ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. In the controlled clinical trial with 89 patients using LOPROX(R) Topical Suspension and 89 patients using the vehicle, the incidence of adverse reactions was low. Those considered possibly related to treatment or occurring in more than one patient were pruritus, which occurred in two patients using ciclopirox suspension and one patient using the suspension vehicle, and burning, which occurred in one patient using ciclopirox suspension.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 1.2 times the maximum recommended human dose based on body surface area comparisons).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Ciclopirox is hydroxypyridone antifungal agent that 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.. Pharmacokinetics. Pharmacokinetic studies in men with radiolabeled ciclopirox solution in polyethylene glycol 400 showed an average of 1.3% absorption of the dose when it was applied topically to 750 cm2 on the back followed by occlusion for hours.The biological half life was 1.7 hours and excretion occurred via the kidney. Two days after application only 0.01% of the dose applied could be found in the urine. Fecal excretion was negligible. Autoradiographic studies with human cadaver skin showed that ciclopirox penetrates into the hair and through the epidermis and hair follicles into the sebaceous glands and dermis, while portion of the drug remains in the stratum corneum.In vitro penetration studies in frozen or fresh excised human cadaver and pig skin indicated that the penetration of LOPROX(R) Topical Suspension is equivalent to that of LOPROX(R) (ciclopirox) Cream, 0.77%. Therapeutic equivalence of cream and suspension formulations also was indicated by studies of experimentally induced guinea pig and human trichophytosis.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. LOPROX(R) Topical Suspension is contraindicated in individuals who have shown hypersensitivity to any of its components.

DESCRIPTION SECTION.

DESCRIPTION. LOPROX(R) (ciclopirox) Topical Suspension, 0.77% is for topical use.Each gram of LOPROX(R) Topical Suspension contains 7.70 mg of ciclopirox (as ciclopirox olamine) in water miscible suspension base consisting of purified water USP, cocamide DEA, octyldodecanol NF, mineral oil USP, stearyl alcohol NF, cetyl alcohol NF, polysorbate 60 NF, myristyl alcohol NF, lactic acid USP, sorbitan monostearate NF, and benzyl alcohol NF (1%) as preservative.LOPROX(R) Topical Suspension contains synthetic, broad spectrum, antifungal agent ciclopirox (as ciclopirox olamine). The chemical name is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt.The CAS Registry Number is 41621-49-2.LOPROX(R) Topical Suspension has pH of 7.The chemical structure is:. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Gently massage LOPROX(R) Topical Suspension into the affected and surrounding skin areas twice daily, in the morning and evening. Clinical improvement with relief of pruritus and other symptoms usually occurs within the first week of treatment. If patient shows no clinical improvement after four weeks of treatment with LOPROX(R) Topical Suspension, the diagnosis should be redetermined. Patients with tinea versicolor usually exhibit clinical and mycological clearing after two weeks of treatment.

HOW SUPPLIED SECTION.

HOW SUPPLIED. LOPROX(R) (ciclopirox) Topical Suspension, 0.77% is supplied in60 mL bottles (NDC 43538-550-60)Bottle space provided to allow for vigorous shaking before each use.. Store between - 25C (41 77F).To report SUSPECTED ADVERSE REACTIONS, contact Medimetriks Pharmaceuticals, Inc., at 1-973-882-7512 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. LOPROX(R) Topical Suspension is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; cutaneous candidiasis (moniliasis) due to Candida albicans; and tinea (pityriasis) versicolor due to Malassezia furfur.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. The patient should be told to:Use the medication for the full treatment time even though signs/symptoms may have improved and notify the physician if there is no improvement after four weeks.Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing) indicative of possible sensitization.Avoid the use of occlusive wrappings or dressings. Use the medication for the full treatment time even though signs/symptoms may have improved and notify the physician if there is no improvement after four weeks.. Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing) indicative of possible sensitization.. Avoid the use of occlusive wrappings or dressings.

MECHANISM OF ACTION SECTION.

Mechanism of Action. Ciclopirox is hydroxypyridone antifungal agent that 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.

NURSING MOTHERS SECTION.

Nursing Mothers. It is not known whether this drug is excreted in human milk. Caution should be exercised when LOPROX(R) Topical Suspension is administered to nursing woman.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 60 mL Bottle Carton. NDC 43538-550-60For Topical Use OnlyNot for use in eyes60 mLLOPROX(R) (ciclopirox)TopicalSuspension,0.77%Rx OnlyMEDIMETRIKSPHARMACEUTICALS, INC.. PRINCIPAL DISPLAY PANEL 60 mL Bottle Carton. PRINCIPAL DISPLAY PANEL Kit Carton. NDC 43538-551-60For Topical Use OnlyNot for use in eyes60mLRx OnlyLOPROX(R) (ciclopirox)TopicalSuspension,0.77%KITKIT CONTAINS:1 -LOPROX(R) (ciclopirox) Topical Suspension, 0.77%60 mL Bottle1 -Rehyla(R) Hair Body CleanserNet wt. 16 oz. (454 g) BottleMEDIMETRIKSPHARMACEUTICALS, INC.. -LOPROX(R) (ciclopirox) Topical Suspension, 0.77%60 mL Bottle. -Rehyla(R) Hair Body CleanserNet wt. 16 oz. (454 g) Bottle. PRINCIPAL DISPLAY PANEL Kit Carton.

PEDIATRIC USE SECTION.

Pediatric Use. Safety and effectiveness in pediatric patients below the age of 10 years have not been established.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Pharmacokinetic studies in men with radiolabeled ciclopirox solution in polyethylene glycol 400 showed an average of 1.3% absorption of the dose when it was applied topically to 750 cm2 on the back followed by occlusion for hours.The biological half life was 1.7 hours and excretion occurred via the kidney. Two days after application only 0.01% of the dose applied could be found in the urine. Fecal excretion was negligible. Autoradiographic studies with human cadaver skin showed that ciclopirox penetrates into the hair and through the epidermis and hair follicles into the sebaceous glands and dermis, while portion of the drug remains in the stratum corneum.In vitro penetration studies in frozen or fresh excised human cadaver and pig skin indicated that the penetration of LOPROX(R) Topical Suspension is equivalent to that of LOPROX(R) (ciclopirox) Cream, 0.77%. Therapeutic equivalence of cream and suspension formulations also was indicated by studies of experimentally induced guinea pig and human trichophytosis.

PRECAUTIONS SECTION.

PRECAUTIONS. If reaction suggesting sensitivity or chemical irritation should occur with the use of LOPROX(R) Topical Suspension, treatment should be discontinued and appropriate therapy instituted.. Information for Patients. The patient should be told to:Use the medication for the full treatment time even though signs/symptoms may have improved and notify the physician if there is no improvement after four weeks.Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing) indicative of possible sensitization.Avoid the use of occlusive wrappings or dressings. Use the medication for the full treatment time even though signs/symptoms may have improved and notify the physician if there is no improvement after four weeks.. Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing) indicative of possible sensitization.. Avoid the use of occlusive wrappings or dressings. Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 1.2 times the maximum recommended human dose based on body surface area comparisons).. Pregnancy. Teratogenic Effects. Pregnancy Category B. There are no adequate or well-controlled studies in pregnant women. Therefore, LOPROX(R) Topical Suspension 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 11, 37, 51 and 24 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 27 and 49 times the maximum recommended human dose based on body surface area comparisons, respectively).. Nursing Mothers. It is not known whether this drug is excreted in human milk. Caution should be exercised when LOPROX(R) Topical Suspension is administered to nursing woman.. Pediatric Use. Safety and effectiveness in pediatric patients below the age of 10 years have not been established.

PREGNANCY SECTION.

Pregnancy. Teratogenic Effects. Pregnancy Category B. There are no adequate or well-controlled studies in pregnant women. Therefore, LOPROX(R) Topical Suspension 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 11, 37, 51 and 24 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 27 and 49 times the maximum recommended human dose based on body surface area comparisons, respectively).

SPL UNCLASSIFIED SECTION.

For Topical Use OnlyNot for use in eyesRx Only.

STORAGE AND HANDLING SECTION.

Store between - 25C (41 77F).To report SUSPECTED ADVERSE REACTIONS, contact Medimetriks Pharmaceuticals, Inc., at 1-973-882-7512 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy Category B. There are no adequate or well-controlled studies in pregnant women. Therefore, LOPROX(R) Topical Suspension 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 11, 37, 51 and 24 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 27 and 49 times the maximum recommended human dose based on body surface area comparisons, respectively).

WARNINGS SECTION.

WARNINGS. General. LOPROX(R) Topical Suspension is not for ophthalmic use.Keep out of reach of children.