Lamisil Product Monograph

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.............................................................................................................5

2 CONTRAINDICATIONS ...................................................................................................5

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.....................................................................................................7

4.5 Missed Dose ........................................................................................................7

5 OVERDOSAGE ...............................................................................................................8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................8

7 WARNINGS AND PRECAUTIONS ....................................................................................9

7.1 Special Populations ............................................................................................ 12

7.1.1 Pregnant Women .........................................................................................12

7.1.2 Breast-feeding..............................................................................................12

7.1.3 Pediatrics .....................................................................................................12

7.1.4 Geriatrics .....................................................................................................13

8 ADVERSE REACTIONS .................................................................................................. 13

8.2 Clinical Trial Adverse Reactions .......................................................................... 13

8.3 Less Common Clinical Trial Adverse Reactions .................................................... 14

8.5 Post-Market Adverse Reactions.......................................................................... 15

9 DRUG INTERACTIONS.................................................................................................. 16

9.2 Drug Interactions Overview................................................................................ 16

9.4 Drug-Drug Interactions ...................................................................................... 16

9.5 Drug-Food Interactions ...................................................................................... 22

9.6 Drug-Herb Interactions ...................................................................................... 23

10 CLINICAL PHARMACOLOGY ......................................................................................... 23

10.1 Mechanism of Action.................................................................................... 23

10.2 Pharmacodynamics ...................................................................................... 23

10.3 Pharmacokinetics ......................................................................................... 23

11 STORAGE, STABILITY AND DISPOSAL ........................................................................... 25

12 SPECIAL HANDLING INSTRUCTIONS............................................................................. 25

PART II: SCIENTIFIC INFORMATION ........................................................................................ 26

13 PHARMACEUTICAL INFORMATION.............................................................................. 26

14 CLINICAL TRIALS.......................................................................................................... 27

14.1 Clinical Trials by Indication............................................................................ 27

Onychomycosis ........................................................................................................... 27

Tinea corporis/Tinea cruris .......................................................................................... 28

Tinea Pedis.................................................................................................................. 33

Cutaneous Candidiasis................................................................................................. 39

Tinea Versicolor .......................................................................................................... 40

15 MICROBIOLOGY .......................................................................................................... 41

16 NON-CLINICAL TOXICOLOGY ....................................................................................... 43

PATIENT MEDICATION INFORMATION ................................................................................... 51

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

LAMISIL^® (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.

LAMISIL tablets:

• the treatment of onychomycosis (fungal infection of the nail) caused by dermatophyte fungi.

  • Prior to initiating treatment with LAMISIL^® 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: LAMISIL tablets are not effective in pityriasis versicolor (also known as Tinea versicolor).

LAMISIL cream and spray:

• Cream

  • the treatment of fungal infections of the skin caused by dermatophytes such as trichophyton, as well as yeast infections of the skin, principally those caused by the genus Candida (e.g. Candida albicans).
  • the treatment of pityriasis (tinea) versicolor due to Malassezia furfur.

• Spray

  • the treatment of fungal infections of the skin caused by dermatophytes such as trichophyton.
  • the treatment of pityriasis (tinea) versicolor due to Malassezia furfur.

Note: LAMISIL cream and spray are not effective in onychomycosis.

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

• LAMISIL tablets and LAMISIL cream and spray are contraindicated in patients with a known hypersensitivity to terbinafine or to any of the excipients of LAMISIL or component of the container. See 6 DOSAGE FORMS, STRENGTHS, and COMPOSITION AND PACKAGING.
• Lamisil 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: LAMISIL 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 LAMISIL tablets for the treatment of onychomycosis and dermatomycosis.
• Baseline liver function test should be recommended before initiating treatment with LAMISIL tablets. LAMISIL 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: LAMISIL tablets are contraindicated for patients with chronic or active hepatic disease. See 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS.
• Renal Impairment: The use of LAMISIL 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

• LAMISIL tablets:

  • 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

* 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 mycolological cure.

• LAMISIL cream:

  • LAMISIL cream can be applied once or twice daily depending on the indication.

  • The duration and frequency of treatment varies with the indication and is dependent on the severity of the infection:

    Table 2

* Two weeks of treatment with LAMISIL cream produced slightly improved efficacy over treatment for one week. The difference in outcome may not be clinically significant.

• Many patients treated with shorter durations of therapy (1-2 weeks) continue to improve during the 2-4 weeks after therapy has been completed. As a consequence, patients should not be considered therapeutic failures until they have been observed for a period of 2-4 weeks after cessation of treatment.
• Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment increases the risk of recurrence. If there are no signs of improvement after two weeks the diagnosis should be verified.
• LAMISIL spray:
• LAMISIL spray is applied once or twice daily, depending on the indication.

• The duration of treatment varies with the indication and is dependent on the severity of the infection:

  Table 3

• Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment increases the risk of recurrence. If there are no signs of improvement after two weeks the diagnosis should be verified.

4.4 Administration

Tablets: 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.

Cream: The affected areas should be cleansed and dried thoroughly before application of LAMISIL. The cream should be applied to the affected skin and surrounding area in a thin layer and rubbed in lightly. In the case of intertriginous infections (submammary, interdigital, intergluteal, inguinal) the area to which the cream has been applied may be covered with a gauze strip, especially at night.

Spray: The affected areas should be cleansed and dried thoroughly before application of LAMISIL. A sufficient amount of spray should be applied to wet the treatment area(s) thoroughly, and to cover the affected skin and surrounding area. See 7 WARNINGS AND PRECAUTIONS.

4.5 Missed Dose

If a dose of LAMISIL 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

LAMISIL Tablets

A few cases of overdosage with Lamisil 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.

LAMISIL cream and spray

No case of overdosage has been reported. The low systemic absorption of LAMISIL cream and spray renders overdosage extremely unlikely. Accidental ingestion of one 30 g tube of LAMISIL cream or one 30 mL bottle of LAMISIL spray, which contain 300 mg terbinafine, is comparable to one LAMISIL tablets. However, should, larger amounts of LAMISIL cream and spray be inadvertently ingested, adverse effects similar to those observed with an overdosage of LAMISIL tablets are to be expected (e.g. headache, nausea, epigastric pain and dizziness). The alcohol content of the spray (28.8% v/v) has to be taken into account.

For management of a suspected drug overdose, contact your regional poison control centre

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 4 – Dosage Forms, Strengths, Composition and Packaging.

LAMISIL 250 mg tablets are whitish to yellow tinged white, circular, biconvex, with bevelled edges tablet, scored on one side and embossed "LAMISIL 250". Available in bottles of 100 and 500 tablets and blister packs of 28 tablets (14 tablets per blister).

LAMISIL cream 1 % is white, smooth or almost smooth, glossy cream with a weak characteristic odor. Available in 15 or 30 gram tubes.

LAMISIL spray 1 % is Colourless to faintly yellow clear liquid. Available in 30 mL bottles.

7 WARNINGS AND PRECAUTIONS

LAMISIL Tablets

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 LAMISIL 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 LAMISIL tablets. Etiology of any blood dyscrasias that occur in patients treated with LAMISIL tablets should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with LAMISIL tablets.

Hepatic/Biliary/Pancreatic

LAMISIL tablets are contraindicated for patients with chronic or active hepatic disease. Before prescribing LAMISIL 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. LAMISIL tablets should be immediately discontinued in case of elevation of liver function tests. Patients prescribed LAMISIL 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 LAMISIL 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 LAMISIL. LAMISIL 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 LAMISIL tablets.

Neurologic

Sensory disturbances:

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

Taste Disturbance Including Loss of Taste:

Taste disturbance, including taste loss, has been reported with the use of LAMISIL 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, LAMISIL tablets should be discontinued.

Smell Disturbance Including Loss of Smell:

Smell disturbance, including loss of smell, has been reported with the use of LAMISIL 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, LAMISIL tablets should be discontinued.

Ophthalmologic

Changes in the ocular lens and retina have been reported following the use of LAMISIL 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, LAMISIL tablets should be discontinued.

Renal

The pharmacokinetics of LAMISIL have been investigated in patients with renal impairment (creatinine clearance ≤ 50 mL/ min); based on this study the use of LAMISIL 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 LAMISIL 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

LAMISIL tablets

Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms) have been very rarely reported in patients taking LAMISIL tablets. If progressive skin rash occurs, treatment with LAMISIL 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.

LAMISIL cream and spray

LAMISIL cream and spray are for external use only. LAMISIL cream and spray formulations may be irritating to the eyes. Contact with the eyes should be avoided. LAMISIL spray should not be used on the face.

In the case of accidental ocular contact, the eyes should be rinsed thoroughly with running water and patients should consult a physician if any symptoms persist. In case of accidental inhalation, patients should be advised to consult a physician if any symptoms develop and persist.

LAMISIL spray should be used with caution in patients with lesions where alcohol could be irritating.

Local skin reactions:

LAMISIL Cream contains cetyl alcohol and stearyl alcohol which may cause local skin reactions (e.g contact dermatitis).

LAMISIL Spray contains propylene glycol which may cause skin irritation.

7.1 Special Populations

7.1.1 Pregnant Women

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

7.1.2 Breast-feeding

Terbinafine is excreted in breast milk; therefore mothers receiving LAMISIL tablets should not breast feed. However, with LAMISIL cream and spray treatment, the small amounts absorbed through the skin are unlikely to affect the infant. Nursing mothers should NOT apply LAMISIL cream and spray to the breast. In addition, infants must not come into contact with any treated skin area, including the breasts.

7.1.3 Pediatrics

The safety and efficacy of LAMISIL have not been established in pediatric patients.

LAMISIL 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 LAMISIL 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).

LAMISIL tablets

Serious and life-threatening hepatic adverse reactions, including fatal outcome or requiring liver transplant, have been reported in patients receiving LAMISIL 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 5 Clinical Trial Adverse events

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 LAMISIL 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 LAMISIL 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 LAMISIL 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 LAMISIL 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 LAMISIL treatment and the incidence rate is about 1:1 000 000 exposed patients.

LAMISIL cream and spray:

Local symptoms such as pruritus, skin lesion, skin disorder, skin exfoliation, application site pain, application site irritation, pigmentation disorder, skin burning sensation, erythema, scab, dry skin, dermatitis contact, eczema may occur at the site of application; however, treatment rarely has to be discontinued for this reason. These minor symptoms must be distinguished from allergic reactions (e.g. bullous eruptions, hives, widespread rash and/or redness, urticaria, angioedema, or positive rechallenge) which are rare but require discontinuation of the drug. In clinical trials, adverse reactions were recorded in 33 of the 1757 (1.8%) patients who received LAMISIL cream, and in 39 of the 898 (4.3%) patients who received LAMISIL spray.

8.5 Post-Market Adverse Reactions

LAMISIL tablets

The following adverse drug reactions have been identified based on post-marketing spontaneous reports with LAMISIL 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 LAMISIL 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 LAMISIL 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 LAMISIL 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 6-A Established or Potential Drug-Drug Interactions

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

Effect of terbinafine on other medicinal products:

Table 6-B Established or Potential Drug-Drug Interactions

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

LAMISIL cream and spray:

No drug interactions are known to date.

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

LAMISIL (terbinafine) is an allylamine which has a broad spectrum of antifungal activity. At low concentrations LAMISIL 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 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.

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

LAMISIL tablets:

Absorption: Following oral administration, terbinafine is well absorbed (>70%) and the absolute bioavailability of terbinafine from LAMISIL tablets as a result of first-pass metabolism is approximately 50 %. A single 250 mg dose of LAMISIL tablets resulted in mean peak plasma concentration of 1.3 μg/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: LAMISIL binds strongly to plasma proteins (99%) and is lipophilic. LAMISIL 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 LAMISIL is distributed in the nail plate within the first few weeks of commencing therapy.

Metabolism: LAMISIL 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 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 LAMISIL 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 7

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.

LAMISIL cream and spray:

Less than 5% of the dose is absorbed after topical application to humans; systemic exposure is thus very slight. Pharmacokinetic studies in humans revealed that absorption of terbinafine cream or spray through skin is less than 5%. In a single dose study of 14C-terbinafine, urinary excretion accounted for ~ 90% of the absorbed dose, and the highest concentration appeared in the urine 2 and 3 days after terbinafine application.

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), LAMISIL 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

Tablets: Store at temperature between 15 and 30°C.

12 SPECIAL HANDLING INSTRUCTIONS

Protect tablets from light.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: INN, BAN, USAN: terbinafine

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

Molecular formula and molecular mass:

Terbinafine base: 291.40

Terbinafine Hydrochloride: C₂₁H₂₆NCl/327.90

Structural formula:

Physicochemical properties:

• White to off-white finely crystalline powder
• Melting Point: ~ 205°C.
• pKa (I) value: 7.10
• pH of a solution (0.5%) in methanol/water 4:6 (V/V): ~ 4.7. at 25°C.
• Solubility: 0.63% (W/V) in water and >2% (W/V) in chloroform

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Onychomycosis

LAMISIL tablets^†

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

TABLE 8 Summary of patient demographics for oral terbinafine clinical trials in onychomycosis

Study Results:

TABLE 9 Results of study SF1501 in onychomycosis

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 10 Results of study SFO0423 in onychomycosis

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

Effective treatment in the LAMISIL 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 LAMISIL appears effective in many patients with onychomycosis due to dermatophyte infections.

Tinea corporis/Tinea cruris

LAMISIL tablets

Study demographics and trial design:

TABLE 11 Summary of patient demographics for oral terbinafine clinical trials in tinea corporis/cruris

Study results:

TABLE 12 Combined results of placebo-controlled studies SF 0041 B, 5-OR, SF 0041C in tinea corporis/cruris¹

¹ Range 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 13 Results of griseofulvin-controlled studies 11-OR and SF 0044 in tinea corporis/cruris¹

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

TABLE 14 Results of ketoconazole-controlled studies SF 3006 and SF 0047 in tinea corporis/cruris¹

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

LAMISIL cream

Study demographics and trial design:

TABLE 15 Summary of patient demographics for terbinafine cream clinical trials in tinea corporis/cruris

¹ Range and distribution by sex provided only for SF 2002.

Study results:

TABLE 16 Combined results of placebo-controlled studies SF 2002 and SF2004, terbinafine cream 1%, in tinea corporis/cruris, 2 wk post-treatment

*Study 2002, p value for mycological cure not provided; p <0.007 for KOH and culture results individually. For study 2004 p <0.001 for mycological cure

^† p <0.001 for both studies

Two double-blind, placebo controlled studies evaluated whether one week of LAMISIL 1% cream was sufficient to treat Tinea corporis/cruris. At the three week follow-up LAMISIL was effective in 81% -87% of patients, clearly demonstrating the efficacy of daily short duration (one week) treatment.

LAMISIL spray

Study demographics and trial design:

TABLE 17 Summary of patient demographics for terbinafine 1% spray clinical trials in tinea corporis/cruris

Study results:

LAMISIL 1% spray was significantly more effective than placebo when applied once daily for one week in patients with Tinea corporis/cruris.

TABLE 18 Number (%) subjects with effective treatment (ET) or with both negative microscopy and culture (NM) at study end-point

Tinea Pedis

LAMISIL tablets

Study demographics and trial design:

TABLE 19 Summary of patient demographics for clinical trials in tinea pedis

Study results:

TABLE 20 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.

TABLE 21 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.

^†LAMISIL 125 mg tablets are not currently available on the Canadian market.

LAMISIL cream

Study demographics and trial design:

TABLE 22 Summary of patient demographics for terbinafine 1% cream clinical trials in tinea pedis

Study results:

TABLE 23 Combined results of placebo-controlled studies terbinafine 1% cream studies in tinea pedis ¹

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

TABLE 24 Combined results of active-controlled studies terbinafine 1% cream studies in tinea pedis

LAMISIL spray

Study demographics and trial design:

TABLE 25 Summary of patient demographics for terbinafine 1% spray clinical trials in tinea pedis

Study Results:

Whether applied once or twice daily for one week or once daily for two weeks, LAMISIL 1% spray was significantly more effective than placebo in the treatment of Tinea pedis but was comparable to cotrimazole.

TABLE 26 Number (%) subjects with effective treatment (ET) or with both negative microscopy and culture (NM) at end of study

Cutaneous Candidiasis

LAMISIL cream

Study demographics and trial design:

TABLE 27 Summary of patient demographics for terbinafine 1% cream clinical trials in cutaneous candidiasis

Study results:

TABLE 28 Combined results of vehicle-controlled studies terbinafine 1% cream studies in cutaneous candidiasis

p-values and results for effective treatment at follow-up are based on ITT population

The efficacy of one week of once-daily treatment with terbinafine 1% cream in cutaneous candidiasis is shown by the significantly greater rate of combined mycological and clinical outcomes, even 3 weeks post-treatment. While mycological cures were not significantly different between treatment groups post-treatment, they were significantly different at the end of treatment. Even though mycological cure appeared to decrease post-treatment, the rates of clinical cure (negative mycology and minimal signs and/or symptoms) increased. In study SF1003, complete clinical cure was noted for 3 terbinafine patients at end of treatment and 15 at Week 4. In study SF1004 for the terbinafine group, there was 1 complete cure at end of treatment but 17 at Week 4. No such increase in complete cures was noted in the vehicle group.

Tinea Versicolor

LAMISIL spray

Study demographics and trial design:

TABLE 29 Summary of patient demographics for terbinafine 1% spray clinical trials in tinea versicolor

Study Results:

When compared to placebo treatment, a one week twice daily application of LAMISIL 1% solution spray was significantly more effective in the treatment of Pityriasis versicolor. Treatment was effective in 70% of LAMISIL treated patients compared to 32% patients who used placebo (p<0.001). At the end of the study there was also a significant difference between the numbers of patients with negative microscopy, who had received LAMISIL treatment (79%) compared to the placebo treated (44%) [p<0.001].

TABLE 30 Number (%) subjects with effective treatment (ET – primary variable¹) or negative microscopy (NM) at end of study

¹Effective treatment is defined as negative microscopy and a total sign/symptom score of 0 or 1.

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 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).

TABLE 31 Summary of results published on in vitro activities of terbinafine against pathogenic and opportunistic fungi

* = 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 32 ACUTE TOXICITY

• Long Term Toxicity:

TABLE 33 LONG-TERM TOXICITY

TABLE 34 Carcinogenicity:

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 35 4-Week oral toxicity study in rats with special emphasis on hepatic alterations

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

TABLE 36 EFFECTS OF A 13-WEEK TREATMENT ON SELECTED TOXICOLOGICAL VARIABLES IN RATS

4-week oral toxicity study in mice

TABLE 37 4-WEEK ORAL TOXICITY STUDY IN MICE

Preliminary toxicity study in monkeys

TABLE 38 PRELIMINARY TOXICITY STUDY IN MONKEYS

32-week oral toxicity in monkeys

TABLE 39 WEEK ORAL TOXICITY STUDY IN MONKEYS

TABLE 40 Reproductive and Developmental Toxicology:

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.