Abstract & Commentary
Synopsis: Terbinafine had higher cure rates and lower relapse rates than itraconazole at 5 years.
Source: Sigurgeirsson B, et al. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis. Arch Dermatol. 2002;138:353-357.
This study follows up the Lamisil vs. Itraconazole in Onychomycosis (LION) study whose results were published in 1999. Briefly, the LION study demonstrated that continuous terbinafine (Lamisil®) had higher mycological and clinical cure rates than itraconazole (Sporanox®). The original cohort of patients was multinational. The trial was prospective, randomized, double-blind, and double-dummy and analysis was intention-to-treat. The doses given were terbinafine 250 mg/d for 12 or 16 weeks and itraconazole 400 mg/d for 1 week every 4 for 12 or 16 weeks. The patients were followed for 18 months.
The current study (the LION Icelandic Extension Study) examined the 144 patients enrolled in the 3 Icelandic centers. The study had 2 parts. The first part sought to determine what happened to the patients over a course of 5 years. The second part took patients who had relapsed under either treatment and treated them with terbinafine for additional 12-week courses, whenever they had clinical signs of infection or when fungal cultures became positive after initial clearing.
Sigurgeirsson and colleagues had 3 definitions of "cure." First, there was mycological cure, which was the primary end point. It was defined as negative culture and no dermatophytes seen on microscopy. Second, there was clinical cure: 100% normal-looking toenail. Finally, there was complete cure, a combination of mycological and clinical. Relapses could also be mycological or clinical and were defined as you might expect, except that mycological was determined at 12 months and clinical at 18 months. The difference allowed toenails that were mycologically cured, but clinically abnormal, to grow out.
The patients were followed for an average of 54 months with visits every 6 months. Both groups were similar. They averaged 48 years old and were two-thirds male. The offending organism in 97% of cases was Trichophyton rubrum. The patients had onychomycosis for little better than 12 years with an average of 5.5 toenails infected.
After 18 months, 46% of terbinafine patients and 13% of itraconazole patients had a mycological cure without need of a second intervention. The clinical cure rates were 42% and 18%, respectively. Complete cure rates were 35% and 14%, respectively.
At the 18-month check, 5 of 57 (9%) terbinafine patients who were mycologically cured at 12 months had relapsed. The corresponding relapse rate among itraconazole patients was 7 of 32 (22%). At the end of the study, 13 of 57 (23%) terbinafine and 17 of 32 (53%) itraconazole patients had a mycological relapse. The clinical relapse rates were similar, 21% and 48%, respectively.
Seventy-two patients, who at 18 months had clinical signs of onychomycosis, accepted an offer of continued treatment with terbinafine. There were 25 patients from the terbinafine group and 47 patients who had taken itraconazole. At the end of the study, 23 (92%) of the terbinafine group and 40 (85%) of the itraconazole group were mycologically cured. Clinical cure rates were 76% and 77%, respectively.
Comment by Allan J. Wilke, MD
In this head-to-head study, terbinafine had better clinical and mycological cure rates when compared to itraconazole. Additionally, most patients, who had failed initial treatment with either drug, responded to repeat courses of terbinafine. This may be explained by the fact that terbinafine is fungicidal and itraconazole is fungistatic. This study did not evaluate itraconazole performance after treatment failure.
Apparently, there is money to be made in foot fungus. No doubt, you have seen the direct-to-consumer advertisements that Janssen and Novartis run, emphasizing the cosmetic improvements achievable with their drugs. Indeed, both companies host web sites (www.sporanox.com and www.lamisil.com/index.jsp) that offer information about the disease, the medications, and coupons for the first prescription. This is not to play down the serious nature of onychomycosis, which can lead to more severe disease and affect quality of life, but to highlight the competition for our patients’ attention and dollars.
One of the criticisms leveled at LION, which the LION Extension Study aimed to answer, was the length of follow-up. Since toenails typically take 12-18 months to grow out, there was concern that the 18-month follow-up was too short. Five years seems long enough.
The cost of therapy was not addressed. A 12-week course of itraconazole 400 mg/d for a week (84 100-mg capsules) would retail around $500. Terbinafine 250 mg/d for the same length of time (also 84 tablets) is about $550. This does not include the cost of physician visits or liver function testing for terbinafine. Because itraconazole has many drug interactions (cyclosporine, digoxin, quinidine, and phenytoin, for instance), there may be additional expense if you monitor those drugs. The dose of itraconazole is not the one that appears in the product information insert. Janssen recommends 200 mg/d for 12 weeks (168 capsules!). Not for the faint hearted or light of wallet!
There are other therapies for onychomycosis. Griseofulvin is cheaper, but less effective. Ciclopirox (Penlac®, which also has a web site www.dermik.com/prod/penlac/penlac.html) is available as a lacquer that is applied once daily for 48 weeks. It costs $180, but its complete cure rate is less than 10% and after 12 weeks of stopping therapy, 40% of patients had relapsed.1
My one caveat is that Novartis funded this study. I will allow the reader to discover which drug Novartis manufactures.
Dr. Wilke is Assistant Professor, Family Medicine, Medical College of Ohio, Toledo.
1. Med Lett Drugs Ther. 2000;42:51-52.