Do I Have To Remove Ciciopirox Each Time I Reapply It To My Nails?

Clarification

Ciclopirox Topical Solution, eight%, (Nail Lacquer) contains a constructed antifungal agent, ciclopirox. It is intended for topical utilise on fingernails and toenails and immediately adjacent pare.

Each gram of Ciclopirox Topical Solution, 8%, (Nail Lacquer), contains fourscore 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 afterwards awarding. Ciclopirox Topical Solution, 8%, (Nail Lacquer), is a clear, colorless to slightly xanthous solution.

The chemical proper name for ciclopirox is six-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, with the molecular formula C 12H 17NO 2 and a molecular weight of 207.27. The CAS Registry Number is [29342- 05-0]. The chemic structure is:

Structure

CLINICAL PHARMACOLOGY

Microbiology
Mechanism of Activity
The mechanism of action of ciclopirox has been investigated using diverse 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.

Activeness in vitro and ex vivo
In vitro methodologies employing various goop or solid media with and without boosted nutrients have been utilized to make up one's mind ciclopirox minimum inhibitory concentration (MIC) values for the dermatophytic molds.(ane-2) Every bit a effect, a wide range of MIC values, 1-twenty 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 confronting new and established Trichophyton rubrum and Trichophyton mentagrophytes infections in ovine hoof material.(3) Later ten 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 non 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 utilize of viii% ciclopirox topical solution and systemic antifungal agents for onychomycosis is not recommended.

Pharmacokinetics
Every bit demonstrated in pharmacokinetic studies in animals and man, ciclopirox olamine is rapidly captivated after oral administration and completely eliminated in all species via feces and urine. Virtually of the compound is excreted either unchanged or as glucuronide. Afterwards oral administration of 10 mg of radiolabeled drug (14C-ciclopirox) to salubrious volunteers, approximately 96% of the radioactivity was excreted renally within 12 hours of administration. Ninety-iv percent of the renally excreted radioactive decay was in the course of glucuronides. Thus, glucuronidation is the main metabolic pathway of this compound.

Systemic assimilation of ciclopirox was determined in 5 patients with dermatophytic onychomycoses, subsequently application of Ciclopirox Topical Solution, 8%, (Nail Lacquer), 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 2 weeks and at 1, 2, iv and six months after initiation of treatment and 4 weeks post-treatment. In this report, ciclopirox serum levels ranged from 12-80 ng/mL. Based on urinary data, mean assimilation of ciclopirox from the dosage form was <5% of the practical dose. Ane calendar month after cessation of treatment, serum and urine levels of ciclopirox were below the limit of detection.

In two vehicle-controlled trials, patients practical Ciclopirox Topical Solution, 8%, (Nail Lacquer), to all toenails and afflicted 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.vi ng/mL). It should be noted that eleven of these 24 patients took concomitant medication containing ciclopirox as ciclopirox olamine foam, 0.77%.

The penetration of the Ciclopirox Topical Solution, 8%, (Nail Lacquer), was evaluated in an in vitro investigation. Radiolabeled ciclopirox applied one time to onychomycotic toenails that were avulsed demonstrated penetration up to a depth of approximately 0.4 mm. As expected, nail plate concentrations decreased equally a role of smash depth. The clinical significance of these findings in smash plates is unknown. Smash bed concentrations were non determined.

INDICATIONS AND USAGE

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

Ciclopirox Topical Solution, 8%, (Blast Lacquer), as a component of a comprehensive management programme, 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 programme includes removal of the unattached, infected nails equally frequently equally monthly, by a wellness care professional who has special competence in the diagnosis and treatment of smash 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 8% ciclopirox topical solution and systemic antifungal agents for onychomycosis, is not recommended.

• Ciclopirox Topical Solution, 8%, (Nail Lacquer), should be used only nether medical supervision equally described in a higher place.

• The effectiveness and rubber of Ciclopirox Topical Solution, eight%,(Smash Lacquer), in the following populations has non been studied. The clinical trials with utilise of Ciclopirox Topical Solution, viii%, (Nail Lacquer), excluded patients who: were pregnant or nursing, planned to get pregnant, had a history of immunosuppression (e.yard., extensive, persistent, or unusual distribution of dermatomycoses, extensive seborrheic dermatitis, recent or recurring herpes zoster, or persistent canker 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 likewise 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 employ 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 bang-up 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, eight%, (Nail Lacquer), was applied for 48 weeks. At baseline, patients had 20-65% interest of the target great toenail plate. Statistical significance was demonstrated in one of ii studies for the endpoint "complete cure" (articulate boom and negative mycology), and in two studies for the endpoint "virtually clear" (≤10% nail involvement and negative mycology) at the terminate of written report. These results are presented beneath.

week 48

The summary of reported patient outcomes for the ITT population at 12 weeks following the cease of treatment are presented below. Note that mail-treatment efficacy assessments were scheduled only for patients who accomplished a consummate cure.

Week 12

*Four patients (from studies 312 and 313) who were completely cured did not have mail-treatment Week 12 planimetry data.

CONTRAINDICATIONS

Ciclopirox Topical Solution, 8%, (Boom Lacquer), is contraindicated in individuals who have shown hypersensitivity to whatsoever of its components.

WARNINGS

Ciclopirox Topical Solution, 8%, (Nail Lacquer), is not for ophthalmic, oral, or intravaginal use. For use on nails and immediately side by side skin only.

PRECAUTIONS

If a reaction suggesting sensitivity or chemic irritation should occur with the utilize of Ciclopirox Topical Solution, viii%, (Nail Lacquer), treatment should be discontinued and advisable therapy instituted.

So far at that place 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 intendance professional and trimming past 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 accept detailed instructions regarding the apply of Ciclopirox Topical Solution, eight%, (Blast Lacquer), as a component of a comprehensive direction programme for onychomycosis in society to accomplish maximum benefit with the utilise of this product. The patient should be told to:
1. Apply Ciclopirox Topical Solution, 8%, (Smash Lacquer), as directed past a health care professional. Avoid contact with the eyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated boom(south) should be avoided. Ciclopirox Topical Solution, 8%, (Nail Lacquer), is for external employ but.

2. Ciclopirox Topical Solution, 8%, (Nail Lacquer), should be applied evenly over the entire nail plate and 5 mm of surrounding peel.If possible, Ciclopirox Topical Solution, eight%, (Blast Lacquer),should exist applied to the nail bed, hyponychium, and the under surface of the nail plate when information technology is free of the nail bed (eastward.g.,onycholysis). Contact with the surrounding peel may produce mild, transient irritation (redness).

3. Removal of the unattached, infected blast, as oftentimes equally monthly, by a health care professional is needed with use of this medication. Inform a wellness care professional if they have diabetes or problems with numbness in your toes or fingers for consideration of the appropriate smash management program.

four. Inform a health intendance professional if the expanse of application shows signs of increased irritation (redness, itching, burning, baking, swelling, oozing).

v. Up to 48 weeks of daily applications with Ciclopirox Topical Solution, 8%, (Boom Lacquer), and professional removal of the unattached, infected blast, as frequently every bit monthly, are considered the full treatment needed to achieve a clear or almost articulate blast (defined as 10% or less remainder nail involvement).

half-dozen. Half-dozen months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.

seven. A completely clear blast may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to attain either a completely clear or almost articulate toenail.

viii. Practice not use the medication for whatsoever disorder other than that for which it is prescribed.

9. Practice not apply blast polish or other nail cosmetic products on the treated nails.

10. Avoid utilize near heat or open flame, considering product is flammable.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity study was conducted with Ciclopirox Topical Solution, viii%, (Nail Lacquer), formulation. A carcinogenicity study of ciclopirox (1% and five% solutions in polyethylene glycol 400) in female mice dosed topically twice per week for 50 weeks followed by a half-dozen-calendar month drug-free observation period prior to necropsy revealed no evidence of tumors at the awarding sites.

In human systemic tolerability studies following daily application (~340 mg of Ciclopirox Topical Solution, 8%, (Blast Lacquer)) in subjects with distal subungual onychomycosis, the average maximal serum level of ciclopirox was 31±28 ng/mL after two months of one time 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 seven.vii and 23.1 mg ciclopirox (as ciclopirox olamine)/kg/24-hour interval.

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 homo A549 cells (negative); and BALB/c3T3 cell transformation assay (negative). In an in vivo Chinese hamster os 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%, (Blast Lacquer): Ames Salmonella test (negative); unscheduled DNA synthesis in the rat hepatocytes (negative); cell transformation assay in BALB/c3T3 jail cell analysis (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 examination. The prison cell transformation assay may have been confounded considering of the motion picture-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 analysis in rat hepatocytes.

Oral reproduction studies in rats at doses up to iii.85 mg ciclopirox (as ciclopirox olamine)/kg/24-hour interval [equivalent to approximately 1.iv times the potential exposure at the maximum recommended human topical dose (MRHTD)] did not reveal any specific furnishings on fertility or other reproductive parameters. MRHTD (mg/m2) is based on the assumption of 100% systemic assimilation of 27.12 mg ciclopirox (~340 mg Ciclopirox Topical Solution, 8%, (Nail Lacquer)) that volition cover all the fingernails and toenails including five 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 every bit ciclopirox olamine/kg/day (14, eight, 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 hazard to the fetus.

Nursing Mothers:
It is not known whether this drug is excreted in human milk. Since many drugs are excreted in homo milk, caution should be exercised when Ciclopirox Topical Solution, eight%, (Nail Lacquer), is administered to a nursing woman.

Pediatric Utilize:
Based on the safety profile in adults, Ciclopirox Topical Solution, eight%, (Nail Lacquer), is considered safe for utilise in children twelve years and older. No clinical trials have been conducted in the pediatric population.

Geriatric Use:
Clinical studies of Ciclopirox Topical Solution, eight%, (Nail Lacquer), did not include sufficient numbers of subjects anile 65 and over to make up one's mind whether they reply differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

Agin REACTIONS

In the vehicle-controlled clinical trials conducted in the US, 9% (30/327) of patients treated with Ciclopirox Topical Solution, viii%, (Nail Lacquer), and seven% (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 torso system, was like between the treatment groups except for Skin and Appendages: 8%(27/327) and 4% (xiv/328) of subjects in the ciclopirox and vehicle groups reported at least one adverse issue, respectively.

The well-nigh 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, eight%, (Nail Lacquer), (five% [16/327]) than in patients treated with vehicle (1% [iii/328]). Other TEAEs thought to be causally related included nail disorders such as shape modify, irritation, ingrown toenail, and discoloration.

The incidence of boom 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 called-for of the pare occurred in 1% of patients treated with Ciclopirox Topical Solution, 8%, (Nail Lacquer), (3/327) and vehicle (4/328).

A 21-Day Cumulative Irritancy report 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, simply all were reactions of mild transient erythema. There was no prove of allergic contact sensitization for either the Ciclopirox Topical Solution, eight%, (Boom Lacquer), or the vehicle base. In a separate study of the photosensitization potential of Ciclopirox Topical Solution, 8%, (Nail Lacquer), in a maximized test pattern 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, i patient treated with Ciclopirox Topical Solution, 8%, (Nail Lacquer), discontinued treatment due to a rash, localized to the palm (causal relation to test cloth undetermined).

Use of Ciclopirox Topical Solution, viii%, (Nail Lacquer), for 48 boosted weeks was evaluated in an open-label extension study conducted in patients previously treated in the vehicle-controlled studies. Three per centum (9/281) of subjects treated with Ciclopirox Topical Solution, eight%, (Nail Lacquer), experienced at to the lowest degree i TEAE that the investigator idea was causally related to the test material. Balmy rash in the form of periungual erythema (ane% [2/281]) and smash disorders (one% [4/281]) were the well-nigh oftentimes reported. Four patients discontinued because of TEAEs. Two of the iv had events considered to be related to test material: one patient's dandy toenail "broke abroad" and some other had an elevated creatine phosphokinase level on Day 1 (after 48 weeks of handling with vehicle in the previous vehicle-controlled report).

To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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, equally oftentimes as monthly, by a health care professional, weekly trimming by the patient, and daily awarding of the medication are all integral parts of this therapy. Conscientious consideration of the appropriate nail management programme should be given to patients with diabetes (see PRECAUTIONS).

Smash Intendance Past Health Care Professionals: Removal of the unattached, infected nail, as frequently every bit monthly, trimming of onycholytic nail, and filing of excess horny textile should exist performed by professionals trained in treatment of boom disorders.

Boom Care By Patient:
Patients should file away (with emery board) loose smash material and trim nails, as required, or equally directed by the wellness care professional, every seven days after Ciclopirox Topical Solution, viii%, (Nail Lacquer), is removed with booze.

Ciclopirox Topical Solution, 8%, (Boom Lacquer), should exist 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%, (Boom Lacquer), should be practical evenly over the entire nail plate.

If possible, Ciclopirox Topical Solution, 8%, (Nail Lacquer), should exist applied to the nail bed, hyponychium, and the under surface of the smash plate when it is complimentary of the nail bed (eastward.g., onycholysis).

The Ciclopirox Topical Solution, viii%, (Nail Lacquer), should not be removed on a daily footing. 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.

HOW SUPPLIED

Ciclopirox Topical Solution, 8%, (Boom Lacquer), is supplied in 3.3 mL (NDC 0713-0317-87) and vi.6 mL (NDC 0713-0317-88) drinking glass bottles with screw caps which are fitted with brushes.

Protect from light (east.g., store the canteen in the carton after every use.)

Ciclopirox Topical Solution, 8%, (Nail Lacquer), should be stored at room temperature between 59° and 86° F (15° and xxx° C).

CAUTION: Flammable. Keep abroad from heat and flame.

REFERENCES

one. Dittmar W., Lohaus G. 1973. HOE296, A new antimycotic compound with a broad antimicrobial spectrum. Arzneim-Forsch./Drug Res.23:670-674.

ii. Niewerth et. al., 1998. Antimicrobial susceptibility testing of dermatophytes: Comparing of the agar macrodilution and broth micro dilution tests. Chemotherapy. 44:31-35.

3. Yang et. al. 1997. A new simulation model for studying in vitro topical penetration of antifungal drugs into hard keratin. J. Mycol.Med. 7:195-98.

Gantrez is a registered trademark of GAF Corporation

Distributed by:
Cosette Pharmaceuticals, Inc.
S Plainfield, NJ 07080
8-0317CP1 Iss. 11/2019

PATIENT PACKAGE INSERT

Ciclopirox
Topical Solution, 8%,
(Nail Lacquer)

Patient Information and Instructions

Patients should accept detailed instructions regarding the utilise of Ciclopirox Topical Solution, viii%, (Blast Lacquer), as a component of a comprehensive management program for onychomycosis in order to achieve maximum do good with the use of this product. Discuss your handling plan with your health care professional for regular removal of the unattached, infected blast. Before using this medication, tell your dr. if you:

• Are pregnant or nursing
• Are an insulin dependent diabetic or accept diabetic neuropathy
• Have a history of immunosuppression
• Are immunocompromised (due east.1000., received an organ transplant, etc.)
• Require medication to control epilepsy

• Use or crave topical corticosteroids on a repeated monthly footing
• Use steroid inhalers on a regular basis

Patient Data:

• Use Ciclopirox Topical Solution, 8%, (Nail Lacquer), as directed by your health care professional.
• Ciclopirox Topical Solution, 8%, (Nail Lacquer), is for external apply merely.
• Contact with skin other than skin immediately surrounding the treated blast(south) should be avoided.
• Avoid contact with the eyes and mucous membranes.
• Removal of the unattached, infected nail, as oftentimes as monthly, past your health intendance professional is needed with utilize of this medication to obtain maximal benefit with utilise of this product. If y'all have diabetes or problems with numbness in your toes or fingers, talk to your health intendance provider before trimming your nails or removing any blast textile.
• Inform your health care professional person if the area of application shows signs of increased irritation (redness, itching, burning,blistering, swelling, oozing).
• Upward to 48 weeks of daily applications with Ciclopirox Topical Solution, 8%, (Nail Lacquer), and professional removal, as oft every bit monthly, of the unattached, infected nail are considered the full handling time to attain a articulate or nearly articulate nail (defined equally 10% or less rest blast involvement). Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.
• A completely clear nail may non be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a articulate or most clear toenail.
• Do not use smash polish or other nail cosmetic products on the treated nails.
• Avoid use near heat or open flame, because product is flammable.

Patient Instructions

one. Earlier starting handling, remove any loose nail or blast material using nail clippers or nail files. If you have diabetes or bug with numbness in your toes or fingers, talk to your wellness care provider earlier trimming your nails or removing any nail material.
2. Utilise Ciclopirox Topical Solution, eight%, (Blast Lacquer), in one case daily (preferably at bedtime) to all affected nails with the applicator brush provided. Apply the lacquer evenly over the unabridged nail. Where possible, smash lacquer should also exist practical to the underside of the smash and to the skin below it. Allow lacquer to dry (approximately thirty seconds) before putting on socks or stockings. Later on applying medication, await 8 hours before taking a bath or shower.
3. Utilize Ciclopirox Topical Solution, eight%, (Nail Lacquer), daily over the previous coat.
4. Once a week, remove the Ciclopirox Topical Solution, 8%, (Nail Lacquer), with alcohol. Remove as much equally possible of the damaged nail using scissors, nail clippers, or boom files.
5. Repeat procedure (steps two through 4).

Please Notation:

i. To prevent spiral cap from sticking to the bottle, practice not allow solution to get into the bottle threads.
2. To prevent the solution from drying out, bottle should be closed tightly after every use.
3. To protect from light, replace bottle into carton subsequently each use.

Distributed by:

Cosette Pharmaceuticals, Inc.
Due south Plainfield, NJ 07080

eight-0317CP1 Iss. 11/2019