Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`NDA 20-539/S-012
`
`
`
`Novartis Pharmaceuticals Corporation
`Attention: Cheryl Elder, Pharm.D.
`Associate Director, Drug Regulatory Affairs
`One Health Plaza
`East Hanover, New Jersey 07936-1080
`
`Dear Dr. Elder:
`
`Please refer to your supplemental new drug application dated July 18, 2003, received July 21, 2003,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for LAMISIL®
`(terbinafine hydrochloride tablets) Tablets, 250 mg.
`
`We also acknowledge receipt of your submission dated July 31, 2003.
`
`This supplemental new drug application provides for labeling revisions to the Drug Interactions Sub-
`section of the PRECAUTIONS Section and to the ADVERSE REACTIONS section.
`
`We have completed our review of this application, as amended. This application is approved, effective
`on the date of this letter, for use as recommended in the agreed-upon labeling text.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert).
`
`Please submit the FPL electronically according to the guidance for industry titled Providing Regulatory
`Submissions in Electronic Format – NDA. Alternatively, you may submit 20 paper copies of the FPL
`as soon as it is available, in no case more than 30 days after it is printed. Please individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, this submission
`should be designated "FPL for approved supplement NDA 20-539/S-012.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
`the following address:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEDWATCH, HFD-410
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
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`NDA 20-539/S-012
`Page 2
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`
`
`If you have any questions, please call Frank H. Cross, Jr., M.A., CDR, Senior Regulatory Management
`Officer, at (301) 827-2020.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Jonathan K. Wilkin, M.D.
`Director
`Division of Dermatologic & Dental Drug Products
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`Enclosure
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2075 - 2/10
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`

`
`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Stanka Kukich
`1/21/04 05:10:40 PM
`signing for Dr. Jonathan Wilkin, Division Director
`
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`

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`
`NDA 20-539/S-012
`Page 3
`
`
`
`
`LAMISIL®
`(terbinafine hydrochloride tablets)
`Tablets
`
`Rx only
`
`Prescribing Information
`
`DESCRIPTION
`LAMISIL® (terbinafine hydrochloride tablets) Tablets contain the synthetic allylamine antifungal
`compound terbinafine hydrochloride.
`(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-
`is
`Chemically,
`terbinafine
`hydrochloride
`naphthalenemethanamine hydrochloride. The empirical formula C21H26CIN with a molecular weight of
`327.90, and the following structural formula:
`
`
`
`
`
`Terbinafine hydrochloride is a white to off-white fine crystalline powder. It is freely soluble in
`methanol and methylene chloride, soluble in ethanol, and slightly soluble in water.
`Each tablet contains:
`Active Ingredients: terbinafine hydrochloride (equivalent to 250 mg base)
`Inactive Ingredients: colloidal silicon dioxide, NF; hydroxypropyl methylcellulose, USP; magnesium
`stearate, NF; microcrystalline cellulose, NF; sodium starch glycolate, NF
`
`CLINICAL PHARMACOLOGY
`Pharmacokinetics
`Following oral administration, terbinafine is well absorbed (>70%) and the bioavailability of
`LAMISIL® (terbinafine hydrochloride tablets) Tablets as a result of first-pass metabolism is
`approximately 40%. Peak plasma concentrations of 1 µg/mL appear within 2 h after a single 250 mg
`dose; the AUC (area under the curve) is approximately 4.56 µg·h/mL. An increase in the AUC of
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`NDA 20-539/S-012
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`terbinafine of less than 20% is observed when LAMISIL® is administered with food. No clinically
`relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been
`reported. In patients with renal impairment (creatinine clearance < 50mL/min) or hepatic cirrhosis, the
`clearance of terbinafine is decreased by approximately 50% compared to normal volunteers. No effect
`of gender on the blood levels of terbinafine was detected in clinical trials. In plasma, terbinafine is
`>99% bound to plasma proteins and there are no specific binding sites. At steady-state, in comparison
`to a single dose, the peak concentration of terbinafine is 25% higher and plasma AUC increases by a
`factor of 2.5; the increase in plasma AUC is consistent with an effective half-life of ~36 hours.
`Terbinafine is distributed to the sebum and skin. A terminal half-life of 200-400 h may represent the
`slow elimination of terbinafine from tissues such as skin and adipose. Prior to excretion, terbinafine is
`extensively metabolized. No metabolites have been identified that have antifungal activity similar to
`terbinafine. Approximately 70% of the administered dose is eliminated in the urine.
`Microbiology
`Terbinafine hydrochloride is a synthetic allylamine derivative. Terbinafine hydrochloride is
`hypothesized to act by inhibiting squalene epoxidase, thus blocking the biosynthesis of ergosterol, an
`essential component of fungal cell membranes. In vitro, mammalian squalene epoxidase is only
`inhibited at higher (4000 fold) concentrations than is needed for inhibition of the dermatophyte
`enzyme. Depending on the concentration of the drug and the fungal species test in vitro, terbinafine
`hydrochloride may be fungicidal. However, the clinical significance of in vitro data is unknown.
`Terbinafine has been shown to be active against most strains of the following microorganisms both in
`vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
`Trichophyton mentagrophytes
`Trichophyton rubrum
`The following in vitro data are available, but their clinical significance is unknown. In vitro,
`terbinafine exhibits satisfactory MIC’s against most strains of the following microorganisms; however,
`the safety and efficacy of terbinafine in treating clinical infections due to these microorganisms have
`not been established in adequate and well-controlled clinical trials:
`Candida albicans
`Epidermophyton floccosum
`Scopulariopsis brevicaulis
`
`CLINICAL STUDIES
`The efficacy of LAMISIL® (terbinafine hydrochloride tablets) Tablets in the treatment of
`onychomycosis is illustrated by the response of patients with toenail and/or fingernail infections who
`participated in three US/Canadian placebo-controlled clinical trials.
`Results of the first toenail study, as assessed at week 48 (12 weeks of treatment with 36 weeks follow-
`up after completion of therapy), demonstrated mycological cure, defined as simultaneous occurrence of
`negative KOH plus negative culture, in 70% of patients. Fifty-nine percent (59%) of patients
`experienced effective treatment (mycological cure plus 0% nail involvement or >5mm of new
`unaffected nail growth); 38% of patients demonstrated mycological cure plus clinical cure (0% nail
`involvement).
`In a second toenail study of dermatophytic onychomycosis, in which non-dermatophytes were also
`cultured, similar efficacy against the dermatophytes was demonstrated. The pathogenic role of the non-
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`NDA 20-539/S-012
`Page 5
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`dermatophytes cultured in the presence of dermatophytic onychomycosis has not been established. The
`clinical significance of this association is unknown.
`Results of the fingernail study, as assessed at week 24 (6 weeks of treatment with 18 weeks follow-up
`after completion of therapy), demonstrated mycological cure in 79% of patients, effective treatment in
`75% of the patients, and mycological cure plus clinical cure in 59% of the patients.
`The mean time to overall success was approximately 10 months for the first toenail study and 4 months
`for the fingernail study. In the first toenail study, for patients evaluated at least six months after
`achieving clinical cure and at least one year after completing LAMISIL® therapy, the clinical relapse
`rate was approximately 15%.
`
`INDICATIONS AND USAGE
`LAMISIL® (terbinafine hydrochloride
`treatment of
`the
`indicated for
`tablets) Tablets are
`onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium) (see DOSAGE AND
`ADMINISTRATION and CLINICAL STUDIES).
`Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation,
`fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.
`
`CONTRAINDICATIONS
`LAMISIL® (terbinafine hydrochloride tablets) Tablets are contraindicated in individuals with
`hypersensitivity to terbinafine or to any other ingredients of the formulation.
`
`WARNINGS
`Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of
`LAMISIL® (terbinafine hydrochloride tablets) Tablets for the treatment of onychomycosis in
`individuals with and without pre-existing liver disease.
`In the majority of liver cases reported in association with LAMISIL® use, the patients had serious
`underlying systemic conditions and an uncertain causal association with LAMISIL®. The severity of
`hepatic events and/or their outcome may be worse in patients with active or chronic liver disease (see
`PRECAUTIONS). Treatment with LAMISIL® Tablets should be discontinued if biochemical or
`clinical evidence of liver injury develops (see PRECAUTIONS below).
`
`There have been isolated reports of serious skin reactions (e.g., Stevens-Johnson Ssyndrome and toxic
`epidermal necrolysis). If progressive skin rash occurs, treatment with LAMISIL® should be
`discontinued.
`
`PRECAUTIONS
`General
`LAMISIL® (terbinafine hydrochloride tablets) Tablets are not recommended for patients with chronic
`or active liver disease. Before prescribing LAMISIL® Tablets, pre-existing liver disease should be
`assessed. Hepatotoxicity may occur in patients with and without pre-existing liver disease.
`Pretreatment serum transaminase (ALT and AST) tests are advised for all patients before taking
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`NDA 20-539/S-012
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`LAMISIL® Tablets. Patients prescribed LAMISIL® Tablets should be warned to report immediately to
`their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal
`pain or jaundice, dark urine or pale stools (see WARNINGS). Patients with these symptoms should
`discontinue taking oral terbinafine, and the patient’s liver function should be immediately evaluated.
`In patients with renal impairment (creatinine clearance <50 mL/ min), the use of LAMISIL® has not
`been adequately studied, and therefore, is not recommended (see CLINICAL PHARMACOLOGY,
`Pharmacokinetics).
`During postmarketing 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.
`Changes in the ocular lens and retina have been reported following the use of LAMISIL® (terbinafine
`hydrochloride tablets) Tablets in controlled trials. The clinical significance of these changes is
`unknown.
`Transient decreases in absolute lymphocyte counts (ALC) have been observed in controlled clinical
`trials. In placebo-controlled trials, 8/465 LAMISIL®-treated patients (1.7%) and 3/137 placebo-treated
`patients (2.2%) had decreases in ALC to below 1000/mm3 on two or more occasions. 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.
`Isolated cases of severe neutropenia have been reported. These were reversible upon discontinuation of
`LAMISIL®, with or without supportive therapy. If clinical signs and symptoms suggestive of
`secondary infection occur, a complete blood count should be obtained. If the neutrophil count is
`<1,000 cells/mm3, LAMISIL® should be discontinued and supportive management started.
`Drug Interactions
`In vivo studies have shown that terbinafine is an inhibitor of the CYP450 2D6 isozyme.
`Coadministration of LAMISIL® with drugs predominantly metabolized by the CYP450 2D6 isozyme
`(e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers and monoamine
`oxidase inhibitors Type B) should be done with careful monitoring and may require a reduction in dose
`of the 2D6-metabolized drug. In a study to assess the effects of terbinafine on desipramine in healthy
`volunteers characterized as normal metabolizers, the administration of terbinafine resulted in a 2-fold
`increase in Cmax and a 5-fold increase in AUC. In this study, these effects were shown to persist at the
`last observation at 4 weeks after discontinuation of LAMISIL®.
`In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism
`of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine.
`In vivo drug-drug interaction studies conducted in healthy volunteer subjects showed that terbinafine
`does not affect the clearance of antipyrine or digoxin.
`Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of
`cyclosporine by 15%.
`There have been spontaneous reports of increase or decrease in prothrombin times in patients
`concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL®
`Tablets and these changes has not been established.
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`NDA 20-539/S-012
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`Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, and decreased 33%
`by cimetidine, a CYP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine.
`There is no information available from adequate drug-drug interaction studies with the following
`classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines,
`phenytoins, thiazide diuretics, and calcium channel blockers.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`In a 28-month oral carcinogenicity study in rats, an increase in the incidence of liver tumors was
`observed in males at the highest dose tested, 69 mg/kg/day [2x the Maximum Recommended Human
`Dose (MRHD) based on AUC comparisons of the parent terbinafine]; however, even though dose-
`limiting toxicity was not achieved at the highest tested dose, higher doses were not tested.
`The results of a variety of in vitro (mutations in E. coli and S. typhimurium, DNA repair in rat
`hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid
`exchanges in Chinese hamster lung cells), and in vivo (chromosome aberration in Chinese hamsters,
`micronucleus test in mice) genotoxicity tests gave no evidence of a mutagenic or clastogenic potential.
`Oral reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12x the MRHD based
`on body surface area comparisons, BSA) did not reveal any specific effects on fertility or other
`reproductive parameters. Intravaginal application of terbinafine hydrochloride at 150 mg/day in
`pregnant rabbits did not increase the incidence of abortions or premature deliveries nor affect fetal
`parameters.
`Pregnancy
`Pregnancy Category B: Oral reproduction studies have been performed in rabbits and rats at doses up
`to 300 mg/kg/day (12x to 23x the MRHD, in rabbits and rats, respectively, based on BSA) and have
`revealed no evidence of impaired fertility or harm to the fetus due to terbinafine. There are, however,
`no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are
`not always predictive of human response, and because treatment of onychomycosis can be postponed
`until after pregnancy is completed, it is recommended that LAMISIL® not be initiated during
`pregnancy.
`Nursing Mothers
`After oral administration, terbinafine is present in breast milk of nursing mothers. The ratio of
`terbinafine in milk to plasma is 7:1. Treatment with LAMISIL® is not recommended in nursing
`mothers.
`Pediatric Use
`The safety and efficacy of LAMISIL® have not been established in pediatric patients.
`
`ADVERSE REACTIONS
`The most frequently reported adverse events observed in the three US/Canadian placebo-controlled
`trials are listed in the table below. The adverse events reported encompass gastrointestinal symptoms
`(including diarrhea, dyspepsia, and abdominal pain), liver test abnormalities, rashes, urticaria, pruritus,
`and taste disturbances. In general, the adverse events were mild, transient, and did not lead to
`discontinuation from study participation.
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`Adverse Event
`LAMISIL®
`Placebo
`(%)
`(%)
`n=465
`n=137
`12.9
`9.5
`
`Discontinuation
`LAMISIL®
`Placebo
`(%)
`(%)
`n=465
`n=137
`0.2
`0.0
`
`NDA 20-539/S-012
`Page 8
`
`
`
`
`
`
`Headache
`Gastrointestinal
` Symptoms:
`
`Diarrhea
`
`Dyspepsia
`
`Abdominal Pain
`
`Nausea
`
`Flatulence
`Dermatological
` Symptoms:
`
`Rash
`
`Pruritus
`
`Urticaria
`Liver Enzyme
`1.4
`3.3
`
`Abnormalities*
`0.7
`2.8
`Taste Disturbance
`1.5
`1.1
`Visual Disturbance
`* Liver enzyme abnormalities >2x the upper limit of the normal range.
`Rare adverse events, based on worldwide experience with LAMISIL® (terbinafine hydrochloride
`tablets) Tablets use, include: idiosyncratic and symptomatic hepatic injury and more rarely, cases of
`liver failure, some leading to death or liver transplant, (see WARNINGS and PRECAUTIONS),
`(see WARNINGS),
`(see PRECAUTIONS),
`serious
`skin
`reactions
`severe neutropenia
`thrombocytopenia, angioedema and allergic reactions (including anaphylaxis). Precipitation and
`exacerbation of cutaneous and systemic lupus erythematosus have been reported infrequently in
`patients taking LAMISIL® . Uncommonly, LAMISIL® may cause taste disturbance (including taste
`loss) which usually recovers within several weeks after discontinuation of the drug. There have been
`isolated reports of prolonged (greater than one year) taste disturbance. Rarely, taste disturbances
`associated with oral terbinafine have been reported to be severe enough to result in decreased food
`intake leading to significant and unwanted weight loss.
`Other adverse reactions which have been reported include malaise, fatigue, vomiting, arthralgia,
`myalgia, and hair loss.
`Clinical adverse effects reported spontaneously since the drug was marketed include altered
`prothrombin time (prolongation and reduction) in patients concomitantly treated with warfarin and
`LAMISIL® Tablets and agranulocytosis (rare).
`
`5.6
`4.3
`2.4
`2.6
`2.2
`
`5.6
`2.8
`1.1
`
`2.9
`2.9
`1.5
`2.9
`2.2
`
`2.2
`1.5
`0.0
`
`0.6
`0.4
`0.4
`0.2
`0.0
`
`0.9
`0.2
`0.0
`
`0.2
`0.2
`0.9
`
`0.0
`0.0
`0.0
`0.0
`0.0
`
`0.7
`0.0
`0.0
`
`0.0
`0.0
`0.0
`
`OVERDOSAGE
`Clinical experience regarding overdose with LAMISIL® (terbinafine hydrochloride tablets) Tablets is
`limited. Doses up to 5 grams (20 times the therapeutic daily dose) have been taken without inducing
`serious adverse reactions. The symptoms of overdose included nausea, vomiting, abdominal pain,
`dizziness, rash, frequent urination, and headache.
`
`DOSAGE AND ADMINISTRATION
`LAMISIL® (terbinafine hydrochloride tablets) Tablets, one 250 mg tablet, should be taken once daily
`for 6 weeks by patients with fingernail onychomycosis. LAMISIL®, one 250 mg tablet, should be
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`taken once daily for 12 weeks by patients with toenail 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.
`
`HOW SUPPLIED
`LAMISIL®
`(terbinafine hydrochloride tablets)
`Tablets
`Supplied as white to yellow-tinged white circular, bi-convex, bevelled tablets containing 250 mg of
`terbinafine imprinted with “LAMISIL” in circular form on one side and code “250” on the other.
`Bottles of 100 tablets…….. NDC 0078-0179-05
`
`
`Bottles of 30 tablets……… NDC 0078-0179-15
`Store tablets below 25 °C (77 °F); in a tight container. Protect from light.
`
`ANIMAL TOXICOLOGY
`A wide range of in vivo studies in mice, rats, dogs, and monkeys, and in vitro studies using rat,
`monkey, and human hepatocytes suggest that peroxisome proliferation in the liver is a rat-specific
`finding. However, other effects, including increased liver weights and APTT, occurred in dogs and
`monkeys at doses giving Css trough levels of the parent terbinafine 2-3x those seen in humans at the
`MRHD. Higher doses were not tested.
`
`Manufactured by:
`Patheon Whitby Inc.
`Whitby, Ontario, Canada L1N 5Z5
`Distributed by:
`Novartis Pharmaceuticals Corporation
`East Hanover, New Jersey 07936
`
`REV: January 2004
`T2003-37
`8900680
`2335-25-03A
`
`
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