Ciclopirox free acid is an antimycotic agent that inhibits the growth of a number of fungi in vitro including Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis, Epidermophyton floccosum, Candida albicans, Candida tropicalis and Candida pseudotropicalis. The mechanism of action of ciclopirox has been investigated using various in vitro and in vivo infection models. One in vitro study suggested that ciclopirox acts by chelation of polyvalent cations (Fe+3 or Al+3) resulting in the inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell. The clinical significance of this observation is not known.
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 radiolabelled drug (14C-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 (nail lacquer), 8% w/w, 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 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(r) Cream). The penetration of ciclopirox topical solution was evaluated in an in vitro investigation. Radiolabelled ciclopirox applied once to onychomycotic toenails that were avulsed demonstrated penetration up to a depth of approximately 0.4 mm. 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.
Please read this entire section carefully to fully understand the indication for this product.
Topical treatment with APO-CICLOPIROX (Ciclopirox Topical Solution, 8% w/w) Nail Lacquer is indicated as part of a comprehensive nail management program in immunocompetent patients with mild to moderate onychomycosis (due to Trichophyton rubrum) of fingernails and toenails without lunula involvement. The comprehensive management program includes frequent removal of unattached, infected nails (e.g., monthly) by a health care professional with special competence in the diagnosis and treatment of nail disorders, including minor nail procedures. APO-CICLOPIROX should therefore be used only under medical supervision. The safety and efficacy of daily use for longer than 48 weeks have not been established. (See PRECAUTIONS)
Pivotal Clinical Trial Data
Ciclopirox topical solution was used to treat onychomycosis of the great toenail (without lunula involvement) in two double-blind, placebo-controlled pivotal studies. Patients were treated once daily for up to 48 weeks in conjunction with monthly removal of the unattached, infected toenail by the investigator. At baseline, patients had 20 - 65% involvement of the target nail plate.
Endpoint ITT Population
| Efficacy Variable | Study 312 ++ | Study 313 ++ | ||
| Ciclopirox | Placebo | Ciclopirox | Placebo | |
| Treatment Success 1 | 8/107 (8%) | 1/107 (1%) | 13/115 (11%) | 1/115 (1%) |
| Treatment Cure 2 | 6/110 (6%) + | 1/109 (1%) | 10/118 (9%) | 0/117 (0%) |
| Mycological Cure 3 | 30/105 (29%) | 14/105 (13%) | 39/113 (35%) | 10/114 (9%) |
Treatment Success: negative culture, negative KOH, <= 10% involvement target nail
Treatment Cure: negative culture & KOH, Global Evaluation Score = Cleared
Mycological Cure: negative culture, negative KOH
++
Denominators differ across variables because of missing data
+
p = 0.055. All other values statistically significant (CMH <=0.02 stratified by centre)
Post-treatment efficacy assessments were scheduled only for patients who achieved treatment cure. Some data on the post-treatment efficacy of the product are available for 12 patients. Twelve weeks after stopping ciclopirox treatment, 3/6 patients maintained treatment success, and 6/9 patients maintained negative mycology reports.
APO-CICLOPIROX (Ciclopirox Topical Solution, 8% w/w) Nail Lacquer is contraindicated in individuals who have shown hypersensitivity to any of its components.
Ciclopirox topical solution, 8% w/w (nail lacquer) is not for ophthalmic, oral, or intravaginal use. For use on nails and immediately adjacent skin only.
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% w/w (nail lacquer) and systemic antifungal agents for onychomycosis, is not recommended. (See INDICATIONS AND CLINICAL USE) The effectiveness and safety in the following populations have not been studied, as the clinical trials with ciclopirox topical solution 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. 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. If a reaction suggesting sensitivity or chemical irritation should occur with the use of ciclopirox topical solution treatment should be discontinued and appropriate therapy instituted.
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, or in rats and rabbits receiving topical doses of up to 92.4 and 77 mg/kg/day, respectively, did not indicate any significant fetal malformations. Teratology studies with ciclopirox free acid were performed in rats with oral doses of 20, 50, or 125 mg/kg/day and in rabbits with oral doses of 12.5, 32, or 80 mg/kg/day; no significant fetal malformations were noted. There are no adequate or well-controlled studies of topically applied ciclopirox in pregnant women. Ciclopirox topical solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Vehicle-controlled clinical trials of ciclopirox topical solution conducted in the US did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.
The patient should be told:
To avoid contact with the eyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided. APO-CICLOPIROX is for external use only.
To apply APO-CICLOPIROX evenly over the entire nail plate and 5 mm of surrounding skin. If possible, APO-CICLOPIROX 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). To file and trim nails on a weekly basis during treatment with APO-CICLOPIROX. That removal of the unattached, infected nail, as frequently as monthly, by a health care professional is needed with use of this medication. To inform a health care professional if they have diabetes or problems with numbness in the toes or fingers for consideration of the appropriate nail management program. To inform a health care professional if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing). That up to 48 weeks of daily application with APO-CICLOPIROX 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). That six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed. That 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. That he/she should not use nail polish or other nail cosmetic products on the treated nails. To not use the medication for any disorder other than that for which it is prescribed. To avoid use near heat or open flame, because product is flammable.
In the vehicle-controlled clinical trials conducted in the US, 9% (30/327) of patients treated with ciclopirox topical solution (nail lacquer), 8% w/w 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. With the exception of Skin and Appendages, the incidence of these adverse events, within each body system, was similar between the treatment groups and was less than 1%. For Skin and Appendages, 8% (27/327) and 4% (14/328) of patients in the ciclopirox and vehicle groups, respectively, reported at least one adverse event. Periungual erythema and erythema of the proximal nail fold were the most common TEAEs causally related to study drug. These events (coded as "rash") were reported in 5% (16/327) of patients treated with ciclopirox topical solution and 1% (3/328) of patients treated with vehicle. Other TEAEs thought to be causally related to study material in the US vehicle-controlled studies 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 group and 2% [7/328] in the vehicle group). Application site reactions and/or burning sensation of the skin were considered causally related to study drug in 1% of both ciclopirox topical solution- and vehicle-treated patients (3/327 and 4/328, respectively). The following table summarizes the most common TEAEs considered causally related to the study drug, as reported in the US Phase II/III vehicle-controlled trials.
| Body System TEAE | Ciclopirox Topical Solution n (%) | Vehicle n (%) |
| No. of Patients Treated | 327 (100.00) | 328 (100.0) |
| Patients with Related TEAEs | 30 (9.2) | 23 (7.0) |
| Skin and Appendages | 27 (8.3) | 14 (4.3) |
| Periungual erythema/erythema of proximal nail fold | 16 (4.9) | 3 (0.9) |
| Nail Disorders + | 6 (1.8) | 7 (2.1) |
| Application Site Reaction/Burning Sensation | 3 (0.9) | 4 (1.2) |
| Other ++ | 2 (0.6) | 0 (0.0) |
| All Other Body Systems | 0 - 1 (0.0 - 0.3) | 0 - 3 (0 - 0.9) |
+
Nail disorders such as shape change, irritation, ingrown toenail and discolouration.
++
Other: Dry skin, pruritis.
Use of ciclopirox topical solution 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 patients treated with ciclopirox topical solution 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. The remainder of TEAEs considered causally related to study drug occurred at an incidence of <1%. In controlled and open-label clinical trials conducted with ciclopirox nail lacquer, 8% outside of the US, adverse events reported were consistent with those seen in the US studies.
Post-Marketing Experience
Contact dermatitis has been reported as an adverse reaction in post-marketing surveillance of ciclopirox-containing products, including ciclopirox nail lacquer, 8%.
The likelihood of overdosage from topical administration of ciclopirox nail lacquer, 8% is extremely low. In a test of acute oral toxicity in the rat, the LD50 was greater than 10 mL/kg of ciclopirox nail lacquer, 8%. This would be equivalent to 600 mL for an adult person weighing 60 kg or more than 1000 vials of 3 mL. Furthermore, overdosage by oral ingestion of nail lacquer would be unlikely because of its unpalatable taste.
APO-CICLOPIROX (Ciclopirox Topical Solution, 8% w/w) 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)
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 the treatment of nail disorders.
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 APO-CICLOPIROX is removed with isopropyl alcohol. APO-CICLOPIROX should be applied once daily (preferably at bedtime or eight hours before washing) to all affected nails with the applicator brush provided. APO-CICLOPIROX should be applied evenly over the entire nail plate. If possible, APO-CICLOPIROX 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). APO-CICLOPIROX should not be removed on a daily basis. Daily applications should be made over the previous coat and removed with isopropyl alcohol every seven days. This cycle should be repeated throughout the duration of therapy.
Common Name: Ciclopirox Chemical Name: 1) 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone 2) 2(1H)-Pyridinone, 6-cyclohexyl-1-hydroxy-4-methyl- Structural Formula: OH
N O
Molecular Formula: C12H17NO2 Molecular Weight: 207.27 pH: 5.0 pKa: 7.2
CH3 Description: Ciclopirox is a white to slightly yellowish white, crystalline powder, with a melting point of 141deg - 143degC. It is slightly soluble in water; freely soluble in dichloromethane and 96% ethanol; soluble in ether.
Each gram of APO-CICLOPIROX (Ciclopirox Topical Solution, 8% w/w) Nail Lacquer contains 80 mg ciclopirox in a solution base consisting of ethyl acetate, isopropyl alcohol, and monobutyl ester of poly (methyl vinyl ether/maleic acid) in isopropyl alcohol. Ethyl acetate and isopropyl alcohol are solvents that vaporize after application.
APO-CICLOPIROX should be stored at room temperature between 15deg and 30degC (59deg - 86degF). To protect from light, replace the bottle into the carton after each use. CAUTION: Flammable. Keep away from heat and flame.
APO-CICLOPIROX (Ciclopirox Topical Solution, 8% w/w) Nail Lacquer is a clear, colourless to slightly yellowish solution for topical application. It is available in 6 gram glass bottles with screw caps which are fitted with applicator brushes.
You must receive detailed instructions regarding the use of APO-CICLOPIROX (Ciclopirox Topical Solution, 8% w/w) Nail Lacquer from your doctor. This product must be used as a part of a treatment program for fungal infections of the nails (onychomycosis) that includes regular removal of the infected nail as well as daily treatment with APO-CICLOPIROX. Discuss your treatment plan with your doctor to plan for regular removal of the loose, infected nail. Before using this medication, tell your doctor if you: Are pregnant or breast-feeding a baby, Are a diabetic who needs insulin injections or has diabetic neuropathy (nerve damage caused by diabetes), Have a history of immunosuppression (e.g., are currently taking oral corticosteroids, have repeated or long lasting shingles (herpes zoster), have oral or genital herpes (herpes simplex), Are immunocompromised (e.g., received an organ transplant, or are HIV positive), Need medicine to control epilepsy, Use or require topical corticosteroids every month, Use steroid inhalers on a regular basis.