`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`KERYDIN safely and effectively. See full prescribing information for
`KERYDIN.
`
`
`KERYDINTM (tavaborole) topical solution, 5%
`
`
`Initial U.S. Approval: 2014
`
`----------------------------INDICATIONS AND USAGE---------------------------
`KERYDIN is an oxaborole antifungal indicated for the topical treatment of
`onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton
`
`mentagrophytes. (1)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`
` Apply KERYDIN to affected toenails once daily for 48 weeks. (2)
`
` KERYDIN should be applied to the entire toenail surface and under the tip
`of each toenail being treated. (2)
`
` For topical use only. (2)
`
`
` Not for oral, ophthalmic, or intravaginal use. (2)
`
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Solution, 5%. (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None. (4)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`Common adverse reactions occurring in ≥1% in subjects treated with
`KERYDIN included application site exfoliation, ingrown toenail, application
`site erythema, and application site dermatitis. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Anacor
`
`Pharmaceuticals at 1-844-4ANACOR [1-844-426-2267] or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`Revised: 07/2014
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are
`not listed.
`_______________________________________________________________________________________________________________________________________
`
`
`
`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 1
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`
`KERYDIN (tavaborole) topical solution, 5% is an oxaborole antifungal indicated for the treatment of
`
`
`onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes.
`
`
`2 DOSAGE AND ADMINISTRATION
`Apply KERYDIN to affected toenails once daily for 48 weeks.
`KERYDIN should be applied to the entire toenail surface and under the tip of each toenail being treated.
`
`KERYDIN is for topical use only and not for oral, ophthalmic, or intravaginal use.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`KERYDIN topical solution, 5% is a clear, colorless alcohol-based solution. Each milliliter of solution
`contains 43.5 mg (5% w/w) of tavaborole.
`
` CONTRAINDICATIONS
`
`None.
`
`4
`
`
`6
`
` ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`
`
`In two clinical trials, 791 subjects were treated with KERYDIN. The most commonly reported adverse
`
` 
`reactions are listed below (Table 1).
`
`
`Table 1: Adverse Reactions Occurring in ≥1% of KERYDIN Topical Solution, 5%-Treated Subjects
`and at a Greater Frequency than Observed with Vehicle
`KERYDIN
`
`N=791
`
`n(%)
`21 (2.7%)
`
`20 (2.5%)
`13 (1.6%)
`10 (1.3%)
`
`Preferred Term
`Application site exfoliation
`
`Ingrown toenail
`
`Application site erythema
`
`Application site dermatitis
`
`Vehicle
`N=395
`
`n(%)
`
`1 (0.3%)
`
`1 (0.3%)
`
`0 (0%)
`
`0 (0%)
`
` 
`
`A cumulative irritancy study revealed the potential for KERYDIN to cause skin irritation. There was no
`
` evidence that KERYDIN causes contact sensitization.
`
` 
`7
`
` DRUG INTERACTIONS
`
`In vitro studies have shown that tavaborole, at therapeutic concentrations, neither inhibits nor induces
`cytochrome P450 (CYP450) enzymes.
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C
`
`
`
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`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 2
`
`

`

`
`There are no adequate and well-controlled studies with KERYDIN in pregnant women. KERYDIN should
`be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Systemic embryofetal development studies were conducted in rats and rabbits and a dermal embryofetal
`development study was conducted in rabbits.
`
`Oral administration:
`In an oral embryofetal development study in rats, oral doses of 30, 100, and 300 mg/kg/day tavaborole were
`administered during the period of organogenesis (gestational days 6-19) to pregnant female rats. In the
`presence of maternal toxicity, embryofetal toxicity (increased embryofetal resorption and/or deaths) and
`drug-related skeletal malformations and variations suggestive of delayed development (i.e., a delay in
`ossification) were noted in fetuses at 300 mg/kg/day tavaborole [570 times the Maximum Recommended
`Human Dose (MRHD) based on Area Under the Curve (AUC) comparisons]. No developmental toxicity
`was noted in rats at 100 mg/kg/day tavaborole (26 times the MRHD based on AUC comparisons).
`
`In an oral embryofetal development study in rabbits, oral doses of 15, 50, and 150 mg/kg/day tavaborole
`were administered during the period of organogenesis (gestational days 7-19) to pregnant female rabbits. In
`the presence of maternal toxicity, excessive embryofetal mortality due to post-implantation loss was noted
`at 150 mg/kg/day tavaborole. No drug related malformations were noted in rabbits at 150 mg/kg/day
`tavaborole (155 times the MRHD based on AUC comparisons). No embryofetal mortality was noted in
`rabbits at 50 mg/kg/day tavaborole (16 times the MRHD based on AUC comparisons).
`
`Topical administration:
`In a dermal embryofetal development study in rabbits, topical doses of 1%, 5%, and 10% tavaborole
`solution were administered during the period of organogenesis (gestational days 6-28) to pregnant female
`rabbits. A dose dependent increase in dermal irritation at the treatment site was noted at 5% and 10%
`tavaborole solution. A decrease in fetal bodyweight was noted at 10% tavaborole solution. No drug related
`malformations were noted in rabbits at 10% tavaborole solution (36 times the MRHD based on AUC
`comparisons). No embryofetal toxicity was noted in rabbits at 5% tavaborole solution (26 times the MRHD
`based on AUC comparisons).
`
`Nonteratogenic effects:
`In an oral pre- and post-natal development study in rats, oral doses of 15, 60, and 100 mg/kg/day tavaborole
`were administered from the beginning of organogenesis (gestation day 6) through the end of lactation
`(lactation day 20). In the presence of minimal maternal toxicity, no embryofetal toxicity or effects on
`postnatal development were noted at 100 mg/kg/day (29 times the MRHD based on AUC comparisons).
`
`8.3 Nursing Mothers
`It is not known whether tavaborole is excreted in human milk following topical application of KERYDIN.
`Because many drugs are excreted in human milk, caution should be exercised when KERYDIN is
`administered to a nursing woman.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`
`
`
`
`
`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 3
`
`

`

`
`
`8.5 Geriatric Use
`In clinical trials of 791 subjects who were exposed to KERYDIN, 19% were 65 years of age and over, while
`4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between
`
`these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
`
`11 DESCRIPTION
`KERYDIN (tavaborole) topical solution, 5% contains tavaborole, 5% (w/w) in a clear, colorless alcohol-
`based solution for topical use. The active ingredient, tavaborole, is an oxaborole antifungal with the
`chemical name of 5 fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. The chemical formula is C7H6BFO2,
`the molecular weight is 151.93 and the structural formula is:
`
`
`
`
`
`
`
`Tavaborole is a white to off-white powder. It is slightly soluble in water and freely soluble in ethanol and
`
` propylene glycol.
`
`Each mL of KERYDIN contains 43.5 mg of tavaborole. Inactive ingredients include alcohol, edetate
`
`
` calcium disodium, and propylene glycol.
`
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
` KERYDIN is an oxaborole antifungal [see Clinical Pharmacology (12.4)].
`
`12.2 Pharmacodynamics
` At therapeutic doses, KERYDIN is not expected to prolong QTc to any clinically relevant extent.
`
`12.3 Pharmacokinetics
` Tavaborole undergoes extensive metabolism. Renal excretion is the major route of elimination.
`
`In a clinical pharmacology trial of six healthy adult male volunteers who received a single topical
`application of 5% 14C-tavaborole solution, tavaborole conjugates and metabolites were shown to be excreted
`primarily in the urine.
`
`
`The pharmacokinetics of tavaborole was investigated in 24 subjects with distal subungual onychomycosis
`involving at least 4 toenails (including at least 1 great toenail) following a single dose and a 2-week daily
`topical application of 200 μL of a 5% solution of tavaborole to all ten toenails and 2 mm of skin surrounding
`each toenail. Steady state was achieved after 14 days of dosing. After a single dose, the mean (± standard
`deviation) peak concentration (Cmax) of tavaborole was 3.54 ± 2.26 ng/mL (n=21 with measurable
`concentrations, range 0.618-10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean AUClast was 44.4 ± 25.5
`ng*hr/mL (n=21). After 2 weeks of daily dosing, the mean Cmax was 5.17 ± 3.47 ng/mL (n=24, range 1.51­
`12.8 ng/mL), and the mean AUCτ was 75.8 ± 44.5 ng*hr/mL.
`
`12.4 Microbiology
`
`Mechanism of Action
`
`
`
`
`
`
`
`
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`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 4
`
`

`

`
`
`The mechanism of action of tavaborole is inhibition of fungal protein synthesis. Tavaborole inhibits protein
`synthesis by inhibition of an aminoacyl-transfer ribonucleic acid (tRNA) synthetase (AARS).
`
`Activity in vitro and in clinical infections
`Tavaborole has been shown to be active against most strains of the following microorganisms, both in vitro
`
`
` and in clinical infections [see Indications and Usage (1)]:
`
`
`Trichophyton rubrum
`
`
`
` Trichophyton mentagrophytes
`
`Mechanism of Resistance
` Trichophyton mentagrophytes and Trichophyton rubrum strains from isolates collected in the clinical trials
`
`have not demonstrated resistance following repeated exposure to tavaborole.
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`In an oral carcinogenicity study in Sprague-Dawley rats, oral doses of 12.5, 25, and 50 mg/kg/day
`tavaborole were administered to rats once daily for 104 weeks. No drug related neoplastic findings were
`noted at oral doses up to 50 mg/kg/day tavaborole (14 times the MRHD based on AUC comparisons).
`
`In a dermal carcinogenicity study in CD-1 mice, topical doses of 5%, 10%, and 15% tavaborole solution
`were administered to mice once daily for 104 weeks. No drug related neoplastic findings were noted at
`topical doses up to 15% tavaborole solution (89 times the MRHD based on AUC comparisons).
`
`Tavaborole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro
`genotoxicity tests (Ames assay and Human lymphocyte chromosomal aberration assay) and one in vivo
`genotoxicity test (rat micronucleus assay).
`
`No effects on fertility were observed in male and female rats that were administered oral doses up to 300
`mg/kg/day tavaborole (107 times the MRHD based on AUC comparisons) prior to and during early
`pregnancy.
`
`
`
`14 CLINICAL STUDIES
`The efficacy and safety of KERYDIN was evaluated in two multicenter, double-blind, randomized, vehicle-
`controlled trials. KERYDIN or vehicle was applied once daily for 48 weeks in subjects with 20% to 60%
`clinical involvement of the target toenail, without dermatophytomas or lunula (matrix) involvement.
`
`A total of 1194 subjects (795 KERYDIN, 399 Vehicle) 18 to 88 years of age, 82% male, 84% white,
`participated in these two trials. Efficacy assessments were made at 52 weeks following a 48-week treatment
`period.
`
`The Complete Cure efficacy endpoint included negative mycology (negative KOH wet mount and negative
`fungal culture) and Completely Clear Nail (no clinical evidence of onychomycosis as evidenced by a normal
`toenail plate, no onycholysis, and no subungual hyperkeratosis). Efficacy results from the two trials are
`summarized in Table 2.
`
`
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`Reference ID: 3537640
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`MYLAN - Ex. 1042, p. 5
`
`

`

`
`
`
`
`Table 2: Efficacy Outcomes
`
`Trial 1
`
`KERYDIN
`Vehicle
`N=399
`N=194
`
`
`
` Efficacy Variable
`n(%)
`n(%)
`Complete Curea
`
`
`1 (0.5%)
`26 (6.5%)
`Complete or Almost Complete Cureb
`
`
`3 (1.5%)
`61 (15.3%)
`Mycologic Curec
`
`
`
`
`14 (7.2%)
`124 (31.1%)
`a. Complete cure defined as 0% clinical involvement of the target toenail plus negative KOH and negative culture.
`
`Trial 2
`
`KERYDIN
`N=396
`
`n(%)
`
`
`36 (9.1%)
`
`
`71 (17.9%)
`
`142 (35.9%)
`
`Vehicle
`N=205
`
`n(%)
`
`3 (1.5%)
`
`8 (3.9%)
`
`
`25 (12.2%)
`
`b. Complete or almost complete cure defined as ≤10% affected target toenail area involved and negative KOH and culture.
`
` 
`
`c. Mycologic cure defined as negative KOH and negative culture.
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`KERYDIN (tavaborole) topical solution, 5% is a clear, colorless solution supplied in a 12-mL amber glass
`bottle with a screw cap. At initial use, the screw cap is replaced with the dropper assembly.
`
`KERYDIN (tavaborole) topical solution, 5% is supplied in the following presentation:
`
`NDC 55724-111-11: One bottle containing 10 mL of solution with one glass pointed-tip dropper
`
`16.2 Storage and Handling
`
`Store at 20–25°C (68–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room
`
`Temperature].
`
`CAUTION: Flammable. Keep away from heat and flame.
`
`Discard product within 3 months after insertion of the dropper.
`
`
`Keep bottle tightly closed. Keep out of reach of children.
`
`
`17 PATIENT COUNSELING INFORMATION
`See FDA-approved patient labeling (Patient Information and Instructions for Use)
`
`
`The patient should be told the following:
`
`
` Use KERYDIN as directed by a health care professional.
`
`
` KERYDIN is for external use only. Avoid contact with eyes, mouth, or vagina. Avoid contact with skin
`
`
`other than skin immediately surrounding the treated nail(s). Wipe away excess solution from
`surrounding skin.
`
` Clean and dry nails prior to KERYDIN use. KERYDIN should be applied to completely cover the nail
`surface and also applied under the tip of each nail being treated. Allow solution to dry following
`application.
`Inform a health care professional if the area of application shows signs of persistent irritation (for
`
`example, redness, itching, swelling).
`
` Forty-eight (48) weeks of daily application with tavaborole is considered the full treatment for toenail
`onychomycosis.
`
`
`
` Do not use KERYDIN for any disorder other than that for which it is prescribed.
`
`
` Product is flammable. Avoid use near heat or open flame.
`
`
`
`
`
`
`
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`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 6
`
`

`

`
`________________________________________________________________________
`Manufactured for:
`
` Anacor Pharmaceuticals, Inc.
`
`
`1020 East Meadow Circle
`
`Palo Alto, CA 94303
`
`
`Issue: 07/2014
`
`
`
`
`
` KERYDIN™ is a trademark of Anacor Pharmaceuticals, Inc.
`
` © 2014 Anacor Pharmaceuticals, Inc.
`
`U.S. Patent Nos. 7,767,657 and 7,582,621
`
`
`
`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 7
`
`

`

`PATIENT INFORMATION
`KERYDINTM (ker' i din)
`(tavaborole) Topical Solution, 5%
`
`Important information: KERYDIN is for use on toenails only. Do not use KERYDIN in your mouth,
`
`
`eyes, or vagina.
`
`What is KERYDIN?
`
`
`KERYDIN is a prescription medicine used to treat fungal infections of the toenails.
`
`
`It is not known if KERYDIN is safe and effective in children.
`What should I tell my healthcare provider before using KERYDIN?
`
`
`
`
`Before using KERYDIN, tell your healthcare provider about all of your medical conditions, including if you:
`
`
`
`
` are pregnant or plan to become pregnant. It is not known if KERYDIN can harm your unborn baby.
`
`
`
`
` are breastfeeding or plan to breastfeed. It is not known if KERYDIN passes into your breast milk.
`
`Tell your healthcare provider about all the medicines you take, including prescription and over-the­
`counter medicines, vitamins, and herbal supplements.
`
`
`How should I use KERYDIN?
`See the “Instructions for Use” at the end of this Patient Information for detailed information
`
`about the right way to use KERYDIN.
`
` Use KERYDIN exactly as your healthcare provider tells you to use it.
`
`
` Apply KERYDIN to your affected toenails 1 time each day.
`
`
`
` KERYDIN is used for 48 weeks.
`
`What should I avoid while using KERYDIN?
`
` Avoid getting KERYDIN on skin that is not surrounding the treated toenail.
`
` ● KERYDIN is flammable. Avoid heat and flame while applying KERYDIN to your toenail.
`
`
`
`
`
`
`
`What are the possible side effects of KERYDIN?
`KERYDIN may cause irritation at the treated site. The most common side effects include: skin peeling,
`
`
`
`ingrown toenail, redness, itching, and swelling. Tell your healthcare provider if you have any side effect
`
`that bothers you or does not go away.
`
`
`These are not all of the possible side effects of KERYDIN.
`Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA­
`1088.
`
`How should I store KERYDIN?
` Store KERYDIN at room temperature, between 68°F to 77°F (20°C to 25°C).
`
`
`
` KERYDIN is flammable. Keep away from heat and flame.
`
` Keep the bottle tightly closed.
`
`
` Safely throw away KERYDIN after 3 months of inserting the dropper.
`
`Keep KERYDIN and all medicines out of the reach of children.
`
`General information about the safe and effective use of KERYDIN
`
`Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
`
`You can ask your pharmacist or healthcare provider for information about KERYDIN that is written for
`
`
`
`health professionals. Do not use KERYDIN for a condition for which it was not prescribed. Do not give
`
`KERYDIN to other people, even if they have the same symptoms that you have. It may harm them.
`
`
`
`
`What are the ingredients in KERYDIN?
`Active ingredient: tavaborole
`
`Inactive ingredients: alcohol, propylene glycol, and edetate calcium disodium
`
`
` Manufactured for: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, CA, 94303
`
`
` For more information, call 1-844-4ANACOR [1-844-426-2267] or go to www.kerydin.com.
`
`
`This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 07/2014
`
`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 8
`
`

`

`Instructions for Use
`
`KERYDINTM (ker' i din)
`
`
`(tavaborole) Topical Solution, 5%
`
`
`
`
` Important information: KERYDIN is for use on toenails only. Do not use KERYDIN in your
`mouth, eyes, or vagina.
`
`Read the Instructions for Use that comes with KERYDIN before you start using it. Talk to your
`
`
`healthcare provider if you have any questions.
`How to apply KERYDIN:
`Your toenails should be clean and dry before you apply KERYDIN.
`Step 1: Before you apply KERYDIN to your affected toenail for the first time, remove the cap
`
`
`from the KERYDIN bottle (See Figure A). Throw away the cap.
`
`Step 2: Remove the wrapping from the dropper that comes with KERYDIN. Insert the dropper
`
`into the KERYDIN bottle. (See Figure B)
`
`
`
` 
`
`Figure B
`Figure A
`
`
`Only apply KERYDIN using the provided dropper. Do not use the dropper for any other
`
`purpose.
`
`Step 3: With the dropper inserted into the KERYDIN, squeeze the bulb and then release the
`
`
`
`
`
`
`bulb to draw KERYDIN into the dropper.
`Step 4: Remove the dropper from the bottle and hold the dropper tip over your affected
`
`
`
`toenail.
`Step 5: Slowly squeeze the bulb to apply KERYDIN to your toenail. Apply enough solution to
`
`
`completely cover your toenail. You may need to use more than one drop. (See Figure
`C)
`
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`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 9
`
`

`

` Figure C
`
`
` 
`
`
`
`Step 6: Use the dropper tip to gently spread KERYDIN to cover the entire toenail up to the
`
`edges of the toenail. (See Figure D)
`
`
`
`Figure D
`
`
`
`Step 7: In addition to the top of the toenail, also apply KERYDIN under the tip of the toenail.
`
`
`
`
`Use the dropper tip to gently spread KERYDIN under the entire tip of the toenail. (See
`
`
`
`Figures E and F)
`
`
`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 10
`
`

`

` 
`
`
`
`
`
`Figure E
`
`Figure F
`
`
`Step 8: Repeat Steps 3 to 7 to apply KERYDIN to each affected toenail.
`
`Step 9: Let the KERYDIN dry completely. This may take a couple of minutes.
`
`
`
`
`If KERYDIN comes in contact with surrounding skin, use a tissue to wipe any excess
`solution from the surrounding skin. Do not wipe KERYDIN off of your toenails.
`
`Step 10: After applying KERYDIN to your toenails, insert the dropper back into the bottle and
`
`
`screw it on tightly.
`Step 11: Wash your hands with soap and water after applying KERYDIN.
`
`
`
`
`This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug
`Administration.
`
`Manufactured for: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, CA, 94303
`
`
`Issued: 07/2014
`
`
`
`Reference ID: 3537640
`
`MYLAN - Ex. 1042, p. 11
`
`