Product Monograph - Auro-Terbinafine (Auro Pharma, 250 mg)

RECENT MAJOR LABEL CHANGES

None at the time of authorization

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

TABLE OF CONTENTS……………………………………………………………………………………………………………..2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .................................................................................................................... 4

1.1 Pediatrics ............................................................................................................................ 4

1.2 Geriatrics ............................................................................................................................ 4

2 CONTRAINDICATIONS ....................................................................................................... 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ..................................................................... 5

4 DOSAGE AND ADMINISTRATION ....................................................................................... 5

4.1 Dosing Considerations ........................................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ................................................................... 5

4.4 Administration .................................................................................................................... 6

4.5 Missed Dose ........................................................................................................................ 6

5 OVERDOSAGE ................................................................................................................... 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING........................................ 6

7 WARNINGS AND PRECAUTIONS ........................................................................................ 7

7.1 Special Populations ........................................................................................................... 10

7.1.1 Pregnant Women .......................................................................................................... 10

7.1.2 Breast-feeding ............................................................................................................... 10

7.1.3 Pediatrics ....................................................................................................................... 10

7.1.4 Geriatrics ....................................................................................................................... 10

8 ADVERSE REACTIONS ...................................................................................................... 10

8.2 Clinical Trial Adverse Reactions ........................................................................................ 10

8.3 Less Common Clinical Trial Adverse Reactions ................................................................ 12

8.5 Post-Market Adverse Reactions ....................................................................................... 12

9 DRUG INTERACTIONS ..................................................................................................... 13

9.2 Drug Interactions Overview .............................................................................................. 13

9.4 Drug-Drug Interactions ..................................................................................................... 13

9.5 Drug-Food Interactions..................................................................................................... 18

9.6 Drug-Herb Interactions ..................................................................................................... 18

10 CLINICAL PHARMACOLOGY ........................................................................................... 18

10.1 Mechanism of Action ...................................................................................................... 18

10.2 Pharmacodynamics ........................................................................................................ 19

10.3 Pharmacokinetics ........................................................................................................... 19

11 STORAGE, STABILITY AND DISPOSAL ............................................................................. 21

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................... 21

PART II: SCIENTIFIC INFORMATION .................................................................................... 22

13 PHARMACEUTICAL INFORMATION ................................................................................ 22

14 CLINICAL TRIALS............................................................................................................ 23

14.1 Clinical Trials by Indication ............................................................................................. 23

Onychomycosis ....................................................................................................................... 23

Tinea corporis/Tinea cruris ..................................................................................................... 24

Tinea Pedis .............................................................................................................................. 27

14.2 Comparative Bio-availability data .................................................................................. 28

15 MICROBIOLOGY ............................................................................................................ 29

16 NON-CLINICAL TOXICOLOGY ......................................................................................... 31

17 SUPPORTING PRODUCT MONOGRAPH .......................................................................... 37

PATIENT MEDICATION INFORMATION ............................................................................... 38

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Auro-Terbinafine (terbinafine hydrochloride) is indicated for:

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.
the treatment of onychomycosis (fungal infection of the nail) caused by dermatophyte fungi.
- Prior to initiating treatment with Auro-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 onychomycosis or dermatomycosis.
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: Auro-Terbinafine tablets are not effective in pityriasis versicolor(also known as Tinea versicolor).

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (> 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. (See 7.1.4 Geriatrics)

2 CONTRAINDICATIONS

Auro-Terbinafine tablets are contraindicated in patients with a known hypersensitivity to terbinafine or to any of the excipients of Auro-Terbinafine or component of the container. See 6 DOSAGE FORMS, STRENGTHS, and COMPOSITION AND PACKAGING.
Auro-Terbinafine tablets are contraindicated for patients with chronic or active hepatic disease. See 7 WARNINGS AND PRECAUTIONS, 8 ADVERSE REACTIONS.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

HEPATIC: Auro-Terbinafine tablets are contraindicated in patients with pre-existing chronic or active hepatic disease. Serious and life-threatening hepatic adverse reactions (including hepatic failure leading to death and liver transplant) have been reported in patients with or without pre-existing chronic or active hepatic disease receiving terbinafine tablets for the treatment of onychomycosis and dermatomycosis.
Baseline liver function test should be recommended before initiating treatment with Auro-Terbinafine tablets. Auro-Terbinafine tablets and should be discontinued if biochemical or clinical evidence of liver injury develops. See 7 WARNINGS AND PRECAUTIONS, Hepatic.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Special Populations

Liver Impairment: Auro-Terbinafine tablets are contraindicated for patients with chronic or active hepatic disease. See 2 CONTRAINDICATIONS and 7 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.

4.2 Recommended Dose and Dosage Adjustment

Adults: 250 mg once daily. See 4.1 Dosing Considerations.
The duration of treatment varies according to the indication and the severity of infection:

Table 1

Indication

Duration of Treatment

Onychomycosis (of fingers and toes)*

6 weeks to 3 months

Skin Infections**

Tinea pedis (interdigital & plantar/moccasin type)

2-6 weeks

Tinea corporis, cruris

2-4 weeks

* 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.

4.4 Administration

The scored tablets are taken orally with water. They should preferably be taken at the same time each day and can be taken on an empty stomach or after a meal.

4.5 Missed Dose

If a dose of Auro-Terbinafine tablets is missed, the patient should be advised to take it as soon as he/she remembers. However, if it is almost time of the next dose (up to 4 hours), the patient should skip the missed dose and go back to the regular dosing schedule. The patient should not double dose.

5 OVERDOSAGE

A few cases of overdosage with terbinafine tablets (up to 5 g) have been reported giving rise to headache, nausea, epigastricpain 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 most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2 – Dosage Forms, Strengths, Composition and Packaging.

Route of Administration	Dosage Form / Strength	Non-medicinal Ingredients
oral	Tablet 250 mg, terbinafine (as terbinafine hydrochloride)	Cellulose microcrystalline, hypromellose, magnesium stearate, silica colloidal anhydrous, sodium starch glycolate.

Auro-Terbinafine 250 mg tablets are white to off white, round uncoated, biconvex, beveled edge tablets with break line and ‘D’ debossed on one side and ‘74’ on the other side.. Available in bottles of 100 and blister packs of 28 tablets (14 tablets per blister).

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Carcinogenesis and Mutagenesis

An increase in liver tumors 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.

Driving and Operating Machinery

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.

Endocrine and Metabolism

In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6 metabolism. Therefore, patients receiving concomitant treatment with drugs 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 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 9 DRUG INTERACTIONS.

Hematologic

Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with terbinafine tablets. Etiology 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 Auro-Terbinafine tablets.

Hepatic/Biliary/Pancreatic

Auro-Terbinafine tablets are contraindicated for patients with chronic or active hepatic disease. Before prescribing Auro-Terbinafine tablets, a baseline liver function test should be performed to assess any pre-existing liver disease since hepatotoxicity may occur in patients with and without pre- existing liver disease. Periodic monitoring (after 4-6 weeks of treatment) of liver function tests is recommended. Auro-Terbinafine tablets should be immediately discontinued in case of elevation of liver function tests. Patients prescribed Auro-Terbinafine tablets should be warned to report immediately to their physician any symptoms of persistent nausea, decreased appetite, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale feces. Patients with these symptoms should be advised to discontinue taking oral terbinafine, and the patient’s hepatic function should be immediately evaluated. See 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; 8 ADVERSE REACTIONS.

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 Auro-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. Auro-Terbinafine therapy should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus.

Monitoring and Laboratory Tests

Measurement of serum transaminases (ALT and AST) is advised for all patients before taking Auro-Terbinafine tablets.

Neurologic

Sensory disturbances:

Disturbances of visual, auditory and tactile senses have been reported. See 8 ADVERSE REACTIONS. If visual or hearing disturbances occur, Auro-Terbinafine tablets should be discontinued.

Taste Disturbance Including Loss of Taste:

Taste disturbance, including taste loss, has been reported with the use of terbinafine tablets. It can be severe enough to result in decreased food intake, weight loss, and depressive symptoms. Taste disturbance usually resolves within several weeks after discontinuation of treatment.

Isolated cases of prolonged taste disturbances have also been reported. If symptoms of a taste disturbance occur, Auro-Terbinafine tablets should be discontinued.

Smell Disturbance Including Loss of Smell:

Smell disturbance, including loss of smell, has been reported with the use of terbinafine tablets. Smell disturbance may resolve after discontinuation of treatment, but may be prolonged (greater than one year), or may be permanent. If symptoms of a smell disturbance occur, Auro-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.

Psychiatric

Anxiety and depressive symptoms:

Anxiety and depressive symptoms have occurred during postmarketing use of terbinafine secondary to taste disturbances, as well as independent of taste disturbances. If depressive symptoms occur, Auro-Terbinafine tablets should be discontinued.

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 10.3 Pharmacokinetics.

Reproductive Health: Female and Male Potential

Please see 7.1.1. Special Population

Women of child-bearing potential: 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.

There are no data to suggest special recommendations for women of child-bearing potential.

Fertility: No effect of terbinafine on fertility has been seen in animal studies (see section 16 NON-CLINICAL TOXICOLOGY) and there are no data to suggest an effect on fertility in humans.

Skin

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

Terbinafine should be used with caution in patients with pre-existing psoriasis or lupus erythematosus as precipitation and exacerbation of psoriasis and cutaneous and systemic lupus erythematosus have been reported in a postmarketing setting.

7.1 Special Populations

7.1.1 Pregnant Women

Animal fetal toxicity studies did not reveal any teratogenic or embryo fetotoxic potential of terbinafine. However, there is only very limited documented clinical experience with terbinafine in pregnant women; therefore, unless the potential benefits outweigh any potential risks, Auro-Terbinafine tablets should not be used during pregnancy.

7.1.2 Breast-feeding

Terbinafine is excreted in breast milk; therefore mothers receiving Auro-Terbinafine tablets should not breast feed.

7.1.3 Pediatrics

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

7.1.4 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 Auro-Terbinafine tablets for patients in this age group, the possibility of pre-existing impairment of liver or kidney function should be considered (see 10.3 Pharmacokinetics).

8 ADVERSE REACTIONS

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Frequency estimate: very common ≥ 10%, common ≥ 1% to < 10%, uncommon ≥ 0.1% to < 1%, rare ≥ 0.01% to < 0.1%, very rare <0.01% (includes isolated reports).

Serious and life-threatening hepatic adverse reactions, including fatal outcome or requiring liver transplant, have been reported in patients receiving terbinafine tablets.

In clinical trials submitted for purposes of marketing approval in Canada adverse events occurred in 10.4% of patients receiving the recommended oral dose. Of these, 5% were mild to moderate gastrointestinal events (abdominal distension, decreased appetite, dyspepsia, nausea, mild abdominal pain, diarrhea), 3% were rash, urticaria and the remainder were for musculoskeletal reactions (arthralgia, myalgia) and miscellaneous non-specific events such as malaise or tiredness.

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

TABLE 3 Clinical Trial Adverse events

Organ System Adverse Event	Terbinafine 250 mg (n = 998)
Organ System Adverse Event	Terbinafine 250 mg (n = 998)
	Number	(%)
	Number	(%)
SKIN (overall)	27	2.7%
Erythema or rash	9	0.9
Urticaria	5	0.5
Eczema	1	0.1
Pruritis	4	0.4
Other	8	0. 8
GI (overall)	52	5.2
Diarrhea and/or cramps	10	1.0
Nausea and/or vomiting	11	1.1
Fullness	5	0.5
Sickness	1	0.1
G.I. irritation, dyspepsia, gastritis	22	2.2
Other	3	0.3
CNS (overall)	12	1.2
Headache	9	0.9
Concentration	2	0.2
Other	1	0.1
OTHER (overall)	11	1.1
Tiredness, fatigue	3	0.3
Pain (back, knee, legs, feet, kidney)	1	0.1
Change of taste or dry mouth	1	0.1
Other	6	0.6
LABORATORY ADVERSE CHANGES (overall)	2	0.2
Hypoglycemia	1	0.1
Elevated Liver enzymes	1	0.1
TOTAL	104	10.4

8.3 Less Common Clinical Trial Adverse Reactions

Adverse events not frequently observed (< 1%) include the following:

Uncommon: Paresthesia and hypoesthesia

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 hepatic 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). Hepatic failure, hepatitis, jaundice, cholestasis, hepatic enzyme increased. See 7 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 1:37 000 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.

8.5 Post-Market Adverse Reactions

The following adverse drug reactions have been identified based on post-marketing spontaneous reports with terbinafine tablets and are organized by system organ classes. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Blood and lymphatic system disorders: neutropenia, agranulocytosis, thrombocytopenia, anemia, pancytopenia, thrombocytopenic purpura (TPP). The mechanism of TPP induction and the role of terbinafine have not been elucidated.
Hepatobiliary disorders: Cases of hepatic failure some leading to liver transplant or death and, idiosyncratic and symptomatic hepatic injury. Cases of hepatitis, cholestasis, and increased hepatic enzymes have been seen with the use of terbinafine Tablets.
Immune system disorders: anaphylactic reaction including anaphylactic shock, respiratory compromised symptoms such as dyspnea, angioedema, serum sickness-like reaction, skin reactions (see Skin section), precipitation or exacerbation of cutaneous or systemic lupus erythematosus
Psychiatric disorders: anxiety and depressive symptoms secondary to taste disturbances. Anxiety and depressive symptoms independent of taste disturbance have also been reported with use of terbinafine Tablets.
Eye disorders: visual impairment, vision blurred, visual acuity reduced.
Ear and labyrinth disorders: hypoacusis, impaired hearing, tinnitus.
Vascular disorders: vasculitis.
Nervous system disorders: dizziness, anosmia including permanent anosmia, hyposmia. Dysgeusia including ageusia (hypogeusia, including ageusia, which usually recover within several weeks after discontinuation of the drug. Isolated cases of prolonged hypogeusia have been reported)
Gastrointestinal disorders: pancreatitis.
Musculoskeletal and connective tissue disorders: rhabdomyolysis, arthritis.
General disorders and administration site conditions: influenza-like illness, pyrexia.
Investigations: blood creatine phosphokinase increased, weight decreased (secondary to dysgeusia)
Skin and subcutaneous tissue disorders: Stevens Johnson syndrome, Toxic Epidermal Necrolysis, erythema multiforme, acute generalized exanthematous pustulosis, toxic skin eruption, dermatitis exfoliative, dermatitis bullous, psoriasiform eruptions or exacerbation of psoriasis, photosensitivity reactions (e.g. photodermatosis, photosensitivity allergic reaction and polymorphic light eruption) and alopecia.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Tablets: 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 (see 10.3 Pharmacokinetics).

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Effects of other medicinal products on terbinafine:

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

Table 4-A Established or Potential Drug-Drug Interactions

Proper/common name	Source of Evidence	Effect	Clinical comment
Proper/common name	Source of Evidence	Effect	Clinical comment
Cimetidine	CT	Decreased the clearance of terbinafine by 33%
Fluconazole	CT	Increased the Cmax and AUC of terbinafine by 52% and 69%, respectively, in a randomized, open-label, single-dose, three- period crossover study (7 day washout) in healthy male adult subjects (n = 18), treated with 750 mg terbinafine, 100 mg fluconazole and 750 mg terbinafine plus 100 mg fluconazole. The interaction likely involves inhibition of CYP2C9 and CYP3A4 enzymes
Theophylline	CT	Increased the Cmax and AUC of terbinafine by 25% each, and decreased the oral clearance of terbinafine by 24% in a randomized, open-label, single- dose, three-period crossover study, in healthy male and female adult subjects (n = 18) treated orally with 250 mg terbinafine, 375 mg theophylline, and 250 mg terbinafine plus 375 mg theophylline
Ketoconazole	T	May increase the systemic exposure to terbinafine, based on predicted inhibition of CYP2C9 and CYP3A4 (no studies were performed)
Amiodarone	T	May increase the systemic exposure to terbinafine, based on predicted inhibition of CYP2C9 and CYP3A4 (no studies were performed).
Cotrimoxazole (trimethoprim sulfamethoxazole)	CT	Did not alter the pharmacokinetics of terbinafine, in a randomized, open-label, single-dose, three- period crossover study (7 day washout) in healthy male and female adult subjects (n = 18), treated with 750 mg terbinafine, 160 mg trimethoprim plus 800 mg sulfamethoxazole, and 750 mg terbinafine plus 160 mg trimethoprim plus 800 mg sulfamethoxazole.
Zidovudine	CT	Did not alter the pharmacokinetics of terbinafine, in a randomized, open-label, single-dose, three- period crossover study (7 day washout) in healthy male and female adult subjects (n = 18), treated with 750 mg terbinafine, 200 mg zidovudine, and 750 mg terbinafine plus 200 mg zidovudine.
Rifampicin	CT	May decrease the effect or plasma concentration of terbinafine (increased the clearance of terbinafine by 100 %)

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Effect of terbinafine on other medicinal products:

Table 4-B Established or Potential Drug-Drug Interactions

Proper / common name	Source of Evidence	Effect	Clinical comment
Proper / common name	Source of Evidence	Effect	Clinical comment
Drugs that are metabolized via the cytochrome P450 system (e.g. terfenadine, triazolam, tolbutamide or oral contraceptives)	C, CT	According to the results from studies undertaken in vitro and in healthy volunteers, terbinafine shows negligible potential for inhibiting or enhancing the clearance except with exception of those drugs that are metabolized via the cytochrome P450 system metabolized through CYP2D6 (see below). 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.
Compounds predominantly metabolized by CYP2D6 (e.g. certain members of the following drug classes: tricyclic antidepressants (TCAs), beta- blockers, selective serotonine reuptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-Is) Type B)	T, CT	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 CYP2D6, e.g. certain members of the following drug classes: tricyclic antidepressants (TCAs), beta- 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 7 WARNINGS AND PRECAUTIONS). Case reports indicating interactions of terbinafine with tricyclic antidepressants e.g nortriptyline and imipramine) have been reported in a post- marketing setting.
Antipyrine or digoxin	CT	Terbinafine does not interfere with the clearance of antipyrine or digoxin.
Desipramine	CT	Terbinafine decreased the clearance of desipramine by 82%.
Dextromethorphan/dextrorphan	CT	Terbinafine increased the dextromethorphan/dextrorphan metabolic ratio in urine by 16- to 97-fold on average, in healthy subjects, converting some extensive CYP2D6 metabolizers to poor metabolizer status after treatment with 250 mg terbinafine once daily for 14 days. The effect of terbinafine on the dextromethorphan/dextrorphan metabolic ratio in urine was shown to be reversible, though the interaction potential may last for several weeks after termination of a terbinafine treatment cycle.
Ciclosporin	CT	Terbinafine increased the clearance of ciclosporin by 15%.

Proper/common name	Source of Evidence	Effect
Fluconazole	CT	Terbinafine did not alter the pharmacokinetics of fluconazole in a randomized, open-label, single-dose, three-period crossover study (7 day washout) in healthy male adult subjects, treated with 750 mg terbinafine, 100 mg fluconazole and 750 mg terbinafine plus 100 mg fluconazole.
Cotrimoxazole (trimethoprim sulfamethoxazole)	CT	Terbinafine did not alter the pharmacokinetics of cotrimoxazole (trimethoprim and sulfamethoxazole), in a randomized, open-label, single- dose, three-period crossover study (7 day washout) in healthy male and female adult subjects (n = 18), treated with 750 mg terbinafine, 160 mg trimethoprim plus 800 mg sulfamethoxazole, and 750 mg terbinafine plus 160 mg trimethoprim plus 800 mg sulfamethoxazole.
Zidovudine	CT	Terbinafine reduced zidovudine Cmax by 25%, increased AUC by 15%, reduced oral clearance by 15% and did not alter zidovudine plasma elimination half-life, in a randomized, open- label, single-dose, three-period crossover study (7 day washout) in healthy male and female adult subjects (n = 18), treated with 750 mg terbinafine, 200 mg zidovudine, and 750 mg terbinafine plus 200 mg zidovudine.
Theophylline	CT	Single dose terbinafine did not significantly alter the pharmacokinetics of theophylline in a randomized, open-label, single-dose, three- period crossover study, in healthy male and female adult subjects (n = 18) treated orally with 250 mg terbinafine, 375 mg theophylline, and 250 mg terbinafine plus 375 mg theophylline.

Proper/common name	Source of Evidence	Effect	Clinical comment
		Multiple dose terbinafine increased the AUC and half-life of theophylline by 16% and 24%, respectively, and decreased the oral clearance of theophylline by 14%, in a randomized, open-label, two- period crossover study in healthy male and female adult subjects (n = 12) treated orally with a single dose of 5 mg/kg theophylline alone (mean 345 mg, range 307 to 397 mg) and 2 hours after the last of 4 daily doses of 250 mg terbinafine.

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

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

9.6 Drug-Herb Interactions

St John’s wort may considerably decrease the plasma concentration and exposure of terbinafine, however the extent of decrease in exposure is not known.

10 CLINICAL PHARMACOLOGY

10.1 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.

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 P450 enzyme upon which terbinafine has no effect. In contrast to many azoles, terbinafine does not bind to cytochromes P 450 in mammalian steroidogenic tissues.

10.2 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, terbinafine accumulates rapidly in skin, hair and nails at levels associated with fungicidal activity.

10.3 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 peak plasma concentration of 1.3 mcg/ml within 1.5 hours after administration. At steady-state (70% steady state is achieved in approximately 28 days), 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 accumulates 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: Terbinafine tablets is excreted mainly in urine (80%) and in feces (20%). Following absorption terbinafine is metabolized 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.

Elimination: Multiple dose administration followed by extended blood sampling revealed a triphasic elimination with a terminal half-life of approximately 16.5 days.

The pharmacokinetics of orally administered terbinafine in plasma can best be described by a 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 mcg/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).

TABLE 5

Day	0	2	6	12	13	16
Stratum corneum	0.11	0.86	2.84	9.05	5.08	3.06
Derm / epiderm	0	0.05	0.23	0.35	0.11	0.14
Sebum	0	38.2	43.1	39.7	45.1	18.8
Hair	0.02	0.24	1.30	2.60	2.11	1.35
Sweat	0	0	0	0	0	0

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_1/2was 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 mcg/ml for the b.i.d. and q.d. doses, respectively, and did not increase over time.

Special Populations and Conditions

Hepatic Insufficiency: Following a single 250 mg dose in 12 hepatically impaired cirrhotic (alcoholic) patients, total clearance of terbinafine was reduced by about 40%.
Renal Insufficiency: 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.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature between 15 and 30°C.

Protect from light.

12 SPECIAL HANDLING INSTRUCTIONS

HDPE bottle: Protect tablets from light.

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

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper 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 g/mol

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: 195ºC to 198ºC
pKa (I) value: 7.10
pH of a solution (0.5%) in methanol/water 4:6 (V/V): ~4.7. at 25ºC.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Onychomycosis

Terbinafine tablets^†

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

TABLE 6 Summary of patient demographics for oral terbinafine clinical trials in onychomycosis

Study #

Trial design

Dosage, route of administration and duration

Study subjects (n=number)

Mean age (Range)

Gender

Race

SF1501

Randomized,

double- blind

multicenter,

parallel group, stratified enrolment

(toe/fingernail) b.i.d. vs

o.d. dosage

Terbinafine

tablets, oral 125

mg b.i.d up to 48

wk (toenail) or 24

wk (fingernail)

51 enrolled

evaluable

(18-74)

Male =

Female

= 9

Not reported

Terbinafine

tablets, 2x125

mg o.d. up to 48

wk (toenail) or 24

wk (fingernail)

52 enrolled

evaluable

(18-74)

Male =

Female

= 14

Not reported

SF00423

Randomized,

double-blind,

multicenter,

parallel

group,

griseofulvin-

comparative

Terbinafine

capsules:

Oral, 250 mg bid

for 3-6 months

47 enrolled

evaluable

44.6

(21-76

yr)

Male =

Caucasian

100%

Griseofulvin

capsules:

Oral 250 mg bid

for up to 6

months (standard

treatment period

is up to 12 months)

34 enrolled

evaluable

43.5

(20-61

yr)

Male =

Caucasian

100%

Study Results:

TABLE 7 Results of study SF1501 in onychomycosis

Primary Endpoints
Mycological cure (negative KOH and culture) – all infections	Toenails
	25/31 (81%)	28/35 (80%)
	25/31 (81%)	Fingernails
	10/10 (100%)	10/11 (91%)
Effective treatment (negative mycology plus continuous or limited nail growth) at end of treatment at week 24 - all infections	Toenails
	24/32 (75%)	26/37 (70%)
	24/32 (75%)	Fingernails
	10/11 (91%)	10/11 (91%)

There were no significant differences between b.i.d and o.d. treatment regimens with respect to mycological cure rates or rates of effective treatment. Mycological cure at end of treatment was 95 % for fingernails and 80% for toenails. At follow-up visit 3-12 months later, over 81% of toenail onychomycosis were cured without relapse.

TABLE 8 Results of study SFO0423 in onychomycosis

Primary Endpoints
Effective treatment (negative mycology plus continuous or limited nail growth) at end of treatment at week 24*	Toenail
	11/20 (55%)	5/12 (42%)
		Fingernail
		7/9 (78%)	8/10 (80%)
Mycological cure (negative culture and KOH) at week 24	Toenail
	12/20 (60%)	5/12 (42%)
		Fingernail
		7/9 (78%)	7/10 (70%)

*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/Tinea cruris

Terbinafine tablets

Study demographics and trial design:

TABLE 9 Summary of patient demographics for oral terbinafine clinical trials in tinea corporis/cruris

Study #

Trial design

Dosage, route of administration and duration

Study subjects (n=number)

Mean age across studies (Range)

Gender

Race: Percent Caucasian

Placebo- controlled: SFO041B 5-OR SFO041C

Randomized, single or multicenter

, parallel group, double- blind, placebo controlled

Terbinafine oral, capsules, 125 mg

bid for 4 wk; 2 wk follow-up

Entered 79

Evaluable 62

34 - 40

Years

(18-74)

Male =

Female

71-

100%

Matching placebo

Entered 77

Evaluable 62

37-42

(18-70)

Male =

Female

= 13

Griseofulvin-controlled:

11-OR

SFO044

Randomized, single or

multicenter

, parallel

group,

double-

blind,

double-

griseofulvin

-controlled

Terbinafine oral

capsules, 125 mg

and placebo bid

for up to 6 wk; 2-

6 wk follow-up

Entered 189

Evaluable 174

37-38

(17-69)

Male =

105

Female

= 69

85-

99%

Griseofulvin oral

capsules 2x250

mg bid for up to

6 wk; 2-6 wk

follow-up

Entered 192

Evaluable 170

31-34

(17-85)

Male =

107

Female

= 63

Ketoconazole

controlled:

SF3006

SF0047

Randomized, single or

multicenter, parallel

group,

double-

blind,

double-

griseofulvin

-controlled

Terbinafine oral

capsules, 125 mg

and placebo bid

for up to 6 wk; 4-

8 wk follow-up

Entered 73

Evaluable 65

34-48

(18-80)

Male =

Female

= 25

60-

92%

Ketoconazole

oral capsules

200 mg od

(placebo od) for

up to 6 wk; 2-6 wk follow-up

Entered = 71

Evaluable = 62

31-43

(16-70)

Male =

Female

= 22

Study results:

TABLE 10 Combined results of placebo-controlled studies SF 0041 B, 5-OR, SF 0041C in tinea corporis/cruris¹

Primary Endpoints	Terbinafine Number (%)	Placebo Number (%)
Mycological cure (negative culture and KOH) at follow-up	7-30 (100 - 64%)	0-4 (0-36%)
Effective treatment (mycological cure and no to minimal signs or symptoms) at follow-up	8-30 (62-91%)	0-4 (0-23%)
5-OR: mycological cure results (combined culture and KOH results) were not provided and too few patients returned at follow-up for meaningful assessments. However, at end of treatment, terbinafine was significantly better than placebo in terms of mycological cures and negative KOH results (Negative KOH of 73% vs 17% for active and placebo, p = 0.043; Negative cultures of 73% vs 0% for active and placebo, p = -.007).
SF 0041B: too few placebo patients returned at follow-up for meaningful assessments; however, at end of therapy the proportion of patients with mycological cures was greater in the terbinafine group compared with placebo; effective treatment was noted in 75% and 23% of active and placebo groups

¹Range of values represents the highest and lowest values noted across the studies represented

The efficacy of a up to 6 weeks of treatment with terbinafine was consistently positive across 3 placebo-controlled trials both in rates of mycological cures and in the combination of mycological and clinical endpoints. In the placebo-controlled trials, placebo patients often did not return at the post-treatment follow-up to provide meaningful results at that visit. However, results at the end of treatment speak to the high degree of efficacy of terbinafine using clinical and/or mycological endpoints. Results of 4 studies with active comparators show terbinafine to be at least as good as, if not better than, systemically administered griseofulvin and ketoconazole.

TABLE 11 Results of griseofulvin-controlled studies 11-OR and SF 0044 in tinea corporis/cruris¹

Primary Endpoints	Terbinafine Number (%)	Comparator Number (%)
Mycological cure (negative culture and KOH) at follow-up	111 - 40 (93-100%)	101- 36 (94 – 95%)
Effective treatment (mycological cure and no to minimal signs or symptoms) at follow-up	119 – 37 (94 – 77%)	108 – 36 (86-82%)

¹Range of values represents the highest and lowest values noted across the studies represented

TABLE 12 Results of ketoconazole-controlled studies SF 3006 and SF 0047 in tinea corporis/cruris¹

Primary Endpoints	Terbinafine Number (%)	Comparator Number (%)
Mycological cure (negative culture and KOH) at follow-up	28-36 (100 – 97%)	23 – 31 (92-86)

¹Range of values represents the highest and lowest values noted across the studies represented

Tinea Pedis

Study demographics and trial design:

TABLE 13 Summary of patient demographics for clinical trials in tinea pedis

Study #	Trial design			Mean age (Range)		Gender	Race
39- 40OR	Randomized, double- blind, multicenter, placebo- controlled	Terbinafine tablets (or matching placebo) 125 mg bid for 6 weeks; 2 week follow- up	Terbinafine Enrolled 26 Evaluable 23	37 years (20-64)		Male = 15 Female =8	92% Caucasian
39- 40OR	Randomized, double- blind, multicenter, placebo- controlled		Placebo Enrolled 24 Evaluable 18	40 years (20-68)		Male = 13 Female=5
SF 0508	Randomized, double- blind, multicenter, placebo- controlled	Terbinafine tablets (or matching placebo) 125x2 mg od for 2 weeks; 6 week follow-up	Terbinafine Enrolled 18 Evaluable 14	39 years (19-72)		Male = 20 Female =6	79% Caucasian
SF 0508	Randomized, double- blind, multicenter, placebo- controlled		Placebo Enrolled 19 Evaluable 14	45 years (20-82)		Male =23 Female = 4
SF 0025	Randomized, double- blind, multicenter, griseofulvin controlled	Terbinafine capsules, 125 mg bid for 6 wk; 2 wk follow-up	Enrolled 39 Evaluable 33	38 years (18-79)	Male = 17 Female = 16		95% Caucasian
SF 0025		Griseofulvin capsules 250 mg bid for 6 wk; 2 wk follow-up	Enrolled 37 Evaluable 33	35 years (14-59)	Male = 18 Female = 15
20-OR	Randomized, double- blind, multicenter, griseofulvin controlled	Terbinafine capsules, 125 mg bid for 6 wk; 2 wk follow-up	Enrolled 18 Evaluable 16	38 years (22-63)		Male = 11 Female = 5	82% Caucasian
20-OR		Griseofulvin capsules 250 mg bid for 6 wk; 2 wk follow-up	Enrolled 18 Evaluable 12	36 years (20-49)		Male = 9 Female = 3

Study results

Primary Endpoints	Terbinafine Number (%)	Comparator Number (%)
Effective treatment (mycological cure and no to minimal signs or symptoms) at follow-up	28 – 35 (100 – 95%)	23 – 29 (92 – 78 %)

TABLE 14 Results of placebo controlled studies 39-40OR, SFO508 in tinea pedis

Primary Endpoints	Terbinafine Number (%)	Placebo Number (%)
Mycological cure (negative culture and microscopy) at follow-up
Study 39-40OR*	17/22 (77%)	0/6 (0%)
Study SF0508†	12/14 (86)%	1/14(7%)
Effective treatment (negative mycology and minimal signs and symptoms) at follow-up
Study 39-40OR*	15/23 (65%)	0/18 (0%)
Study SF0508†	10/14 (71%)	0/14 (0%)

* 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.

TABLE 15 Results of study griseofulvin-controlled studies SF 0025 and 20-OR in tinea pedis

Primary Endpoints	Terbinafine Number (%)	Comparator Number (%)
Mycological cure (negative culture and microscopy) at follow-up
SF 0025*	32/33 (97%)	28/31 (90%)
20-OR*	16/16 (100%)	6/11 (55%)
Effective treatment (negative mycology and minimal signs and symptoms) at follow-up
SF 0025†	32/33 (97%)	26/33 (79%)
20-OR†	14/16 (88%)	5/11 (45%)

* 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.

^†Auro-Terbinafine 125 mg tablets are not currently available on the Canadian market.

14.2 Comparative Bio-availability data

An open label, randomized, two-treatment, two-sequence, cross-over, comparative oral bioavailability study of ^PrAuro-Terbinafine 250 mg tablets (Auro Pharma Inc.) and ^PrLAMISIL 250 mg tablets (Novartis Pharmaceuticals Canada Inc.) was conducted in healthy, adult, Asian male subjects under fasting conditions. Comparative bioavailability data from the 37 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Terbinafine (1 x 250 mg) Geometric Mean Arithmetic Mean (CV %)
Parameter	Test¹	Reference²	% Ratio of Geometric Means	90% Confidence Interval
AUC0-72 (ng·h/mL)	4928.27 5766.03 (61.8)	4849.22 5602.02 (54.0)	101.5	91.8 – 112.3
AUC_I (ng·h/mL)	5619.95 6847.49 (65.8)	5580.27 6554.99 (55.5)	100.7	90.8 – 111.7
Cmax (ng/mL)	767.61 869.96 (51.0)	778.91 888.63 (49.9)	98.6	87.6 – 110.9
Tmax3 (h)	2.25 (0.75 – 5.00)	2.00 (0.75 – 5.00)
T½4 (h)	42.70 (51.2)	38.81 (34.9)

¹Auro-Terbinafine (terbinafine as terbinafine hydrochloride) tablets, 250 mg (Auro Pharma Inc.)

^{2 Pr}LAMISIL^®(terbinafine as terbinafine hydrochloride) tablets, 250 mg (Novartis Pharmaceuticals Canada Inc.)

³Expressed as the median (range) only

⁴Expressed as the arithmetic mean (CV %) only

15 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 mcg/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 mcg/mL).

TABLE 16 Summary of results published on in vitro activities of terbinafine against pathogenic and opportunistic fungi

Fungus

MIC range (mcg/mL)

I. Dermatophytic Fungi

Trichophyton mentagrophytes

rubrum

rubrum verrucosum

Epidermophyton floccosum

Microsporum canis

Microsporum gypseum

Microsporum persicolor

0.001-0.01

0.001- 0.01

0.001- 0.006

0.001-<0.06

0.005-0.01

0.002-0.003

II. Filamentous Fungi

Aspergillus spp.

Aspergillus flavus

Aspergillus fumigatus

Aspergillus niger

Aspergillus terreus

Pseudallescheria boydii

Mucor, Rhizopus spp.

Acremonium spp.

Curcularia fallax

Fusarium spp.

Hendersonulatoruloidea

Lasiodiplodiat heobromae

Paecilomycea spp.

Scopulariopsis brevicaulis

Scytalidium hyalinum

0.005-5.0

0.01-0.5

0.02-5.0

0.005-0.5

0.05-5.0

32.00->64.0

64.0->128.00

1.0-4.0

0.25-0.5

32.0->64.0

1.0-4.0

0.25-0.5

8.0-64.0

0.5-8.8

1.0-4.0

III. Dimorphic Fungi

Blastomyces dermatitidis

Histoplasma capsulatum

Sporothrix schenckii

0.05-0.39

0.05-0.2

0.05-2.0

IV. Pathogenic Yeasts

Candida albicans (yeast form)

Candida albicans (mycelial form)

Candida parapsilosis

Candida tropicalis

Candida pseudotropicalis

Candida krusei

Candida guilliermondii

Candida glabrata (T.glabrata)

Cryptococcus neoformans

Pityrosporum spp.

6.25->128.0

0.098-0.78

0.1-3.13

10.0-128.0

0.5-50.0

50.0->100.0

6.25-100.0

>100.0->128.0

0.25-2.0

0.2-0.8

V. Dematiacese

Phaechyphomycosis complex* Chromoblastomycosis complex**

<0.06- 0.5

0.06-2.0

* = 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.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity:

TABLE 17 ACUTE TOXICITY

Species	Sex	Route	LD50
Mouse	M,F	Oral	>4 g/kg
	M,F M,F	i.v. 1% solution orally	393 mg/kg > 250 mg/kg
Rat	M,F	Oral	>4 g/kg
	M,F	i.v.	213 mg/kg
	M,F M,F	1% cream orally 1% solution orally	25 mg/kg (no mortalities) >200 mg/kg
Rabbits	M,F	Topical (suspension)	>1.5 g/kg

Long Term Toxicity:

TABLE 18 LONG-TERM TOXICITY

SPECIES	LENGTH OF ADMIN.	ROUTE	DOSES (mg/kg)	RESULTS
RAT	26 weeks	oral	0, 30, 100, & 300	↑ in liver weights in the mid & high dose groups; ↑ in kidney and heart weights in high dose group; ↑adrenal weight all dose groups. In all animals allowed a recovery period organ weights showed signs of reversibility. At all doses males showed ↑ incidence & severity of spontaneous nephropathy. At mid & high doses, livers of female rats showed enlargement of centrilobular hepatocytes. Histological evidence of recovery in liver but not in kidney on cessation of treatment.
	52 weeks	oral	M: 6.9, 20, 68 F: 9.3, 28, 95	Reversible ↑ in kidney weight in mid and high-dose males and liver weight in high dose females. No histopathological organ or tissue changes or evidence of drug-related tumorigenesis. No proliferation of smooth endoplasmic reticulum or peroxisomes. No-toxic-effect level in males 68 mg/kg; in females 95 mg/kg.
Pre and Post pubertal RATS	55 days	oral	0, 25, 75, 250	In 15 day old rats treated until 70 days of age, the mid and high doses were toxic as shown by death of some animals at these dose levels. Reduction in mean body weight gain was also seen in these dose groups.
Juvenile RATS	55 days	oral	0, 10, 25, 45, 100	Well tolerated in rats treated from 15 to 70 days of age. 1 death in low dose group. Slight increase in liver weight of high dose females.
DOGS	26 weeks	oral	0, 20, 60, 200	Initial hypersalivation in mid and high dose groups; sporadic emesis in high dose group. Hematological parameters remained unchanged throughout experiment. At end of treatment livers of 3 of 4 high dose dogs contained lamellated intracytoplasmic inclusions. The no-toxic-effect level was 60 mg/kg.
	52 weeks	oral	0, 10, 25, 100	Mid and high dose groups showed sporadic emesis and slightly inhibited body weight gain. High dose groups showed sporadic hypersalivation and reduced food intake. Females of all dose groups showed slightly lower triglyceride values.
RABBITS	4 weeks	topical (2%cream)	10, 20, 40	Moderate reactions (erythema) at the application site.
	4 weeks	topical (1% solution)	0, 5, 15, 30	Skin site showed erythema, edema and papules in all groups including placebo controls.
	26 weeks	topical (1% & 2%cream)	10, 20, 40	Slight erythema and edema in all groups including placebo controls.

TABLE 19 Carcinogenicity:

SPECIES

DURATION

ROUTE

DOSES (mg/kg)

RESULTS

MICE

100 weeks

oral

M: 14, 40, 130

F: 16, 60, 156

There was a slight inhibition of body weight gain in the mid- and high-dose females. Macroscopic and microscopic examinations revealed no neoplastic or other findings which were attributable to treatment with terbinafine.

RATS

123 weeks

oral

M: 6.9, 20, 69

F: 9.6, 28, 97

Ophthalmoscopy revealed an ↑ in incidence of cataracts in males at high doses. No treatment related cataract changes occurred after 52 weeks, and such eye changes are known to occur spontaneously in old rats. ↑ incidence of enlarged swollen livers and liver nodules in the high dose animals, particularly males. Slight ↑ incidence of hepatocellular tumours in the high dose males. Females of the high dose group showed a slightly greater incidence and extent of hepatocellular necrosis, suggesting the high dose was at the threshold of a toxic response.

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.

Genotoxicity: 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

TABLE 20 4-Week oral toxicity study in rats with special emphasis on hepatic alterations

SPECIES	DURATION
ROUTE
DOSES (mg/kg)
SPECIES	DURATION
ROUTE
DOSES (mg/kg)
RAT	4 weeks
oral
M: 100, 465; F: 108, 530
RESULTS
FEED INTAKE & BODY WEIGHT GAIN	Only at the high dose level were significant decreases in food intake and body weight gain recorded.
CLINICAL CHEMISTRY	At the high-dose level reduced serum glucose (both sexes) and serum triglyceride levels (both sexes) and increased SGPT, SAP (females), and BUN (males) were seen. Significantly lower corticosterone plasma levels were found in high-dose animals and higher testosterone and estradiol plasma levels in low-dose males and females respectively.
LIVER MEASUREMENTS	Increased cytochrome P-450 content (high dose males) cytochrome b5 contents (high dose males and females), cytochrome b5 reductase activity (high dose males), 7-ethoxy-coumarin-O- deethylase activity (per mg cytochrome P-450; in low- and high-dose females), and peroxisomal palmitoyl-CoA epoxidase activity (low dose females and high dose males and females). Determination of liver compartments indicated a slight reduction of water content (high dose males), an unchanged protein content, and an increased lipid moiety (low dose males and high- dose males and females).
POSTMORTEM FINDINGS	Increased absolute and relative liver, and relative kidney weights (high dose males and females), mild hepatic centrilobular hypertrophy (high-dose only), increase in peroxisome numbers, and abnormal peroxisome shape (high-dose males). Slight increase in hepatic peroxisome size and number (high dose males and females). In high-dose group, numerous abnormal peroxisomes were found in both sexes, as well as a slight proliferation of the SER.

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

TABLE 21 EFFECTS OF A 13-WEEK TREATMENT ON SELECTED TOXICOLOGICAL VARIABLES IN RATS

SPECIES

DURATION

ROUTE

DOSES (mg/kg)

RESULTS

RATS

13 weeks

oral

M: 72

F: 102

Slight decrease in serum triglycerides (significant in males only), slight increase in albumin (females); these changes were observed in test weeks 5 and 8 only. Relative liver weights were increased as was palmitoyl-CoA epoxidase activity. There was no evidence of hepatic peroxisomal morphological abnormalities; however peroxisome numbers were increased in both sexes.

4-week oral toxicity study in mice

TABLE 22 4-WEEK ORAL TOXICITY STUDY IN MICE

SPECIES

DURATION

ROUTE

DOSES (mg/kg)

RESULTS

MICE

4 weeks

oral

M: 103, 510

F: 107, 512

Slightly impaired liver function in males only. Slight induction of the cytochrome P-450 and b5 systems was seen (biologically relevant only at the high-dose level and more marked in males than females), as well as ethoxy coumarin-O-deethylase activity. The peroxisomal marker palmitoyl-CoA-epoxidase was slightly increased at all dose levels (in both sexes); no changes in the size or number of peroxisomes were seen. There seemed to be a link between the degree of induction of some major hepatic enzyme systems and the moderate hepatic centrilobular hypertrophy observed histologically (and more generally the liver weight increases). Endocrinological examinations revealed higher basal corticosterone levels in a number of low and high-dose animals.

Preliminary toxicity study in monkeys

TABLE 23 PRELIMINARY TOXICITY STUDY IN MONKEYS

SPECIES	DURATION	ROUTE	DOSES (mg/kg)	RESULTS
MONKEYS	28 days	by gavage	500	Emesis and hypersalivation were observed on several occasions. The female showed consistent weight loss during the first 3 weeks and slight recovery thereafter. Liver weights were increased in both the treated animals, but there were no histopathological changes. No treatment-related changes in the peroxisome population or general cellular ultrastructure were seen. Increased activity of hepatic palmitoyl CoA-epoxidase indicated increased peroxisomal fatty oxidation. Cytosolic epoxide hydrolase activity was below detectable limit.

32-week oral toxicity in monkeys

TABLE 24 WEEK ORAL TOXICITY STUDY IN MONKEYS

SPECIES	DURATION	ROUTE	DOSE (mg/kg)	RESULTS
MONKEY	32 weeks	Oral	0, 150, 300	Eye lesions were seen after 26 weeks of treatment. Ophthalmoscopy revealed white spots on the retina in mid and high dose animals. No similar changes were seen at earlier examination. No morphological changes were seen in any layer of the retina. After withdrawal of terbinafine, the changes described recover fully (after a 13 week recovery period).

TABLE 25 Reproductive and Developmental Toxicology:

SPECIES	DURATION	ROUTE OF ADMIN.	DOSE (mg/kg)	RESULTS
RATS	Fertility & Reproduction Study M: 63 days prior to mating F: 14 days prior to mating to weaning	oral	10, 50, 250	In the high dose group a lower pregnancy rate, mean number of implants and living pups per dam were observed as well as a high pre- and perinatal offspring mortality. Physical and functional development of the offspring was also retarded. The fertility and general reproductive performance of the offspring were normal at all dose levels tested.
	Embryotoxicity study Days 6 to 15 postcoitum	oral	30, 100, 300	Inseminated female rats treated with terbinafine tolerated doses up to 100 mg/kg well. Lower body weight gain was seen at 300 mg/kg. No embryo lethal or teratogenic effects were seen.
	Peri & post-natal study Day 15 postcoitum to day 21 postpartum	oral	30, 100, 300	Inseminated female rats treated with terbinafine tolerated all doses well. No clinical signs or relevant reproductive changes in any group.
	Embryotoxicity study Day 6 to 15 postcoitum	subcutaneous	10, 30, 100	In the high dose group dams gained less body weight and had skin irritation at the injection site. A tendency to lower body weight gains was also noted in the mid-dose group. No adverse effects observed on pregnancy or embryonic or fetal development in any group.
RABBITS	Embryotoxicity study Day 6 to 18 postcoitum	oral	30, 100, 300	Inseminated female rabbits treated with terbinafine tolerated doses up to 100 mg/kg well. In the high-dose group weight loss was observed in some dams, 2 of which had to be euthanized due to poor health. No relevant reproductive alterations were seen at any dose level.

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-nitroso morpholine [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.

17 SUPPORTING PRODUCT MONOGRAPH

1. ^PrLAMISIL®, Tablets 250 mg, submission control 261997, Product Monograph, Novartis Pharmaceuticals Canada Inc., (AUG 15, 2022).

Rx or OTC	Prescription (Rx)?
DIN	02320134
Schedule(s)	PRESCRIPTION
Active ingredient(s)	Terbinafine (terbinafine hydrochloride) 250 MG
Dosage form(s)	Tablet
Route(s) of administration	Oral
Drug class (WHO ATC)	D Dermatologicals D01 Antifungals for dermatological use D01B Antifungals for systemic use D01BA Antifungals for systemic use D01BA02 Terbinafine
Company	AURO PHARMA INC
Current status	Marketed
Current status date	May 30, 2011

Auro-Terbinafine (Auro Pharma, 250 mg) Product Monograph

Product Monograph - Auro-Terbinafine (Auro Pharma, 250 mg)

RECENT MAJOR LABEL CHANGES

1 INDICATIONS

1.1 Pediatrics

1.2 Geriatrics

2 CONTRAINDICATIONS

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Special Populations

4.2 Recommended Dose and Dosage Adjustment

Table 1

4.4 Administration

4.5 Missed Dose

5 OVERDOSAGE

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

7 WARNINGS AND PRECAUTIONS

Carcinogenesis and Mutagenesis

Driving and Operating Machinery

Endocrine and Metabolism

Hematologic

Hepatic/Biliary/Pancreatic

Immune

Monitoring and Laboratory Tests

Neurologic

Ophthalmologic

Psychiatric

Renal

Reproductive Health: Female and Male Potential

Skin

7.1 Special Populations

7.1.1 Pregnant Women

7.1.2 Breast-feeding

7.1.3 Pediatrics

7.1.4 Geriatrics

8 ADVERSE REACTIONS

8.2 Clinical Trial Adverse Reactions

TABLE 3 Clinical Trial Adverse events

8.3 Less Common Clinical Trial Adverse Reactions

8.5 Post-Market Adverse Reactions

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

9.4 Drug-Drug Interactions

Table 4-A Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Table 4-B Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

9.6 Drug-Herb Interactions

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

10.2 Pharmacodynamics

10.3 Pharmacokinetics

TABLE 5

Special Populations and Conditions

11 STORAGE, STABILITY AND DISPOSAL

12 SPECIAL HANDLING INSTRUCTIONS

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Onychomycosis

Terbinafine tablets†

TABLE 6 Summary of patient demographics for oral terbinafine clinical trials in onychomycosis

TABLE 7 Results of study SF1501 in onychomycosis

TABLE 8 Results of study SFO0423 in onychomycosis

Tinea corporis/Tinea cruris

Terbinafine tablets

TABLE 9 Summary of patient demographics for oral terbinafine clinical trials in tinea corporis/cruris

TABLE 10 Combined results of placebo-controlled studies SF 0041 B, 5-OR, SF 0041C in tinea corporis/cruris1

TABLE 11 Results of griseofulvin-controlled studies 11-OR and SF 0044 in tinea corporis/cruris1

TABLE 12 Results of ketoconazole-controlled studies SF 3006 and SF 0047 in tinea corporis/cruris1

Tinea Pedis

TABLE 13 Summary of patient demographics for clinical trials in tinea pedis

TABLE 14 Results of placebo controlled studies 39-40OR, SFO508 in tinea pedis

TABLE 15 Results of study griseofulvin-controlled studies SF 0025 and 20-OR in tinea pedis

14.2 Comparative Bio-availability data

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Terbinafine tablets^†

TABLE 10 Combined results of placebo-controlled studies SF 0041 B, 5-OR, SF 0041C in tinea corporis/cruris¹

TABLE 11 Results of griseofulvin-controlled studies 11-OR and SF 0044 in tinea corporis/cruris¹

TABLE 12 Results of ketoconazole-controlled studies SF 3006 and SF 0047 in tinea corporis/cruris¹