Ciclopirox Nail Lacquer Topical Solution 8%

A.K. Gupta MD, FRCPC
Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Sciences Center (Sunnybrook site), and the University of Toronto, Toronto, Canada

ABSTRACT

Ciclopirox nail lacquer 8% (Penlac, Aventis Pharma) was approved by the US FDA in December 1999, as a component of a comprehensive management program, for use in immunocompetent patients who have mild to moderate onychomycosis of the fingers and toes without lunula involvement due to Trichophyton rubrum. The comprehensive management program includes removal of the unattached, infected nails as frequently as once per month, by a health care professional who has special competence in the diagnosis and treatment of nail disorders, including minor nail procedures. The nail lacquer is not approved in Canada.

Key Words: onychomycosis, management

In North America there are no other approved topical therapies for the treatment of onychomycosis. However, amorolfine is used in Europe and results¹ are comparable to those found with ciclopirox nail lacquer. Oral treatments approved in North America for the management of onychomycosis are terbinafine and itraconazole. In some countries fluconazole is also approved.

Mechanism of Action

The exact mechanism of action is not known. However, investigators have shown that ciclopirox has a high affinity for polyvalent cations such as Fe³⁺ and Al³⁺ and may chelate them.^2,3 Trapping these essential enzymatic cofactors may have an inhibitory effect on enzymes such as cytochromes, which are involved in the mitochondrial electron transport processes in the course of energy production. As well, ciclopirox may inhibit the activity of catalase and peroxidase, which are responsible for the intracellular degradation of toxic peroxides.³ Other studies have shown that ciclopirox may also impair fungal metabolism by affecting transport mechanisms located in the fungus membrane. In some cells there may be an intracellular depletion of essential amino acids and nucleotides which may result in reduced synthesis of proteins and nucleic acids.³

Pharmacokinetics

When ciclopirox olamine is administered orally it is rapidly absorbed with the majority of the compound undergoing glucuronidation and subsequent renal excretion. In 5 patients with fingernail onychomycosis ciclopirox nail lacquer was applied once daily to all 20 digits and the adjacent 5mm of skin once daily for 6 months.² The mean absorption of ciclopirox was less than 5% of the applied dose with the ciclopirox serum levels ranging from 12-80ng/ml. One month after stopping treatment, the levels of ciclopirox in the serum and urine were below the limit of detection. In another trial patients applied ciclopirox nail lacquer topical solution 8% once daily to all toenails and affected fingernails for 48 weeks.² Twenty-four of 66 randomly chosen patients had detectable ciclopirox levels at some point during the dosing interval ranging from 10.0-24.6ng/ml, usually in the last week of the study. Eleven of the 24 patients with detectable ciclopirox levels were applying ciclopirox olamine cream 0.77% as a concomitant medication, usually for tinea pedis.

This nail lacquer delivery system contains 8% ciclopirox free acid. Following application of the lacquer to the nail plate, the solvents evaporate and the concentration of ciclopirox in the film increases to 34.8%, thus resulting in a high concentration gradient, which favors the delivery of the ciclopirox to the dorsal aspect of the nail plate and the nail bed.^4,5 In excised human toenails, 24 hours following application, labeled ciclopirox nail lacquer was detectable to a depth of 0.4mm.² The nails had a treatment surface of at least 1cm². In general, penetration was observed to be more pronounced if the nail appeared rougher or more fissured.

In a study conducted in 5 healthy volunteers ciclopirox nail lacquer 8% was applied daily to the toenails, and the lacquer was removed once per week. The distal portion of the nail was sampled 7, 14, 30, and 45 days after the start of treatment, and 7 and 14 days post-treatment. After 7 days of application, ciclopirox appeared to be uniformly distributed in all layers of the nail with a concentration of 284-384µg/g of nail. At day 45 the concentration of drug in the nail ranged from 1448-1899µg/g of nail. The above concentrations indicate a high level of biological activity at all depths of nail. Fourteen days after treatment was stopped, residual amounts of ciclopirox were detected in the nail, indicating that the levels had decreased substantially.

Clinical trials

Table 1 outlines the results of US clinical studies for ciclopirox. During the 48 week treatment period physicians’ assessments were carried out every 4 weeks, and mycological evaluation and photographic planimetry using standardized photographs were performed every 12 weeks. Non-US studies had similar outcome measures, although a non-photographic planimetric method was used to quantify disease extent.

Trial	Disease	n	Treatment Regime	Mycologic Cure Rate*		“Almost Clear” Rate**		Complete Cure Rate***
				Treatment Group	Vehicle Group	Treatment Group	Vehicle Group	Treatment Group	Vehicle Group
US – I Doubleblind Placebo	Dermatophyte Onychomycosis	Ciclopirox grp: 112 Vehicle grp: 111 n=223	Daily for 48 wks to all toenails & affected fingernails, covering entire nail plate + 5mm surrounding skin	29% (30/105)	11% (12/106)	6.5% (7/107)	0.9% (1/108)	5.5% (6/110)	0.9% (1/109)
US – II Doubleblind Placebo	Dermatophyte Onychomycosis	Ciclopirox grp: 119 Vehicle grp: 118 n=237	Daily for 48 wks to all toenails & affected fingernails, covering entire nail plate + 5mm surrounding skin	36% (41/115)	9% (10/114)	12% (14/116)	0.9% (1/115)	8.5% (10/118)	0% (0/117)

Table 1: Clinical trial results from US studies.2,6
*Negative culture and negative light microscopic examination
**10%nail involvement and negative mycology
***Clear nail and negative mycology

In studies conducted outside of the US, patients also had clinical, microscopic and culture evidence of onychomycosis. However, these studies included some patients with non-dermatophyte organisms (e.g., Candida spp.), and the area of nail involvement was generally greater than that observed in the US studies. Treatment regimens also varied in the non-US studies with lacquer applications that were sometimes less frequent than the once daily treatment utilized in the US studies (e.g., alternate day or twice weekly). In addition, the typical duration of treatment was 26 weeks in the non-US studies as compared to 48 weeks in the US. Outcome measures were similar to those used in the US trials, although a non-photographic planimetric method was used to quantify disease extent.⁶

The meta-analytic average of mycologic cure rates for US and non-US studies that are randomized, or open studies with ≥50 patients is 52.6 ± 4.2%, (n=2027 patients from 10 studies).7 In terms of the clinical response rates, the meta-analytic average for US and non-US studies that are randomized or open studies with ≥50 patients is 53.7 ± 7.4%, (n=2179 patients from 11 studies).⁷

Ciclopirox nail lacquer has demonstrated a broad spectrum of activity with efficacy against Candida species and some nondermatophyte moulds in the non-US studies.^6,8

There are limited data to suggest that ciclopirox nail lacquer may have a role in special nail presentations such as a dermatophytoma, lateral onychomycosis, extensive onycholysis, longitudinal streak and a thickened nail, especially when combined with the judicious use of debridement or mechanical/chemical avulsion.^4,9 Ciclopirox nail lacquer may also prove useful in cases of early recurrence of disease.⁹ It is possible that there may be a role for combination therapy using ciclopirox nail lacquer and oral antifungal agents.^9,10

Adverse-effects

Ciclopirox nail lacquer appears to be safe as observed in studies conducted in the US and worldwide. Adverse effects are generally localized and consist primarily of erythema and, less frequently, of a burning/tingling sensation or edema at the application site. Nail disorders such as change in shape, irritation, ingrown nail or discoloration, are also seen.2 In most instances the adverse effects are mild and resolve with continued application of the ciclopirox nail lacquer.^2,6 In the US trials treatment-emergent adverse events, considered by the investigator to be causally related to the test material, were reported in 9% (30/327) of patients applying the ciclopirox nail lacquer and 7% (23/328) of patients using the vehicle. Within each body system the incidence of the adverse events was similar except for the skin and appendages. The incidence in the ciclopirox and vehicle treated groups was 8% and 4%, respectively.²

Drug interaction

Following systemic absorption, ciclopirox is rapidly metabolized by glucuronidation.^2,6 Ciclopirox is not metabolized through the cytochrome system and no drug interactions are expected.

Dosage and cost

The US package insert recommends that the ciclopirox nail lacquer should be applied evenly over the entire nail plate once daily (preferably at bedtime or 8 hours before washing) to all affected nails with the applicator brush that is provided. If possible, the nail lacquer should be applied to the nail bed, the hyponychium and the ventral surface of the nail plate that is free off the nail bed (i.e., all areas that may be onycholytic). The nail lacquer should be applied daily over the coat that is present from the application of the previous day, with the lacquer film being removed once every 7 days with alcohol. Treatment may need to be continued for 48 weeks and initial improvement of symptoms may not be observed for 26 weeks. Patients are advised not to apply nail polish or other nail cosmetics to the treated nail.

In many of the non-US studies the duration of therapy was 26 weeks and in some cases the frequency of application is less frequent compared to the US studies, e.g., once daily application for 4 weeks and then twice weekly for the next 21 weeks. Patients should trim the nails weekly and unattached, infected nails should be removed as frequently as monthly by a health care professional trained in the treatment of nail disorders. Ciclopirox nail lacquer topical solution 8% is supplied in 3.3ml glass bottles, which should be protected from exposure to light. The average wholesale price in the US is $59.94 USD per bottle.

Conclusion

Ciclopirox nail lacquer is the first topical nail lacquer to be approved in the US for the treatment of mild to moderate onychomycosis of the fingers and toes, without lunula involvement, due to Trichophyton rubrum. The lacquer should be used as a component of a comprehensive management program for onychomycosis involving the patient and a health care professional. In the 2 US pivotal studies the mycological cure rates for ciclopirox 8% nail lacquer and placebo were 34% and 10%, respectively (p<0.001). In studies conducted outside the US efficacy rates were higher, with a meta-analytic average mycological cure rate of 53% when studies conducted worldwide were evaluated as a group. Ciclopirox has a broad spectrum of activity, including Candida species and some non-dermatophyte moulds. It remains to be seen to what extent ciclopirox nail lacquer will be used for the management of onychomycosis and whether there will be a paradigm shift in the direction of topical treatment for certain types of onychomycosis.

References

1. Reinel D. Topical treatment of onychomycosis with amorolfine 5% nail lacquer: Comparative efficacy and tolerability of once and twice weekly use. Dermatology 184(suppl 1):21-4 (1992).
2. Ciclopirox nail lacquer topical solution 8% package insert. Dermik Laboratories Inc, PA, USA. (2000 Jan).
3. Markus A. Hydroxy-Pyridones. In: Shuster S, editor. Hydroxy-Pyridones as antifungal agents with special emphasis on onychomycosis. 1st ed. Berlin:Springer-Verlag pp1-10 (1999).
4. Baran R, Hay R, Haneke E, Tosti A. Review of current antifungal therapy. 1st ed. London:Martin Dunitz Ltd pp 44-69 (1999).
5. Bohn M, Kraemer K. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Dermatol. In press 2000.
6. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. In press 2000.
7. Gupta AK. Pharmacoeconomic analysis of ciclopirox nail lacquer solution 8% and the new oral antifungal agents used to treat dermatophyte toe onychomycosis in the USA. J Am Acad Dermatol. In press 2000.
8. Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophyte moulds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 42:217-224 (2000).
9. Gupta AK, Baran R. The role of ciclopirox nail lacquer solution 8% in the 21st century. J Am Acad Dermatol. In press 2000.
10. Markus A. Hydroxy-Pyridones. In: Shuster S, editor. Hydroxy-Pyridones as antifungal agents with special emphasis on onychomycosis. 1st ed. Berlin:Springer-Verlag pp75-80 (1999).

In this issue:

1. Ciclopirox Nail Lacquer Topical Solution 8%
2. Treatment Options For The Cutaneous Manifestations Of Systemic Sclerosis
3. Update on Drugs and Drug News - Number 1 2000