nly under medical supervision as described above. the effectiveness and safety of ciclopirox topical solution, 8% in the following populations has not been studied. the clinical trials with use of ciclopirox topical solution, 8% excluded patients who: were pregnant or nursing, planned to become pregnant, had a history of immunosuppression (e.g., extensive, persistent, or unusual distribution of dermatomycoses, extensive seborrheic dermatitis, recent or recurring herpes zoster, or persistent herpes simplex), were hiv seropositive, received organ transplant, required medication to control epilepsy, were insulin dependent diabetics or had diabetic neuropathy. patients with severe plantar (moccasin) tinea pedis were also excluded. the safety and efficacy of using ciclopirox topical solution, 8% daily for greater than 48 weeks have not been established. clinical trials data the results of use of ciclopirox topical solution, 8% in treatment of onychomycosis of the toenail without lunula involvement were obtained from two double-blind, placebo-controlled studies conducted in the us. in these studies, patients with onychomycosis of the great toenails without lunula involvement were treated with ciclopirox topical solution, 8%, in conjunction with monthly removal of the unattached, infected toenail by the investigator. ciclopirox topical solution, 8% was applied for 48 weeks. at baseline, patients had 20-65% involvement of the target great toenail plate. statistical significance was demonstrated in one of two studies for the endpoint “complete cure” (clear nail and negative mycology) and in two studies for the endpoint “almost clear” ≤10% nail involvement and negative mycology) at the end of study. these results are presented below. at week 48 (plus last observation carried forward) for the intent-to-treat (itt) population study 312 study 313 active vehicle active vehicle complete clear * 6/110 (5.5%) 1/109 (0.9%) 10/118 (8.5%) 0/117 (0%) almost clear ** 7/107 (6.5%) 1/108%) 14/116 (12%) 1/115 (0.9%) negative mycology alone*** 30/105 (29%) 12/106 (11%) 41/115 (36%) 10/114 (9%) *clear nail and negative mycology ** ≤10% nail involvement and negative mycology *** negative koh and negative culture the summary of reported patient outcomes for the itt population at 12 weeks following the end of treatment are presented below. note that post-treatment efficacy assessments were scheduled only for patients who achieved a complete cure. post-treatment week 12 data for patients who achieved complete cure at week 48 study 312 study 313 active vehicle active vehicle number of treated patients 112 111 119 118 complete cure at 12 weeks 6 1 10 0 post-treatment week 12 outcomes patients missing all week assessments 2 0 2 0 patients with week 12 assessments 4 1 8 0 complete clear 3 1 4 0 almost clear 2* 1 1* 0 negative mycology 3 1 5 0 * four patients (from studies 312 and 313) who were completely cured did not have post-treatment week 12 planimetry data.

olution, 8% should be applied once daily (preferably at bedtime or eight hours before washing) to all affected nails with the applicator brush provided. the ciclopirox topical solution, 8% should be applied evenly over the entire nail plate. if possible, ciclopirox topical solution, 8% should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis). the ciclopirox topical solution, 8% should not be removed on a daily basis. daily applications should be made over the previous coat and removed with alcohol every seven days. this cycle should be repeated throughout the duration of therapy.

nce of nail disorders was similar between the treatment groups (2% [6/327] in the ciclopirox topical solution, 8% group and 2% [7/328] in the vehicle group). moreover, application site reactions and/or burning of the skin occurred in 1% of patients treated with ciclopirox topical solution, 8% (3/327) and vehicle (4/328). a 21-day cumulative irritancy study was conducted under conditions of semi-occlusion. mild reactions were seen in 46% of patients with the ciclopirox topical solution, 8%, 32% with the vehicle and 2% with the negative control, but all were reactions of mild transient erythema. there was no evidence of allergic contact sensitization for either the ciclopirox topical solution, 8% or the vehicle base. in a separate study of the photosensitization potential of ciclopirox topical solution, 8% in a maximized test design that included the occluded application of sodium lauryl sulfate, no photoallergic reactions were noted. in four subjects localized allergic contact reactions were observed. in the vehicle-controlled studies, one patient treated with ciclopirox topical solution, 8% discontinued treatment due to a rash, localized to the palm (causal relation to test material undetermined). use of ciclopirox topical solution, 8% for 48 additional weeks was evaluated in an open-label extension study conducted in patients previously treated in the vehicle-controlled studies. three percent (9/281) of subjects treated with ciclopirox topical solution, 8% experienced at least one teae that the investigator thought was causally related to the test material. mild rash in the form of periungual erythema (1% [2/281]) and nail disorders (1% [4/281]) were the most frequently reported. four patients discontinued because of teaes. two of the four had events considered to be related to test material: one patient’s great toenail “broke away” and another had an elevated creatine phosphokinase level on day 1 (after 48 weeks of treatment with vehicle in the previous vehicle-controlled study).

luating 8% ciclopirox against new and established trichophyton rubrum and trichophyton mentagrophytes infections in ovine hoof material. (3) after 10 days of treatment the growth of t. rubrum and t. mentagrophytes in the established infection model was very minimally affected. elimination of the molds from hoof material was not achieved in either the new or established infection models. susceptibility testing for trichophyton rubrum species in vitro susceptibility testing methods for determining ciclopirox mic values against the dermatophytic molds, including trichophyton rubrum species, have not been standardized or validated. ciclopirox mic values will vary depending on the susceptibility testing method employed, composition and ph of media and the utilization of nutritional supplements. breakpoints to determine whether clinical isolates of trichophyton rubrum are susceptible or resistant to ciclopirox have not been established. resistance studies have not been conducted to evaluate drug resistance development in t. rubrum species exposed to 8% ciclopirox topical solution. studies assessing cross-resistance to ciclopirox and other known antifungal agents have not been performed. antifungal drug interactions no studies have been conducted to determine whether ciclopirox might reduce the effectiveness of systemic antifungal agents for onychomycosis. therefore, the concomitant use of 8% ciclopirox topical solution and systemic antifungal agents for onychomycosis is not recommended. pharmacokinetics as demonstrated in pharmacokinetic studies in animals and man, ciclopirox olamine is rapidly absorbed after oral administration and completely eliminated in all species via feces and urine. most of the compound is excreted either unchanged or as glucuronide. after oral administration of 10 mg of radiolabeled drug ( 14 c-ciclopirox) to healthy volunteers, approximately 96% of the radioactivity was excreted renally within 12 hours of administration. ninety-four percent of the renally excreted radioactivity was in the form of glucuronides. thus, glucuronidation is the main metabolic pathway of this compound. systemic absorption of ciclopirox was determined in 5 patients with dermatophytic onychomycoses, after application of ciclopirox topical solution, 8% to all 20 digits and adjacent 5 mm of skin once daily for six months. random serum concentrations and 24 hour urinary excretion of ciclopirox were determined at two weeks and at 1, 2, 4 and 6 months after initiation of treatment and 4 weeks post-treatment. in this study, ciclopirox serum levels ranged from 12-80 ng/ml. based on urinary data, mean absorption of ciclopirox from the dosage form was <5% of the applied dose. one month after cessation of treatment, serum and urine levels of ciclopirox were below the limit of detection. in two vehicle-controlled trials, patients applied ciclopirox topical solution, 8% to all toenails and affected fingernails. out of a total of 66 randomly selected patients on active treatment, 24 had detectable serum ciclopirox concentrations at some point during the dosing interval (range 10.0- 24.6 ng/ml). it should be noted that eleven of these 24 patients took concomitant medication containing ciclopirox as ciclopirox olamine (loprox® cream, 0.77%). the penetration of the ciclopirox topical solution, 8% was evaluated in an in vitro investigation. radiolabeled ciclopirox applied once to onychomycotic toenails that were avulsed demonstrated penetration up to a depth of approximately 0.4 mm. as expected, nail plate concentrations decreased as a function of nail depth. the clinical significance of these findings in nail plates is unknown. nail bed concentrations were not determined.