ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS oThe most frequently reported adverse reactions are pruritus, burning, and erythema. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Fougera Pharmaceuticals Inc. at 1-800-645-9833 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oThe most frequently reported adverse reactions are pruritus, burning, and erythema. (6.1). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 Ciclopirox 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 Post Marketing Experience. The following adverse reactions have been identified during post approval use of Ciclopirox Shampoo 1%: hair discoloration and abnormal hair texture, alopecia, irritation and rash. Because these events are reported voluntarily from population of uncertain size, it is not possible to reliably estimate their frequency or establish causal relationship to drug exposure.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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/m2/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 Fe3+, with and without metabolic activation (negative); gene mutation assays in the HGPRT-test with V79 Chinese hamster lung fibroblast cells (negative); and 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 dosage of 5000 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ciclopirox is 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 (Fe3+ or Al3+), 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 Ciclopirox Shampoo 1% are unknown.. 12.3 Pharmacokinetics In study in patients with seborrheic dermatitis of the scalp, application of mL ciclopirox shampoo 1% twice weekly for weeks, with an exposure time of minutes per application, resulted in detectable serum concentrations of ciclopirox in out of 18 patients. The serum concentrations measured throughout the dosing interval on Days 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.

CLINICAL STUDIES SECTION.

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 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 scale of = none, = slight, = mild, = moderate, = pronounced, and = severe. Effective treatment was defined as achieving score of (or score of 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 below.Table 1. Effective Treatment Rates at Week in Trials and Ciclopirox Shampoo Vehicle Study 220/380 (58%) 60/192 (31%) Study 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.. Ciclopirox Shampoo. Vehicle. Study 1. 220/380 (58%). 60/192 (31%). Study 2. 65/250 (26%). 32/249 (13%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None (4). None (4).

DESCRIPTION SECTION.

11 DESCRIPTION Ciclopirox Shampoo 1% contains the synthetic antifungal agent, ciclopirox for topical use. Each gram (equivalent to 0.96 mL) of Ciclopirox Shampoo contains 10 mg ciclopirox in shampoo base consisting of Purified Water USP, Sodium Laureth Sulfate, Disodium Laureth Sulfosuccinate, Sodium Chloride USP, and Laureth-2. Ciclopirox Shampoo is colorless, translucent solution. The chemical name for ciclopirox is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, with the empirical formula C12H17NO2 and molecular weight of 207.27. The CAS Registry Number is [29342-05-0]. The chemical structure is: chemical structure.

DOSAGE & ADMINISTRATION SECTION.

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

DOSAGE FORMS & STRENGTHS SECTION.

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

GERIATRIC USE SECTION.

8.5 Geriatric Use In clinical trials, the safety and tolerability of Ciclopirox 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 Ciclopirox Shampoo, and in 15 of 61 (25%) subjects treated with the vehicle; due to the small sample size, 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Ciclopirox Shampoo 1% is supplied in 120 mL plastic bottles (NDC 0168-0449-04). Discard unused product after initial treatment duration.Store between 15C and 30C (59F and 86F). Keep out of reach of children.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Ciclopirox Shampoo 1% is indicated for the topical treatment of seborrheic dermatitis of the scalp in adults.. oCiclopirox Shampoo is an antifungal indicated for the topical treatment of seborrheic dermatitis of the scalp in adults. (1). oCiclopirox Shampoo is an antifungal indicated for the topical treatment of seborrheic dermatitis of the scalp in adults. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) The patient should be instructed to:oUse Ciclopirox Shampoo 1% as directed by the physician. Avoid contact with the eyes. If contact occurs, rinse thoroughly with water. Ciclopirox Shampoo 1% is for external use on the scalp only. Do not swallow.oUse Ciclopirox Shampoo 1% for seborrheic dermatitis for the full treatment time even though symptoms may have improved. Notify the physician if there is no improvement after weeks.oInform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, or oozing).. oUse Ciclopirox Shampoo 1% as directed by the physician. Avoid contact with the eyes. If contact occurs, rinse thoroughly with water. Ciclopirox Shampoo 1% is for external use on the scalp only. Do not swallow.. oUse Ciclopirox Shampoo 1% for seborrheic dermatitis for the full treatment time even though symptoms may have improved. Notify the physician if there is no improvement after weeks.. oInform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, or oozing).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Ciclopirox is 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 (Fe3+ or Al3+), resulting in the inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell.

MICROBIOLOGY SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

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/m2/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 Fe3+, with and without metabolic activation (negative); gene mutation assays in the HGPRT-test with V79 Chinese hamster lung fibroblast cells (negative); and 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 dosage of 5000 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).

NURSING MOTHERS SECTION.

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 Ciclopirox Shampoo is administered to nursing woman.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel 120 mL Bottle NDC 0168-0449-04Fougera(R) CICLOPIROXSHAMPOO 1%FOR TOPICAL USE ONLY.NOT FOR OPHTHALMIC, ORALOR INTRAVAGINAL USE.KEEP OUT OF REACH OF CHILDREN.This package is not child resistant.Rx only120 mLE.Fougera CO.A division ofFougera Pharmaceuticals Inc.Melville, New York 11747. container.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics The pharmacodynamics of Ciclopirox Shampoo 1% are unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics In study in patients with seborrheic dermatitis of the scalp, application of mL ciclopirox shampoo 1% twice weekly for weeks, with an exposure time of minutes per application, resulted in detectable serum concentrations of ciclopirox in out of 18 patients. The serum concentrations measured throughout the dosing interval on Days 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.

PREGNANCY SECTION.

8.1 Pregnancy Teratogenic Effects: Pregnancy Category BThere are no adequate or well-controlled studies in pregnant women. Therefore, Ciclopirox Shampoo 1% 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).

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationCiclopirox Shampoo 1%Important: For use on the scalp only. Do not get Ciclopirox Shampoo in your eyes, mouth, or vagina. What is Ciclopirox ShampooCiclopirox Shampoo is prescription medicine used on the scalp to treat adults with skin condition called seborrheic dermatitis.It is not known if Ciclopirox Shampoo is safe and effective in children under 16 years of age. What should tell my doctor before using Ciclopirox Shampoo Before using LOPROX Shampoo, tell your doctor if you:ohave any other medical conditionsoare pregnant or plan to become pregnant. It is not known if Ciclopirox Shampoo will harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not know if Ciclopirox Shampoo passes into your breast milk.oare taking prescription and non-prescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should use Ciclopirox ShampoooUse Ciclopirox Shampoo exactly as your doctor tells you to use it.oWash your hair using Ciclopirox Shampoo times each week for weeks. There should be at least days between each time you use Ciclopirox Shampoo.oUse Ciclopirox Shampoo for weeks even if your skin condition improves.oTell your doctor if your scalp condition is not getting better after you have used Ciclopirox Shampoo for weeks.oDo not swallow Ciclopirox Shampoo.oAvoid getting Ciclopirox Shampoo in your eyes. If Ciclopirox Shampoo gets into your eyes, rinse them well with water. How should apply Ciclopirox ShampoooWet your hair and apply approximately teaspoon of Ciclopirox Shampoo to your scalp. You may use up to teaspoons of Ciclopirox Shampoo if you have long hair. Lather and leave Ciclopirox Shampoo on your hair and scalp for minutes. You may use timer.oAfter minutes have passed, rinse your hair and scalp.What are the possible side effects of Ciclopirox ShampooThe most common side effects of Ciclopirox Shampoo include: itching, burning, and redness of the scalp. Tell your doctor if you get any of these symptoms and they become worse or do not go away, or if you get blistering, swelling, or oozing in your scalp.These are not all the possible side effects of Ciclopirox Shampoo. For more information, ask your doctor.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Ciclopirox ShampoooStore Ciclopirox Shampoo at room temperature, between 59F to 86F (15C to 30C).oSafely throw away any unused Ciclopirox Shampoo after you finish your treatment.Keep Ciclopirox Shampoo and all medicines out of the reach of children. General information about Ciclopirox ShampooMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Ciclopirox Shampoo for condition for which it was not prescribed. Do not give Ciclopirox Shampoo to other people, even if they have the same symptoms you have. It may harm them.You can ask your pharmacist or doctor for information about Ciclopirox Shampoo that is written for health professionals.For more information about Ciclopirox Shampoo, call 1-800-645-9833.What are the ingredients in Ciclopirox Shampoo Active ingredient: ciclopiroxInactive ingredients: Purified Water, Sodium Laureth Sulfate, Disodium Laureth Sulfosuccinate, Sodium Chloride and Laureth-2.E. FOUGERA CO.A division of FougeraPHARMACEUTICALS INC.Melville, New York 11747 IF2449BR07/17222. ohave any other medical conditions. oare pregnant or plan to become pregnant. It is not known if Ciclopirox Shampoo will harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not know if Ciclopirox Shampoo passes into your breast milk.. oare taking prescription and non-prescription medicines, vitamins, and herbal supplements.. Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.. oUse Ciclopirox Shampoo exactly as your doctor tells you to use it.. oWash your hair using Ciclopirox Shampoo times each week for weeks. There should be at least days between each time you use Ciclopirox Shampoo.. oUse Ciclopirox Shampoo for weeks even if your skin condition improves.. oTell your doctor if your scalp condition is not getting better after you have used Ciclopirox Shampoo for weeks.. oDo not swallow Ciclopirox Shampoo.. oAvoid getting Ciclopirox Shampoo in your eyes. If Ciclopirox Shampoo gets into your eyes, rinse them well with water. oWet your hair and apply approximately teaspoon of Ciclopirox Shampoo to your scalp. You may use up to teaspoons of Ciclopirox Shampoo if you have long hair. Lather and leave Ciclopirox Shampoo on your hair and scalp for minutes. You may use timer.. oAfter minutes have passed, rinse your hair and scalp.. oStore Ciclopirox Shampoo at room temperature, between 59F to 86F (15C to 30C).. oSafely throw away any unused Ciclopirox Shampoo after you finish your treatment.

SPL UNCLASSIFIED SECTION.

5.1 Local Effects If reaction suggesting sensitivity or irritation occurs with the use of Ciclopirox Shampoo 1%, treatment should be discontinued and appropriate therapy instituted.Contact of Ciclopirox Shampoo 1% with the eyes should be avoided. If contact occurs, rinse thoroughly with water. In patients with lighter hair color, hair discoloration has been reported.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category BThere are no adequate or well-controlled studies in pregnant women. Therefore, Ciclopirox Shampoo 1% 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 Ciclopirox Shampoo is administered to 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 Ciclopirox 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 Ciclopirox Shampoo, and in 15 of 61 (25%) subjects treated with the vehicle; due to the small sample size, 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oIf signs of irritation occur, discontinue use. (5.1)oAvoid contact with eyes. (5.1)oHair discoloration has been reported with Ciclopirox use. (5.1). oIf signs of irritation occur, discontinue use. (5.1). oAvoid contact with eyes. (5.1). oHair discoloration has been reported with Ciclopirox use. (5.1). 5.1 Local Effects If reaction suggesting sensitivity or irritation occurs with the use of Ciclopirox Shampoo 1%, treatment should be discontinued and appropriate therapy instituted.Contact of Ciclopirox Shampoo 1% with the eyes should be avoided. If contact occurs, rinse thoroughly with water. In patients with lighter hair color, hair discoloration has been reported.