Loprox

6 ADVERSE REACTIONS • The most frequently reported adverse reactions are pruritus, burning, and erythema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 clinical practice. In 626 subjects treated with LOPROX Shampoo twice weekly in the two pivotal clinical trials, the most frequent adverse events were increased itching in 1% of subjects, and application site reactions, such as burning, erythema, and itching, also in 1% of subjects. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of LOPROX Shampoo: hair discoloration and abnormal hair texture, alopecia, irritation, and rash. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

4 CONTRAINDICATIONS None. None ( 4 )

11 DESCRIPTION LOPROX (ciclopirox) Shampoo, 1% contains the synthetic antifungal agent ciclopirox for topical use. Each gram (equivalent to 0.96 mL) of LOPROX Shampoo contains 10 mg ciclopirox in a shampoo base consisting of disodium laureth sulfosuccinate, laureth-2, purified water, sodium chloride, and sodium laureth sulfate. LOPROX Shampoo is a colorless, translucent solution. The chemical name for ciclopirox is 6-cyclohexyl-1-hydroxy-4-methyl-2(1 H )-pyridone, with the empirical formula C 12 H 17 NO 2 and a molecular weight of 207.27. The CAS Registry Number is [29342-05-0]. The chemical structure is: loprox-01.jpg

2 DOSAGE AND ADMINISTRATION LOPROX Shampoo is not for ophthalmic, oral, or intravaginal use. Wet hair and apply approximately 1 teaspoon (5 mL) of LOPROX Shampoo to the scalp. Up to 2 teaspoons (10 mL) may be used for long hair. Lather and leave on hair and scalp for 3 minutes. A timer may be used. Avoid contact with eyes. Rinse off. Treatment should be repeated twice per week for 4 weeks, with a minimum of 3 days between applications. If a patient with seborrheic dermatitis shows no clinical improvement after 4 weeks of treatment with LOPROX Shampoo, the diagnosis should be reviewed. • Apply approximately 1 teaspoon of LOPROX Shampoo to the scalp twice per week for 4 weeks. ( 2 ) • For topical use only. Not for ophthalmic, oral, or intravaginal use. ( 2 )

1 INDICATIONS AND USAGE LOPROX ® (ciclopirox) Shampoo, 1% is indicated for the topical treatment of seborrheic dermatitis of the scalp in adults. • LOPROX Shampoo is an antifungal indicated for the topical treatment of seborrheic dermatitis of the scalp in adults. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ciclopirox is a hydroxypyridone antifungal agent although the relevance of this property for the indication of seborrheic dermatitis is not known. Ciclopirox acts by chelation of polyvalent cations (Fe 3+ or Al 3+ ), resulting in the inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell. 12.2 Pharmacodynamics The pharmacodynamics of LOPROX Shampoo are unknown. 12.3 Pharmacokinetics In a study in patients with seborrheic dermatitis of the scalp, application of 5 mL ciclopirox shampoo, 1% twice weekly for 4 weeks, with an exposure time of 3 minutes per application, resulted in detectable serum concentrations of ciclopirox in 6 out of 18 patients. The serum concentrations measured throughout the dosing interval on Days 1 and 29 ranged from 10.3 ng/mL to 13.2 ng/mL. Total urinary excretion of ciclopirox was less than 0.5% of the administered dose. 12.4 Microbiology Ciclopirox is fungicidal in vitro against Malassezia furfur ( Pityrosporum spp.), P. ovale , and P. orbiculare . The clinical significance of antifungal activity in the treatment of seborrheic dermatitis is not known.

12.1 Mechanism of Action Ciclopirox is a hydroxypyridone antifungal agent although the relevance of this property for the indication of seborrheic dermatitis is not known. Ciclopirox acts by chelation of polyvalent cations (Fe 3+ or Al 3+ ), resulting in the inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell.

12.2 Pharmacodynamics The pharmacodynamics of LOPROX Shampoo are unknown.

12.3 Pharmacokinetics In a study in patients with seborrheic dermatitis of the scalp, application of 5 mL ciclopirox shampoo, 1% twice weekly for 4 weeks, with an exposure time of 3 minutes per application, resulted in detectable serum concentrations of ciclopirox in 6 out of 18 patients. The serum concentrations measured throughout the dosing interval on Days 1 and 29 ranged from 10.3 ng/mL to 13.2 ng/mL. Total urinary excretion of ciclopirox was less than 0.5% of the administered dose.

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3 DOSAGE FORMS AND STRENGTHS LOPROX is a shampoo containing 1% ciclopirox. Each gram (equivalent to 0.96 mL) of LOPROX Shampoo contains 10 mg ciclopirox in a colorless and translucent shampoo base. • Shampoo, 1% ( 3 )

Loprox ciclopirox ciclopirox ciclopirox disodium laureth sulfosuccinate laureth-2 water sodium chloride sodium laureth-3 sulfate

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dermal carcinogenicity study in mice was conducted with ciclopirox cream applied at doses up to 1.93% (100 mg/kg/day or 300 mg/m 2 /day). No increase in drug-related neoplasms was noted when compared to control. The following in vitro genotoxicity tests have been conducted with ciclopirox: evaluation of gene mutation in the Ames Salmonella and E. coli assays (negative); chromosome aberration assays in V79 Chinese hamster lung fibroblast cells, with and without metabolic activation (positive); chromosome aberration assays in V79 Chinese hamster lung fibroblast cells in the presence of supplemental Fe 3+ , with and without metabolic activation (negative); gene mutation assays in the HGPRT-test with V79 Chinese hamster lung fibroblast cells (negative); and a primary DNA damage assay (i.e., unscheduled DNA synthesis assay in A549 human cells) (negative). An in vitro cell transformation assay in BALB/c 3T3 cells was negative for cell transformation. In an in vivo Chinese hamster bone marrow cytogenetic assay, ciclopirox was negative for chromosome aberrations at a dosage of 5,000 mg/kg body weight. A combined oral fertility and embryofetal developmental study was conducted in rats with ciclopirox olamine. No effect on fertility or reproductive performance was noted at the highest dose tested of 3.85 mg/kg/day ciclopirox (approximately 1.3 times the maximum recommended human dose based on body surface area comparisons).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dermal carcinogenicity study in mice was conducted with ciclopirox cream applied at doses up to 1.93% (100 mg/kg/day or 300 mg/m 2 /day). No increase in drug-related neoplasms was noted when compared to control. The following in vitro genotoxicity tests have been conducted with ciclopirox: evaluation of gene mutation in the Ames Salmonella and E. coli assays (negative); chromosome aberration assays in V79 Chinese hamster lung fibroblast cells, with and without metabolic activation (positive); chromosome aberration assays in V79 Chinese hamster lung fibroblast cells in the presence of supplemental Fe 3+ , with and without metabolic activation (negative); gene mutation assays in the HGPRT-test with V79 Chinese hamster lung fibroblast cells (negative); and a primary DNA damage assay (i.e., unscheduled DNA synthesis assay in A549 human cells) (negative). An in vitro cell transformation assay in BALB/c 3T3 cells was negative for cell transformation. In an in vivo Chinese hamster bone marrow cytogenetic assay, ciclopirox was negative for chromosome aberrations at a dosage of 5,000 mg/kg body weight. A combined oral fertility and embryofetal developmental study was conducted in rats with ciclopirox olamine. No effect on fertility or reproductive performance was noted at the highest dose tested of 3.85 mg/kg/day ciclopirox (approximately 1.3 times the maximum recommended human dose based on body surface area comparisons).

NDA021159

Loprox

ciclopirox

99207-010

HUMAN PRESCRIPTION DRUG

TOPICAL

12.4 Microbiology Ciclopirox is fungicidal in vitro against Malassezia furfur ( Pityrosporum spp.), P. ovale , and P. orbiculare . The clinical significance of antifungal activity in the treatment of seborrheic dermatitis is not known.

PRINCIPAL DISPLAY PANEL - 120 mL Bottle Carton NDC 99207-010-10 Rx only LOPROX ® SHAMPOO (ciclopirox) 1% FOR TOPICAL USE ONLY NOT FOR OPHTHALMIC, ORAL OR INTRAVAGINAL USE KEEP OUT OF REACH OF CHILDREN 120 mL Ortho Dermatologics carton.jpg

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). The patient should be instructed to: • Use LOPROX Shampoo as directed by the physician. Avoid contact with the eyes. If contact occurs, rinse thoroughly with water. LOPROX Shampoo is for external use on the scalp only. Do not swallow. • Use LOPROX Shampoo for seborrheic dermatitis for the full treatment time even though symptoms may have improved. Notify the physician if there is no improvement after 4 weeks. • Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, or oozing). Manufactured for: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada LOPROX is a trademark of Bausch Health Companies Inc. or its affiliates. © 2019 Bausch Health Companies Inc. or its affiliates 9505303

14 CLINICAL STUDIES In two randomized, double-blind clinical trials, subjects 16 years and older with seborrheic dermatitis of the scalp applied LOPROX Shampoo or its vehicle twice weekly for 4 weeks. Subjects who were immunocompromised, those with psoriasis or atopic dermatitis, women of childbearing potential not using adequate contraception, and pregnant or lactating women were excluded from the clinical trials. An evaluation of the overall status of the seborrheic dermatitis, the presence and severity of erythema or inflammation, and scaling was made at Week 4, using a scale of 0=none, 1=slight, 2=mild, 3=moderate, 4=pronounced, and 5=severe. Effective treatment was defined as achieving a score of 0 (or a score of 1 if the baseline score was ≥3) simultaneously for status of the seborrheic dermatitis, erythema or inflammation, and scaling at Week 4. Ciclopirox shampoo was shown to be statistically significantly more effective than vehicle in both trials. Efficacy results for the two trials are presented in Table 1 below. Table 1. Effective Treatment Rates at Week 4 in Trials 1 and 2 Ciclopirox Shampoo Vehicle Study 1 220/380 (58%) 60/192 (31%) Study 2 65/250 (26%) 32/249 (13%) Efficacy for African American subjects was not demonstrated, although only 53 African American subjects were enrolled in the two pivotal trials.

8.5 Geriatric Use In clinical trials, the safety and tolerability of LOPROX Shampoo in the population 65 years and older was comparable to that of younger subjects. Results of the efficacy analysis in those subjects 65 years and older showed effectiveness in 25 of 85 (29%) subjects treated with LOPROX Shampoo, and in 15 of 61 (25%) subjects treated with the vehicle; due to the small sample size, a statistically significant difference was not demonstrated. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity to adverse effects in some older individuals cannot be ruled out.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOPROX Shampoo is administered to a nursing woman.

8.4 Pediatric Use No clinical trials have been conducted in subjects younger than 16 years.

8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate or well-controlled studies in pregnant women. Therefore, LOPROX Shampoo should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral embryofetal developmental studies were conducted in mice, rats, rabbits, and monkeys. Ciclopirox or ciclopirox olamine was orally administered during the period of organogenesis. No maternal toxicity, embryotoxicity or teratogenicity were noted at the highest doses of 77, 125, 80, and 38.5 mg/kg/day ciclopirox in mice, rats, rabbits, and monkeys, respectively (approximately 13, 42, 54, and 26 times the maximum recommended human dose based on body surface area comparisons, respectively). Dermal embryofetal developmental studies were conducted in rats and rabbits with ciclopirox olamine dissolved in PEG 400. Ciclopirox olamine was topically administered during the period of organogenesis. No maternal toxicity, embryotoxicity, or teratogenicity were noted at the highest doses of 92 mg/kg/day and 77 mg/kg/day ciclopirox in rats and rabbits, respectively (approximately 31 and 54 times the maximum recommended human dose based on body surface area comparisons, respectively).

Teratogenic Effects: Pregnancy Category B There are no adequate or well-controlled studies in pregnant women. Therefore, LOPROX Shampoo should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral embryofetal developmental studies were conducted in mice, rats, rabbits, and monkeys. Ciclopirox or ciclopirox olamine was orally administered during the period of organogenesis. No maternal toxicity, embryotoxicity or teratogenicity were noted at the highest doses of 77, 125, 80, and 38.5 mg/kg/day ciclopirox in mice, rats, rabbits, and monkeys, respectively (approximately 13, 42, 54, and 26 times the maximum recommended human dose based on body surface area comparisons, respectively). Dermal embryofetal developmental studies were conducted in rats and rabbits with ciclopirox olamine dissolved in PEG 400. Ciclopirox olamine was topically administered during the period of organogenesis. No maternal toxicity, embryotoxicity, or teratogenicity were noted at the highest doses of 92 mg/kg/day and 77 mg/kg/day ciclopirox in rats and rabbits, respectively (approximately 31 and 54 times the maximum recommended human dose based on body surface area comparisons, respectively).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate or well-controlled studies in pregnant women. Therefore, LOPROX Shampoo should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral embryofetal developmental studies were conducted in mice, rats, rabbits, and monkeys. Ciclopirox or ciclopirox olamine was orally administered during the period of organogenesis. No maternal toxicity, embryotoxicity or teratogenicity were noted at the highest doses of 77, 125, 80, and 38.5 mg/kg/day ciclopirox in mice, rats, rabbits, and monkeys, respectively (approximately 13, 42, 54, and 26 times the maximum recommended human dose based on body surface area comparisons, respectively). Dermal embryofetal developmental studies were conducted in rats and rabbits with ciclopirox olamine dissolved in PEG 400. Ciclopirox olamine was topically administered during the period of organogenesis. No maternal toxicity, embryotoxicity, or teratogenicity were noted at the highest doses of 92 mg/kg/day and 77 mg/kg/day ciclopirox in rats and rabbits, respectively (approximately 31 and 54 times the maximum recommended human dose based on body surface area comparisons, respectively). 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOPROX Shampoo is administered to a nursing woman. 8.4 Pediatric Use No clinical trials have been conducted in subjects younger than 16 years. 8.5 Geriatric Use In clinical trials, the safety and tolerability of LOPROX Shampoo in the population 65 years and older was comparable to that of younger subjects. Results of the efficacy analysis in those subjects 65 years and older showed effectiveness in 25 of 85 (29%) subjects treated with LOPROX Shampoo, and in 15 of 61 (25%) subjects treated with the vehicle; due to the small sample size, a statistically significant difference was not demonstrated. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity to adverse effects in some older individuals cannot be ruled out.

16 HOW SUPPLIED/STORAGE AND HANDLING LOPROX (ciclopirox) Shampoo, 1% is colorless and translucent, and supplied in 120 mL plastic bottles (NDC 99207-010-10). Discard unused product after initial treatment duration. Store between 15° to 30°C (59° to 86°F). Keep out of reach of children.

Store between 15° to 30°C (59° to 86°F). Keep out of reach of children.