CNL8

CNL8 — ciclopirox solution
Innocutis Holdings LLC

DESCRIPTION

CNL8 (ciclopirox topical solution, 8%) nail lacquer.

For use on fingernails and toenails and immediately adjacent skin only.

Not for use in eyes.

CNL8 (ciclopirox topical solution, 8%) nail lacquer contains a synthetic antifungal agent, ciclopirox. It is intended for topical use on fingernails and toenails and immediately adjacent skin.

Each gram of CNL8 (ciclopirox topical solution, 8%) nail lacquer contains 80 mg ciclopirox in a solution base consisting of ethyl acetate, NF; isopropyl alcohol, USP; and butyl monoester of poly[methylvinyl ether/maleic acid] in isopropyl alcohol. Ethyl acetate and isopropyl alcohol are solvents that vaporize after application.

CNL8 (ciclopirox topical solution, 8%) nail lacquer is a clear, colorless to slightly yellowish solution.

The chemical name for ciclopirox is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, with the molecular formula C12H17NO2 and a molecular weight of 207.27. The CAS Registry Number is 29342-05-0. The chemical structure is:

Image of Chemical StructureImage of Chemical Structure

CLINICAL PHARMACOLOGY

Microbiology Mechanism of Action: 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.
Activity in vitro and ex vivo: In vitro methodologies employing various broth or solid media with and without additional nutrients have been utilized to determine ciclopirox minimum inhibitory concentration (MIC) values for the dermatophytic molds.(1-2) As a consequence, a broad range of MIC values, 1-20 mcg/mL were obtained for Trichophyton rubrum and Trichophyton mentagrophytes species. Correlation between in vitro MIC results and clinical outcome has yet to be established for ciclopirox.
One ex vivo study was conducted evaluating 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 for 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 crossresistance to ciclopirox and other known antifungal agents have not been performed.
Antifungal Drug Interaction: 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 (14Cciclopirox) 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.


In two vehicle-controlled trials, patients applied CNL8 (ciclopirox topical solution, 8%) nail lacquer 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 CNL8 (ciclopirox topical solution, 8%) nail lacquer 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.

INDICATIONS & USAGE

(To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of the labeling.)

CNL8 (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 Tricho-phyto 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.


CNL8 (ciclopirox topical solution, 8%) nail lacquer should be used only under medical supervision as described above.
The effectiveness and safety of CNL8 (ciclopirox topical solution, 8%) nail lacquer in the following populations have not been studied. The clinical trials with use of CNL8 (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 derma-tomycoses, 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 CNL8 (ciclopirox topical solution, 8%) nail lacquer daily for greater than 48 weeks have not been established.

CLINICAL STUDIES

The results of use of CNL8 (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 CNL8 (ciclopirox topical solution, 8%) nail lacquer in conjunction with monthly removal of the unattached, infected toenail by the investigator. CNL8 (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.


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%)
Negative Mycology Alone *** 30/105 (29%) 12/106 (11%) 41/115 (36%) 10/114 (9%)
*Clear nail and negative Mycology
** Less than or equal to 10% nail involvement and negative mycology
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
Completed Cure at Week 48 6 1 10 1
Post-treatment Week 12 Outcomes:
Patients Missing all Week 12 Assessments 2 0 2 0
Patients with Week 12 Assessments 4 1 8 0
Complete Cure 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.
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