Introduction
Penlac is the first topical anti-fungal preparation approved specifically for the treatment of onychomycosis. The product was available for use in Canada in July 2004. Topical preparations utilizing ciclopirox (Loprox) have been available since 1984 for the treatment of cutaneous dermatophyte infections.
The effectiveness of the Penlac is related to the unique topical delivery system and the drug (ciclopirox) pharmacokinetics in the nail plate.
Disclaimer: This A-Detail™ is meant to be a practical guide and does not necessarily reflect all risks, side effects or situations associated with this product.
The Drug
Ciclopiroxs’ mechanism of action is fungicidal by affecting intracellular metabolic processes reducing the organisms ability to process nutrients and detoxify toxic metabolites. This complexity, in contrast to the majority of antifungals which alter sterol synthesis alone, reduces the possibility of the development of fungal resistance. Ciclopirox also shows fungicidal activity against non-growing cells which is important in nail infections where the conditions do not enhance rapid growth.
Ciclopirox inhibits all of the clinically important dermatophyte, yeast and molds at concentrations that are within a narrow range. Specifically, the dermatophytes, trichophyton and epidermophyton, and the yeasts, candida and scopulariopsis are inhibited at concentrations between 0.5 and 4 ug\ml.*
[Bohn M, Kraemer KT. J Am Acad Dermatol 43(4 Pt 2):S57-S69 (2000 Oct)]
Delivery System
Ciclopirox is incorporated into a clear nail lacquer at an 8% concentration which is applied directly onto the nail plate.This transungual delivery system is unique allowing for prolonged nail contact time and the development of a concentration gradient across the nail plate to enhance nail plate penetration. The lacquer adheres the drug to the nail plate and the evaporation of the lacquer solvents increases the drug concentration to 34%. The lacquer base also reduces transplate water loss which enhances transport of the drug within the nail plate.
[Onychomycosis, Baran et al 1999]
Pharmacokinetics
The penetration of ciclopirox through the nail plate is well documented by invitro studies utilizing cow horn and sheep and bovine nailplate. Studies of penetration in human finger and toe nail plates, both in vitro and in vivo, show similar penetration patterns. “There are limited data regarding the optimal corticosteroid concentration, duration and frequency of application”.
In vitro human C14 studies on excised onychomycotic nailplates showed drug penetration with 24hours and it was also noted that the more damaged the nailsurface by mycotic infection the greater the penetration.
The most clinically relevant report documents an invivo study of 5 healthy volunteers who applied the nail laquer daily to their toenails and removed it weekly according to the current treatment recommendations. Distal nail plate samples taken as early as day 7 showed uniform distribution of the drug within the nail plate at fungicidal concentrations. This persisted through the 45 days of application. Once the applications were stopped the concentrations declined dramatically by day 14 post application.
[JAAD supp October 2000 vol. 43 #4]
Application Technique
Ciclopirox nail lacquer (Penlac) is applied evenly by brush to the entire nail plate including the undersurface at the distal end and at the sites of onycholysis. Penlac The surrounding 5mm of paronychial tissue should also be covered but some irritation may occur.
The applications are daily and after 7 days the Penlac should be removed using isopropyl alcohol or acetone and the nails trimmed of unattached nail plate and debris.
It is imperative to advise patients not to use nail polish during the use of Penlac or for 14 days after the last application of Penlac. The metal ions in the penlac may attach to the nail pigment and the transungual delivery system may result in permanent tattooing of the nailbed.
The Penlac bottle should be securely closed to avoid inadvertent evaporation of the solvents and the bottle should be kept in the carton to protect it from light. A 6 gram bottle offers 1000 applications.
Clinical Efficacy
The Studies – Monotherapy
The two pivotal US trials were double blind placebo controlled trials involving 549 patients randomized 1:1, placebo:drug who applied ciclopirox daily for 48 weeks to their great toenails. The toenails had to have 20% to 65% ( mean 40%) of the plate involved without lunular involvement. These two studies showed a mycological cure (neg. culture and KOH) of 29% and 36% versus placebo of 11% and 9%.
A meta analysis of 10 studies performed world –wide involving 2027 patients with mild to moderate onychomycosis (20 to 65 % involvement without lunular involvement) showed a mean mycological cure (neg culture and KOH) of 52.6 % (range 46.7% to 85.7%).
[Gupta JAAD suppl October 2000 vol 43 #4]
The Studies – Combination Therapy
In my opinion, the combination of systemic therapy with Penlac is desirable in three clinical circumstances.
1. to reduce the amount of drug patients are exposed in situations that require systemic therapy (>75% involvement and lunula involvement)
A three arm study comparing 8 or 12 weeks of terbinafine with daily Penlac application versus 12 weeks of terbinafine monotherapy revealed mycological cure rates of 66.7% (8L) versus 70.4% (12L) versus 56%(12). 73 patients participated each with an average infection duration of 10 years, >60% nail involvement (mean84-89%) with lunular involvement. This study clearly demonstrates an effective combination with reduced drug exposure for the patient
2. to try and improve the response to systemic therapy in situations that are known to be difficult to treat (ie lateral nail disease, extensive onycholysis
3. to try to reduce the incidence of relapse\recurrence that occurs following systemic therapy alone
Ref: Gupta, et al. J Am Acad Dermatol 43(4 Pt 2):S70-S80 (2000 Oct)
Safety
The data gathered from clinical trials and post-marketing reports have not shown any significant systemic side effects related to the topical application of Penlac nail lacquer. Application site reactions including erythema and site burning discomfort are generally mild and have affected 1-5% of treated patients.
There is so little systemic absorption of ciclopirox ( < 5% of applied dose) that it is of no clinical significance. There have been no associated systemic drug interactions.
Patient Selection
In my experience, the patients most likely to have the best experience and be most successful with the use of Penlac are:
Monotherapy
1. patients with mild to moderate onychomycosis
a. < 75% involvement with no lunular disease
2. patients who do not wish or are unable to take systemic medications
3. children wishing to avoid systemic medications
4. patients wishing to try to reduce their chance of relapse\reinfection following systemic therapy
Combination Therapy
1. patients who are interested in trying to reduce their systemic drug exposure
2. patients who wish to try and reduce their relapse\reinfection rate
3. patients with lateral nail disease or extensive onycholysis
