JUBLIA®
`(efinaconazole)
`topical solution, 10%
`9462902 Rev. 05/2016
`
`JUBLIA®
`(efinaconazole)
`topical solution, 10%
`9462902 Rev. 05/2016
`
`HIGHLIGHTS OF PRESCRIBING
`INFORMATION
`These highlights do not include all the information
`needed to use JUBLIA safely and effectively. See
`full prescribing information for JUBLIA.
`
`JUBLIA® (efinaconazole) topical solution, 10%
`For topical use
`Initial U.S. Approval: 2014
`-----------INDICATIONS AND USAGE -----------
`JUBLIA is an azole antifungal indicated for
`the topical treatment of onychomycosis of
`the toenails due to Trichophyton rubrum and
`Trichophyton mentagrophytes. (1)
`------ DOSAGE AND ADMINISTRATION ------
`• Apply JUBLIA to affected toenails once daily
`for 48 weeks using the integrated flow-through
`brush applicator. (2)
`• When applying JUBLIA, ensure the toenail,
`the toenail folds, toenail bed, hyponychium,
`and the undersurface of the toenail plate, are
`completely covered. (2)
`
`• For topical use only. (2)
`• Not for oral, ophthalmic, or intravaginal use. (2)
`
`-----DOSAGE FORMS AND STRENGTHS ----
`Solution: 10%. (3)
`--------------CONTRAINDICATIONS -------------
`None. (4)
`-------------- ADVERSE REACTIONS --------------
`The most common adverse reactions (incidence
`>1%) were ingrown toenails, application
`site dermatitis, application site vesicles, and
`application site pain. (6.1)
`To report SUSPECTED ADVERSE
`REACTIONS, contact Valeant Pharmaceuticals
`North America LLC at 1-800-321-4576 or FDA
`at 1-800-FDA-1088 or www.fda.gov/medwatch.
`See 17 for PATIENT COUNSELING
`INFORMATION and FDA-approved
`patient labeling.
`
`Revised: 05/2016
`
`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
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`DESCRIPTION
`
`7
`8
`
`11
`
`12
`
`13
`
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`12.4 Microbiology
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`CLINICAL STUDIES
`14
`16 HOW SUPPLIED/STORAGE
`AND HANDLING
`PATIENT COUNSELING
`INFORMATION
`
`17
`
`*Sections or subsections omitted from the full
`prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`INDICATIONS AND USAGE
`1
`JUBLIA (efinaconazole) topical solution,
`10% is an azole antifungal indicated for the
`topical treatment of onychomycosis of the
`toenail(s) due to Trichophyton rubrum and
`Trichophyton mentagrophytes.
`2
`DOSAGE AND ADMINISTRATION
`Apply JUBLIA to affected toenails once daily
`for 48 weeks, using the integrated flow-through
`brush applicator. When applying JUBLIA,
`ensure the toenail, the toenail folds, toenail bed,
`hyponychium, and the undersurface of the toenail
`plate, are completely covered.
`JUBLIA is for topical use only and not for oral,
`ophthalmic, or intravaginal use.
`3
`DOSAGE FORMS AND STRENGTHS
`JUBLIA (efinaconazole) topical solution,
`10% contains 100 mg of efinaconazole in each
`gram of clear, colorless to pale yellow solution.
`4
`CONTRAINDICATIONS
`None.
`ADVERSE REACTIONS
`6
`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, 1227 subjects were treated
`with JUBLIA, 1161 for at least 24 weeks and 780
`for 48 weeks. Adverse reactions reported within
`48 weeks of treatment and in at least 1% of
`subjects treated with JUBLIA and those reported
`in subjects treated with the vehicle are presented
`in Table 1.
`Table 1: Adverse Reactions Reported by at Least
`1% of Subjects Treated for up to 48 Weeks
`
`Adverse Event, n (%)
`
`JUBLIA
`N = 1227
`
`Vehicle
`N = 413
`
`Ingrown toenail
`
`28 (2.3%)
`
`3 (0.7%)
`
`Application site dermatitis
`
`27 (2.2%)
`
`1 (0.2%)
`
`Application site vesicles
`
`20 (1.6%)
`
`0 (0.0%)
`
`Application site pain
`
`13 (1.1%)
`
`1 (0.2%)
`
`DRUG INTERACTIONS
`7
`In vitro studies have shown that JUBLIA, at
`therapeutic concentrations, neither inhibits nor
`induces cytochrome P450 (CYP450) enzymes.
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`Pregnancy Category C
`There are no adequate and well-controlled studies
`with JUBLIA in pregnant women. JUBLIA
`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. Subcutaneous
`doses of 2, 10 and 50 mg/kg/day efinaconazole
`were administered during the period of
`organogenesis (gestational days 6-16) to pregnant
`female rats. In the presence of maternal toxicity,
`embryofetal toxicity (increased embryofetal
`deaths, decreased number of live fetuses, and
`placental effects) was noted at 50 mg/kg/day
`[559 times the Maximum Recommended Human
`Dose (MRHD) based on Area Under the
`Curve (AUC) comparisons]. No embryofetal
`toxicity was noted at 10 mg/kg/day (112 times
`the MRHD based on AUC comparisons).
`No malformations were observed at
`50 mg/kg/day (559 times the MRHD based on
`AUC comparisons).
`Subcutaneous doses of 1, 5, and 10 mg/kg/day
`efinaconazole were administered during the
`period of organogenesis (gestational days 6-19)
`to pregnant female rabbits. In the presence of
`maternal toxicity, there was no embryofetal
`toxicity or malformations at 10 mg/kg/day (154
`times the MRHD based on AUC comparisons).
`In a pre- and post-natal development study
`in rats, subcutaneous doses of 1, 5 and
`25 mg/kg/day efinaconazole were administered
`from the beginning of organogenesis (gestation
`day 6) through the end of lactation (lactation
`day 20). In the presence of maternal toxicity,
`embryofetal toxicity (increased pre-natal pup
`mortality, reduced live litter sizes and increased
`post-natal pup mortality) was noted at
`25 mg/kg/day. No embryofetal toxicity was noted
`at 5 mg/kg/day (17 times the MRHD based on
`AUC comparisons). No effects on post-natal
`development were noted at 25 mg/kg/day (89
`times the MRHD based on AUC comparisons).
`8.3
`Nursing Mothers
`It is not known whether efinaconazole is excreted
`in human milk. After repeated subcutaneous
`administration, efinaconazole was detected
`in milk of nursing rats. Because many drugs
`are excreted in human milk, caution should
`be exercised when JUBLIA is administered to
`nursing women.
`8.4
`Pediatric Use
`Safety and effectiveness of JUBLIA in pediatric
`subjects have not been established.
`8.5
`Geriatric Use
`Of the total number of subjects in clinical trials
`of JUBLIA, 11.3% were 65 and over, while none
`were 75 and over. No overall differences in safety
`and effectiveness were observed between these
`subjects and younger subjects, and other reported
`clinical experience has not identified differences
`in responses between the elderly and the younger
`subjects, but greater sensitivity of some older
`individuals cannot be ruled out.
`
`PATIENT INFORMATION
`JUBLIA (joo-blee-uh)
`(efinaconazole) topical solution, 10%
`
`Important information: JUBLIA is for use on toenails and surrounding skin only. Do not use
`JUBLIA in your mouth, eyes, or vagina.
`
`What is JUBLIA?
`JUBLIA is a prescription medicine used to treat fungal infections of the toenails.
`It is not known if JUBLIA is safe and effective in children.
`
`What should I tell my healthcare provider before using JUBLIA?
`Before you use JUBLIA, tell your healthcare provider about all your medical conditions,
`including if you:
`• are pregnant or plan to become pregnant. It is not known if JUBLIA can harm your
`unborn baby.
`• are breastfeeding or plan to breastfeed. It is not known if JUBLIA 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 JUBLIA?
`See the “Instructions for Use” at the end of this Patient Information leaflet for detailed
`information about the right way to use JUBLIA.
`• Use JUBLIA exactly as your healthcare provider tells you to use it. Apply JUBLIA to your
`affected toenails 1 time each day. Wait for at least 10 minutes after showering, bathing, or
`washing before applying JUBLIA. JUBLIA is used for 48 weeks.
`• It is not known if the use of nail polish or other cosmetic nail products (such as gel nails or
`acrylic nails) will affect how JUBLIA works.
`
`What should I avoid while using JUBLIA?
`• JUBLIA is flammable. Avoid heat and flame while applying JUBLIA to your toenail.
`
`What are the possible side effects of JUBLIA?
`JUBLIA may cause irritation at the treated site. The most common side effects include:
`ingrown toenail, redness, itching, swelling, burning or stinging, blisters, and pain. Tell your
`healthcare provider if you have any side effects that bother you or that do not go away.
`These are not all the possible side effects of JUBLIA.
`Call your doctor for medical advice about side effects. You may report side effects to the FDA
`at 1-800-FDA-1088.
`
`How should I store JUBLIA?
`• Store JUBLIA at room temperature, between 68°F to 77°F (20°C to 25°C).
`Do not freeze JUBLIA.
`• Keep the bottle tightly closed and store in an upright position.
`• JUBLIA is flammable. Keep away from heat and flame.
`Keep JUBLIA and all medicines out of the reach of children.
`
`General information about the safe and effective use of JUBLIA
`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 JUBLIA that is written for health professionals. Do not use JUBLIA for a condition for
`which it was not prescribed. Do not give JUBLIA to other people, even if they have the same
`condition you have. It may harm them.
`
`ARGENTUM EX1043
`
`Page 1
`
`

`

`What are the ingredients in JUBLIA?
`Active ingredients: efinaconazole
`Inactive ingredients: alcohol, anhydrous citric acid, butylated hydroxytoluene, C12-15 alkyl
`lactate, cyclomethicone, diisopropyl adipate, disodium edetate, and purified water.
`Manufactured for:
`Valeant Pharmaceuticals North America LLC
`Bridgewater, NJ 08807 USA
`by:
`Valeant Pharmaceuticals International Inc.
`Laval, Quebec H7L 4A8, Canada
`
`For more information, call 1-800-321-4576.
`
`This Patient Information has been approved by the U.S. Food and Drug Administration.
`Rev. 05/2016
`
`9462902
`
`Instructions for Use
`JUBLIA® (joo-blee-uh)
`(efinaconazole) topical solution, 10%
`
`Important information: JUBLIA is for use on toenails and surrounding skin only.
`Do not use JUBLIA in your mouth, eyes or vagina.
`
`Step 2:
`
`Read the Instructions for Use that comes with
`JUBLIA before you start using it. Talk to your
`healthcare provider if you have any questions.
`How to apply JUBLIA:
`Your toenails should be clean and
`dry before you apply JUBLIA.
`Step 1:
` Before you apply
`JUBLIA to your affected
`toenail, remove the cap
`from the JUBLIA bottle
`(See Figure A).
` Hold the bottle upside
`down directly over the
`affected toenail and allow
`the product to moisten
`the brush. By turning
`the bottle upside down,
`the entire brush will
`become wet with the drug
`solution. Apply one drop
`of JUBLIA onto the
`toenail. Do not squeeze
`the bottle or press/rub the
`brush firmly against the toenail while
`applying JUBLIA (See Figure B).
` For the big toenail, also
`apply a second drop to
`the end of the toenail
`by touching the tip
`of the moist brush to
`the end of the toenail
`(See Figure C).
`If needed, repeat step 2
`to re-wet brush.
`
`Step 3:
`
`Step 4:
`
`Step 5:
`
`Step 6:
`Step 7:
`
` Use the brush attached
`to the bottle to gently
`apply JUBLIA. The
`goal is to make sure
`that the entire toenail
`including the cuticle,
`folds of the skin next to
`the sides of the toenail,
`and underneath the
`nail are covered with
`the drug solution. (See Figure D).
`Pressing or rubbing firmly against the
`toenail while applying JUBLIA could
`cause brush deformation and over
`application of the drug solution.
` Repeat Steps 2 to 4 to apply
`JUBLIA to each affected toenail.
` Let JUBLIA dry completely.
` After applying JUBLIA to your
`affected toenails, place the cap on
`the bottle and screw it on tightly.
` Wash your hands with soap and
`water after applying JUBLIA.
`This Patient Information and Instructions for
`Use has been approved by the U.S. Food and
`Drug Administration.
`Manufactured for:
`Valeant Pharmaceuticals North America LLC,
`Bridgewater, NJ 08807 USA
`by:
`Valeant Pharmaceuticals International Inc.
`Laval, Quebec H7L 4A8, Canada
`Rev. 05/2016
`
`Step 8:
`
`9462902
`
`DESCRIPTION
`11
`JUBLIA (efinaconazole) topical solution,
`10% is a clear colorless to pale yellow solution
`for topical use. Each gram of JUBLIA contains
`100 mg of efinaconazole. Efinaconazole is
`an azole antifungal with a chemical name
`of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-
`methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-
`1-yl)butan-2-ol). The structural formula for
`efinaconazole is represented below:
`
`Molecular Formula: C18H22F2N4O
`Molecular Weight: 348.39
`JUBLIA contains the following inactive
`ingredients: alcohol, anhydrous citric acid,
`butylated hydroxytoluene, C12-15 alkyl lactate,
`cyclomethicone, diisopropyl adipate, disodium
`edetate, and purified water.
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`JUBLIA topical solution is an azole antifungal
`[see Clinical Pharmacology (12.4)].
`12.2
`Pharmacodynamics
`The pharmacodynamics of JUBLIA is unknown.
`12.3
`Pharmacokinetics
`Systemic absorption of efinaconazole in 18
`adult subjects with severe onychomycosis was
`determined after application of JUBLIA once
`daily for 28 days to patients’ 10 toenails and
`0.5 cm adjacent skin. The concentration of
`efinaconazole in plasma was determined at
`multiple time points over the course of 24-hour
`periods on days 1, 14, and 28. Efinaconazole
`mean ± SD plasma Cmax on Day 28 was
`0.67 ± 0.37 ng/mL and the mean ± SD AUC was
`12.15 ± 6.91 ng*h/mL. The plasma concentration
`versus time profile at steady state was generally
`flat over a 24-hour dosing interval. In a separate
`study of healthy volunteers, the plasma half-life
`of efinaconazole following daily applications
`when applied to all 10 toenails for 7 days was
`29.9 hours.
`Drug Interactions
`JUBLIA is considered a non-inhibitor of the
`CYP450 enzyme family. In in vitro studies using
`human liver microsomes, efinaconazole did not
`inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9,
`CYP2C19, CYP2D6, CYP2PE1 and CYP3A4
`enzyme activities at expected clinical systemic
`
`concentrations. In vitro studies in human primary
`hepatocytes showed that efinaconazole did not
`induce CYP1A2 or CYP3A4 activities.
`12.4 Microbiology
`Mechanism of Action
`Efinaconazole is an azole antifungal.
`Efinaconazole inhibits fungal lanosterol
`14α-demethylase involved in the biosynthesis of
`ergosterol, a constituent of fungal cell membranes.
`Activity In Vitro and In Vivo
`Efinaconazole has been shown to be active
`against isolates of the following microorganisms,
`both in vitro and in clinical infections.
`Efinaconazole exhibits in vitro minimum
`inhibitory concentrations (MICs) of 0.06 mcg/mL
`or less against most (≥90%) isolates of the
`following microorganisms:
`Trichophyton rubrum
`Trichophyton mentagrophytes
`Mechanism of Resistance
`Efinaconazole drug resistance development
`was studied in vitro against T. mentagrophytes,
`T. rubrum and C. albicans. Serial passage of
`fungal cultures in the presence of sub-growth
`inhibitory concentrations of efinaconazole
`increased the MIC by up to 4-fold. The clinical
`significance of these in vitro results is unknown.
`13
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`A 2-year dermal carcinogenicity study in mice
`was conducted with daily topical administration
`of 3%, 10% and 30% efinaconazole solution.
`Severe irritation was noted at the treatment site
`in all dose groups, which was attributed to the
`vehicle and confounded the interpretation of skin
`effects by efinaconazole. The high dose group
`was terminated at week 34 due to severe skin
`reactions. No drug-related neoplasms were noted
`at doses up to 10% efinaconazole solution (248
`times the MRHD based on AUC comparisons).
`Efinaconazole revealed no evidence of mutagenic
`or clastogenic potential based on the results of
`two in vitro genotoxicity tests (Ames assay and
`Chinese hamster lung cell chromosome aberration
`assay) and one in vivo genotoxicity test (mouse
`peripheral reticulocyte micronucleus assay).
`No effects on fertility were observed in male and
`female rats that were administered subcutaneous
`doses up to 25 mg/kg/day efinaconazole (279 times
`the MRHD based on AUC comparisons) prior
`to and during early pregnancy. Efinaconazole
`delayed the estrous cycle in females at
`25 mg/kg/day but not at 5 mg/kg/day (56 times
`MRHD based on AUC comparisons).
`14
`CLINICAL STUDIES
`The safety and efficacy of once daily use of
`JUBLIA for the treatment of onychomycosis
`of the toenail were assessed in two 52-week
`prospective, multi-center, randomized, double-
`
`blind clinical trials in patients 18 years and
`older (18 to 70 years of age) with 20% to 50%
`clinical involvement of the target toenail,
`without dermatophytomas or lunula (matrix)
`involvement. The trials compared 48 weeks of
`treatment with JUBLIA to the vehicle solution.
`The Complete Cure rate was assessed at Week 52
`(4 weeks after completion of therapy). Complete
`cure was defined as 0% involvement of the target
`toenail (no clinical evidence of onychomycosis
`of the target toenail) in addition to Mycologic
`Cure, defined as both negative fungal culture and
`negative KOH. Table 2 lists the efficacy results for
`trials 1 and 2.
`Table 2: Efficacy Endpoints
`Trial 1
`
`Trial 2
`
`JUBLIA Vehicle
`JUBLIA Vehicle
`N = 656 N = 214 N = 580 N = 201
`117
`7
`88
`11
`17.8%
`3.3%
`15.2%
`5.5%
`173
`15
`136
`15
`26.4%
`7.0%
`23.4%
`7.5%
`
`Complete
`Curea
`Complete
`or Almost
`Complete
`Cureb
`
`Mycologic
`Curec
`
`362
`55.2%
`
`36
`16.8%
`
`310
`53.4%
`
`34
`16.9%
`
`a Complete cure defined as 0% clinical
`involvement of the target toenail plus negative
`KOH and negative culture.
`b Complete or almost complete cure defined as
`≤5% 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
`JUBLIA (efinaconazole) topical solution, 10% is
`a clear, colorless to pale yellow solution supplied
`in a white plastic bottle with an integrated flow-
`through brush applicator as follows:
`• 4 mL (NDC 0187-5400-04)
`• 8 mL (NDC 0187-5400-08)
`
`Storage and Handling Conditions:
`Store at 20°C to 25°C (68°F to 77°F); excursions
`permitted to 15°C to 30°C (59°F to 86°F) [see
`USP Controlled Room Temperature].
`• Solution is flammable; keep away from
`heat or flame
`• Protect from freezing
`• Keep out of the reach of children
`• Keep bottle tightly closed
`• Store in upright position
`17
`PATIENT COUNSELING
`INFORMATION
`Advise the patient to read the FDA-approved
`patient labeling (Patient Information and
`Instructions for Use).
`• JUBLIA is for external use only and is not for
`ophthalmic, oral, or intravaginal use. It is for use
`on toenails and immediately adjacent skin only.
`• Apply JUBLIA once daily to clean dry toenails.
`Wait for at least 10 minutes after showering,
`bathing, or washing before applying.
`• Use JUBLIA only on the affected toenails, as
`directed by your healthcare provider.
`• Inform a healthcare professional if the area of
`application shows signs of persistent irritation
`(for example, redness, itching, swelling).
`• The impact of nail polish or other cosmetic
`nail products on the efficacy of JUBLIA has
`not been evaluated.
`• Flammable, avoid use near heat or open flame.
`
`Manufactured for:
`Valeant Pharmaceuticals North America LLC
`Bridgewater, NJ 08807 USA
`by:
`Valeant Pharmaceuticals International Inc.
`Laval, Quebec H7L 4A8, Canada
`Jublia is a trademark of Valeant Pharmaceuticals
`International, Inc. or its affiliates.
`© Valeant Pharmaceuticals North America LLC
`U.S. Patents 7,214,506; 8,039,494; 8,486,978; and
`9,302,009
`Rev. 05/2016
`
`9462902
`
`Page 2
`
`