LOPROX ® CREAM (ciclopirox) 0.77%

Ciclopirox is a 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.

Pharmacokinetic studies in men with tagged 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 6 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.

Penetration studies in human cadaverous skin from the back, with LOPROX^® Cream with tagged ciclopirox showed the presence of 0.8 to 1.6% of the dose in the stratum corneum 1.5 to 6 hours after application. The levels in the dermis were still 10 to 15 times above the minimum inhibitory concentrations.

Autoradiographic studies with human cadaverous skin showed that ciclopirox penetrates into the hair and through the epidermis and hair follicles into the sebaceous glands and dermis, while a portion of the drug remains in the stratum corneum.

Draize Human Sensitization Assay, 21-Day Cumulative Irritancy study, Phototoxicity study, and Photo-Draize study conducted in a total of 142 healthy male subjects showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity, and no photo-contact sensitization due to LOPROX^® Cream.

The patient should be told to:

1. Use the medication for the full treatment time even though symptoms may have improved and notify the physician if there is no improvement after four weeks.
2. Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, or oozing) indicative of possible sensitization.
3. Avoid the use of occlusive wrappings or dressings

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 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 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).

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^® Cream is administered to a nursing woman.

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

Store at 15º - 30ºC (59º - 86ºF).

To report SUSPECTED ADVERSE REACTIONS, contact Medimetriks Pharmaceuticals, Inc., at 1-973-882-8812 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.