also reported: dizziness, anemia, CPK elevations, rhabdomyolysis, pancytopenia, paresthesia and hypoaesthesia.

DRUG INTERACTIONS

Overview

Many categories of drugs are known to inhibit or induce drug metabolism by cytochrome P450 (CYP) enzymes located in the liver and intestine. Co-administration of such drugs may impact metabolic elimination of drugs, and in some cases, bioavailability may be either increased or decreased and accordingly, possibly necessitate dosage adjustments.

Drug-Drug Interactions:

The following medicinal products may increase the effect or plasma concentration of terbinafine:

Cimetidine decreased the clearance of terbinafine by 33%.

The following medicinal products may decrease the effect or plasma concentration of terbinafine:

Rifampicin increased the clearance of terbinafine by 100%.

Effect of terbinafine on other medicinal products;

According to the results from studies undertaken in vitro and in healthy volunteers, terbinafine shows negligible potential for inhibiting or enhancing the clearance of most drugs that are metabolised via the cytochrome P450 system (e.g. terfenadine, triazolam, tolbutamide or oral contraceptives) with exception of those metabolised through CYP2D6 (see below).

Terbinafine does not interfere with the clearance of antipyrine or digoxin.

Some cases of menstrual irregularities have been reported in patients taking terbinafine tablets concomitantly with oral contraceptives, although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.

Terbinafine may increase the effect or plasma concentration of the following medicinal products:

Caffeine: Terbinafine decreased the clearance of caffeine administered intravenously by 19%.

Compounds predominantly metabolised by CYP2D6

In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6-mediated metabolism. This finding may be of clinical relevance for compounds predominantly metabolized by this enzyme, e.g. certain members of the following drug classes tricyclic antidepressants (TCAs), β-blockers, selective serotonine reuptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-Is) Type B, particularly if they also have a narrow therapeutic window (see WARNINGS AND PRECAUTIONS).

Terbinafine decreased the clearance of desipramine by 82%.

Terbinafine may decrease the effect or plasma concentration of the following medicinal products:

Terbinafine increased the clearance of ciclosporin by 15%.

DOSAGE AND ADMINISTRATION

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

mycolological cure.

Administration:

Oral

DOSING CONSIDERATIONS

Special populations:

Liver impairment

Terbinafine tablets are not recommended for patients with chronic or active liver disease (see Warnings and Precautions).

Renal impairment

The use of terbinafine tablets has not been adequately studied in patients with renal impairment and is therefore not recommended in this population (see Warnings and Precautions).

OVERDOSAGE

A few cases of overdosage with terbinafine tablets (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.

For the management of suspected overdose, contact your local Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

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. Its activity against yeasts is fungicidal or fungistatic, depending on the species.

Pharmacodynamics

Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane. The enzyme squalene epoxidase is not linked to the cytochrome P450 system.

When given orally, the drug concentrates rapidly in skin, hair and nails at levels associated with fungicidal activity.

Pharmacokinetics

Absorption:

Following oral administration, terbinafine is well absorbed (>70%) and the absolute bioavailability of terbinafine from terbinafine tablets as a result of first-pass metabolism is approximately 50 %. A single 250 mg dose of terbinafine tablets resulted in mean a peak plasma concentration of 1.3 µg/ml within 1.5 hours after administration. At steady-state, in comparison to a single dose, peak

concentration of terbinafine was on average 25% higher and plasma AUC increased by a factor of 2.3. From the increase in plasma AUC an effective half-life of ~30 hours can be calculated. The bioavailability of terbinafine is moderately affected by food (increase in the AUC of less than 20%), but not sufficiently to require dosing adjustments.

Distribution:

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 lipophilic stratum corneum. It is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and sebum-rich skin. There is evidence that terbinafine is distributed in the nail plate within the first few weeks of commencing therapy.

Metabolism & Excretion:

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 isoenzymes are involved in its metabolism with major contributions from CYP 2C9, CYP 1A2, CYP 3A4, CYP 2C8 and CYP 2C19. Biotransformation results in metabolites with no antifungal activity which are excreted predominantly through the urine. No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been observed.

Following a single 250 mg dose in 12 hepatically impaired cirrhotic (alcoholic) patients, total clearance of terbinafine was reduced by about 40%. In a sample of 12 renally impaired patients (median creatinine clearance of 17.6 mL/min), 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.

STORAGE AND STABILITY

Store at room temperature between 15 and 30 ⁰C.

Protect from light.

SPECIAL HANDLING INSTRUCTIONS

HDPE bottle: Protect from light.

Blister Pack: Store in the original pack in order to protect from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Common Name:

Terbinafine Hydrochloride

Chemical Name: (2E)-N,6,6-Trimemyl-N- (naphthalen-1-ylmethyl) hept-2-

en-4-yn-1-amine hydrochloride.

Molecular Formula: C₂₁H₂₆NCl

Molecular Mass: 327.9

Structural formula:

Physicochemical

properties:

• White or almost white powder.

• Solubility: very slightly or slightly soluble in water.

  Freely soluble in anhydrous ethanol and in methanol, slightly soluble in acetone. 0.63% (W/V) in water and > 2% (W/V) in chloroform

• Melting point: 195 ^oC to 198 ^oC
• PKa (I) value: 7.10

• pH of a solution (0.5%) in methanol/water 4:6 (v/v): ~

  4.7. at 25 ⁰C.

CLINICAL TRIALS

Comparative Bio-availability data

An open label, randomised, two treatment, two sequence, two period, cross-over, single-dose, comparative oral bioavailability study of Terbinafine hydrochloride 250 mg tablets (Test) of Aurobindo Pharma Ltd., India and LAMISIL 250 mg tablets (Reference) of Novartis Pharmaceuticals Canada Inc., CANADA in 37 healthy, adult, male, human subjects under fasting conditions.

Summary Table of the Comparative Bio-availability Data

* Auro-Terbinafine 250 mg manufactured by Aurobindo Pharma Ltd. India for Auro Pharma Inc. ^† Lamisil 250 mg manufactured by Novartis Pharmaceuticals Canada Inc. were purchased in Canada ^§Expressed as the Median (Range) instead of Arithmetic Mean (%CV)

^$ Expressed as Arithmetic Mean (%CV) only

^#Based on the least squares mean estimates

Onychomycosis

Two studies evaluated the efficacy of oral terbinafine in the treatment of toe or fingernail onychomycosis

SF1501

SF00423

*The combined clinical/mycological endpoint was not specified in the protocol

Effective treatment in the terbinafine treated group was 78% fingernail and 55% toenail with treatment durations of 3-6 months. Griseofulvin was 80% and 42% effective for fingernails and toenails respectively. Thus, short duration therapy (3-6 months) using 500 mg per day of terbinafine appears effective in many patients with onychomycosis due to dermatophyte infections.

Tinea corporis/cruris

Study demographics and trial design

Summary of patient demographics for oral terbinafine clinical trials in tinea corporis/cruris

Study results

Combined results of placebo-controlled studies SF 0041 B, 5-OR, SF 0041C in tinea corporis/cruris¹

39-40OR

SF 0508

SF 0025

Study results

Results of placebo controlled studies 39-40OR, SFO508 in tinea pedis

* Too few placebo patients at follow-up to determine

† P<0.001, Fisher Exact test, one-sided

Placebo-controlled trials demonstrated a consistent treatment effect 2-6 weeks after cessation of treatment, whether assessed solely by mycological results, or when assessed by combined mycological and clinical parameters. Both 6-week and 2-week, o.d., and b.i.d. regimens were effective. In study 39-40OR, too few placebo patients returned at the follow-up visit to allow meaningful statistical analysis of results. Mycological cures and effective treatment rates at end of the 6 week treatment period, however, were significantly greater in the terbinafine treatment group than in the placebo group.

Results of study griseofulvin-controlled studies SF 0025 and 20-OR in tinea pedis

* Statistical significance not reported

† p = 0.054 Fishers Exact test

Two weeks after the end of 6 week courses of treatment, two small studies showed terbinafine to be better than griseofulvin in terms of mycological or combined mycological and clinical parameters.

DETAILED 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 α -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.

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.

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 µg/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 (MIC 50=0.195 µg/mL).

* = Exophiala jeanselmei, Wangiella dermatitidies, Cladosporium bantianum ** = Fonseceas pedrosoi, Phialophora spp.

Terbinafine was primarily fungicidal against T.mantagrophytes, M. canis, A. fumigatus, Sc. brevicaulis, S. schenkii, and C. parapsilosis, and fungistatic against C. albicans.

TOXICOLOGY

Long-term toxicity

LONG-TERM TOXICITY

Reproduction Studies

REPRODUCTION STUDIES

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

4-WEEK ORAL TOXICITY STUDY IN RATS WITH SPECIAL EMPHASIS ON HEPATIC ALTERATIONS

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

EFFECTS OF 13-WEEK TREATMENT ON SELECTED TOXICOLOGICAL VARIABLES IN RATS

4-week oral toxicity study in mice

4-WEEK ORAL TOXICITY STUDY IN MICE

Preliminary toxicity study in monkeys

PRELIMINARY TOXICITY STUDY IN MONKEYS

32-week oral 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 tumour-initiating potential even in combination with a tumour 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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