CICLOPIROX: 536 Adverse Event Reports & Safety Profile

DESCRIPTION Ciclopirox Topical Solution, USP 8% (Nail Lacquer), contains a synthetic antifungal agent, Ciclopirox, USP. It is intended for topical use on fingernails and toenails and immediately adjacent skin. Each gram of Ciclopirox Topical Solution, USP 8% (Nail Lacquer), contains 80 mg Ciclopirox, USP in a solution base consisting of ethyl acetate, isopropyl alcohol, and butyl monoester of poly[methylvinyl ether/maleic acid] in isopropyl alcohol. Ethyl acetate and isopropyl alcohol are solvents that vaporize after application.

Ciclopirox Topical

Solution, USP 8% (Nail Lacquer), is a clear, colorless to slightly yellow 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: image description

INDICATIONS AND USAGE (To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of thelabeling.) Ciclopirox topical solution, 8% (nail lacquer), as a component of a comprehensive management program, is indicated as topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum . The comprehensive management program includes removal of the unattached, infected nails as frequently as monthly, by a health care professional who has special competence in the diagnosis and treatment of nail disorders, including minor nail procedures.

• No studies have been conducted to determine whether ciclopirox might reduce the effectiveness of systemic antifungal agents for onychomycosis. Therefore, the concomitant use of ciclopirox topical solution, 8% (nail lacquer) and systemic antifungal agents for onychomycosis, is not recommended.
• Ciclopirox topical solution, 8% (nail lacquer), should be used only under medical supervision as described above.
• The effectiveness and safety of ciclopirox topical solution, 8% (nail lacquer), in the following populations has not been studied. The clinical trials with use of ciclopirox topical solution, 8% (nail lacquer), 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% (nail lacquer), daily for greater than 48 weeks have not been established.

Clinical Trials Data

The results of use of ciclopirox topical solution, 8% (nail lacquer), 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% (nail lacquer), in conjunction with monthly removal of the unattached, infected toenail by the investigator. Ciclopirox topical solution, 8% (nail lacquer), 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 Cure* 6/110 (5.5%) 1/109 (0.9%) 10/118 (8.5%) 0/117 (0%)

Almost

Clear** 7/107 (6.5%) 1/108 (0.9%) 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 Week 48 6 1 10 0 Post-treatment Week 12 Outcomes: Patients Missing All Week 12 Assessments Patients with Week 12 Assessments Complete Cure Almost Clear Negative Mycology 2 4 3 2* 3 0 1 1 1 1 2 8 4 1* 5 0 0 0 0 0 *Four patients (from studies 312 and 313) who were completely cured did not have post-treatment Week 12 planimetry data.

DOSAGE AND ADMINISTRATION Ciclopirox topical solution, 8% (Nail Lacquer), should be used as a component of a comprehensive management program for onychomycosis. Removal of the unattached, infected nail, as frequently as monthly, by a health care professional, weekly trimming by the patient, and daily application of the medication are all integral parts of this therapy. Careful consideration of the appropriate nail management program should be given to patients with diabetes (see PRECAUTIONS ).

Nail Care By Health Care

Professionals : Removal of the unattached, infected nail, as frequently as monthly, trimming of onycholytic nail, and filing of excess horny material should be performed by professionals trained in treatment of nail disorders.

Nail Care By

Patient : Patients should file away (with emery board) loose nail material and trim nails, as required, or as directed by the health care professional, every seven days after ciclopirox topical solution, 8% (Nail Lacquer), is removed with alcohol. Ciclopirox topical solution, 8% (Nail Lacquer), 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% (Nail Lacquer), should be applied evenly over the entire nail plate. If possible, ciclopirox topical solution, 8% (Nail Lacquer), 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% (Nail Lacquer), 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.

CONTRAINDICATIONS Ciclopirox topical solution, 8% (nail lacquer), is contraindicated in individuals who have shown hypersensitivity to any of its components.

ADVERSE REACTIONS In the vehicle-controlled clinical trials conducted in the US, 9% (30/327) of patients treated with ciclopirox topical solution, 8% (nail lacquer), and 7% (23/328) of patients treated with vehicle reported treatment-emergent adverse events (TEAE) considered by the investigator to be causally related to the test material. The incidence of these adverse events, within each body system, was similar between the treatment groups except for Skin and Appendages: 8% (27/327) and 4% (14/328) of subjects in the ciclopirox and vehicle groups reported at least one adverse event, respectively. The most common were rash-related adverse events: periungual erythema and erythema of the proximal nail fold were reported more frequently in patients treated with ciclopirox topical solution, 8% (nail lacquer), (5% [16/327]) than in patients treated with vehicle (1% [3/328]). Other TEAEs thought to be causally related included nail disorders such as shape change, irritation, ingrown toenail, and discoloration. The incidence of nail disorders was similar between the treatment groups (2% [6/327] in the ciclopirox topical solution, 8% (nail lacquer), 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% (nail lacquer), (3/327) and vehicle (4/328). A21-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% (nail lacquer), 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% (nail lacquer), or the vehicle base. In a separate study of the photosensitization potential of ciclopirox topical solution, 8% (nail lacquer), 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% (nail lacquer), discontinued treatment due to a rash, localized to the palm (causal relation to test material undetermined). Use of ciclopirox topical solution, 8% (nail lacquer), 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% (nail lacquer), 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).

AND PRECAUTIONS

• If signs of irritation occur, discontinue use. ( 5.1 )
• Avoid contact with eyes. ( 5.1 )
• Hair discoloration has been reported with Ciclopirox Shampoo, 1% use. ( 5.1 )

5.1 Local Effects If a 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.

PRECAUTIONS If a reaction suggesting sensitivity or chemical irritation should occur with the use of ciclopirox topical solution, 8% (nail lacquer), treatment should be discontinued and appropriate therapy instituted. So far there is no relevant clinical experience with patients with insulin dependent diabetes or who have diabetic neuropathy. The risk of removal of the unattached, infected nail, by the health care professional and trimming by the patient should be carefully considered before prescribing to patients with a history of insulin dependent diabetes mellitus or diabetic neuropathy. Information for Patients Patients should have detailed instructions regarding the use of ciclopirox topical solution, 8% (nail lacquer), as a component of a comprehensive management program for onychomycosis in order to achieve maximum benefit with the use of this product. The patient should be told to: 1. Use ciclopirox topical solution, 8% (nail lacquer), as directed by a health care professional. Avoid contact with the eyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided. Ciclopirox topical solution, 8% (nail lacquer), is for external use only. 2. Ciclopirox topical solution, 8% (nail lacquer), should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, ciclopirox topical solution, 8% (nail lacquer), 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). Contact with the surrounding skin may produce mild, transient irritation (redness). 3. Removal of the unattached, infected nail, as frequently as monthly, by a health care professional is needed with use of this medication. Inform a health care professional if they have diabetes or problems with numbness in your toes or fingers for consideration of the appropriate nail management program. 4. Inform a health care professional if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing). 5. Up to 48 weeks of daily applications with ciclopirox topical solution, 8% (nail lacquer), and professional removal of the unattached, infected nail, as frequently as monthly, are considered the full treatment needed to achieve a clear or almost clear nail (defined as 10% or less residual nail involvement). 6. Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed. 7. A completely clear nail may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a completely clear or almost clear toenail. 8. Do not use the medication for any disorder other than that for which itis prescribed. 9. Do not use nail polish or other nail cosmetic products on the treated nails. 10. Avoid use near heat or open flame, because product is flammable. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity study was conducted with ciclopirox topical solution, 8% (nail lacquer), formulation. A carcinogenicity study of ciclopirox (1% and 5% solutions in polyethylene glycol 400) in female mice dosed topically twice per week for 50 weeks followed by a 6- month drug-free observation period prior to necropsy revealed no evidence of tumors at the application sites. In human systemic tolerability studies following daily. application (~340 mg of ciclopirox topical solution, 8% (nail lacquer)), in subjects with distal subungual onychomycosis, the average maximal serum level of ciclopirox was 31±28 ng/mL after two months of once daily applications. This level was 159 times lower than the lowest toxic dose and 115 times lower than the highest nontoxic dose in rats and dogs fed 7.7 and 23.1 mg ciclopirox (as ciclopirox olamine)/kg/day. The following in vitro genotoxicity tests have been conducted with ciclopirox: evaluation of gene mutation in Ames Salmonella and E. coli assays (negative): chromosome aberration assays in V79 Chinese hamster lung fibroblasts, with and without metabolic activation (positive); gene mutation assay in the HGPRT-test with V79 Chinese hamster lung fibroblasts (negative); unscheduled DNA synthesis in human A549 cells (negative); and BALB/c3T3 cell transformation assay (negative). In an in vivo Chinese hamster bone marrow cytogenetic assay, ciclopirox was negative for chromosome aberrations at 5,000 mg/kg. The following in vitro genotoxicity tests were conducted with ciclopirox topical solution, 8% (nail lacquer): Ames Salmonella test (negative); unscheduled DNA synthesis in the rat hepatocytes (negative); cell transformation assay in BALB/c3T3 cell assay (positive). The positive response of the lacquer formulation in the BALB/c3T3 test was attributed to its butyl monoester of poly [methylvinyl ether/maleic acid] resin component (Gantrez® ES-435), which also tested positive in this test. The cell transformation assay may have been confounded because of the film-forming nature of the resin. Gantrez® ES-435 tested nonmutagenic in both the in vitro mouse lymphoma forward mutation assay with or without activation and unscheduled DNA, synthesis assay in rat hepatocytes. Oral reproduction studies in rats at doses up to 3.85 mg ciclopirox (as ciclopirox olamine)/kg/day [equivalent to approximately 1.4 times the potential exposure at the maximum recommended human topical dose (MRHTD)] did not reveal any specific effects on fertility or other reproductive parameters. MRHTD (mg/m2) is based on the assumption of 100% systemic absorption of 27.12 mg ciclopirox (~340 mg ciclopirox topical solution, 8% (nail lacquer)), that will cover all the fingernails and toenails including 5 mm proximal and lateral fold area plus onycholysis to a maximal extent of 50%.

Pregnancy

Teratogenic effects: Pregnancy Category B Teratology studies in mice, rats, rabbits, and monkeys at oral doses of up to 77, 23, 23, or 38.5 mg, respectively, of ciclopirox as ciclopirox olamine/kg/day (14, 8, 17, and 28 times MRHTD), or in rats and rabbits receiving topical doses of up to 92.4 and 77 mg/kg/day, respectively (33 and 55 times MRHTD), did not indicate any significant fetal malformations. There are no adequate or well-controlled studies of topically applied ciclopirox in pregnant women. Ciclopirox topical solution, 8% (nail lacquer), should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when ciclopirox topical solution, 8% (nail lacquer), is administered to a nursing woman.

Pediatric Use

Based on the safety profile in adults, ciclopirox topical solution, 8% (nail lacquer), is considered safe for use in children twelve years and older. No clinical trials have been conducted in the pediatric population.

Geriatric Use

Clinical studies of ciclopirox topical solution, 8% (nail lacquer), did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients.