Treatment options for onychomycosis

February 2002

Onychomycosis is a common fungal infection of the nail bed, matrix or plate. The prevalence of onychomycosis may be 10% and higher in patients with diabetes or HIV. Causative pathogens include dermatophytes (most commonly tinea unguium), yeasts and nondermatophyte molds, with toenails more frequently infected than fingernails.

The introduction of new, more effective antifungal therapies has improved therapy. Itraconazole (Sporanox, Janssen/Ortho-Biotech) and terbinafine (Lamisil, Novartis) are the only agents indicated for the systemic treatment of onychomycosis. Although these agents may be associated with improved efficacy compared with older agents, they incur risk for severe adverse events and the potential for multiple drug-drug interactions. In May 2001, the FDA issued a public health advisory concerning these agents and their association with cardiac and hepatic adverse events.

Itraconazole

Itraconazole is a triazole antifungal that was first synthesized in 1980. It exerts its antifungal activity through the inhibition of fungal cytochrome P450. The triazole ring allows for improved tissue penetration, greater specificity for fungal enzymes and a longer serum half-life. Itraconazole has a high affinity for keratin and achieves high concentrations in the nail matrix and nail bed. The FDA-labeled dosage for toenail infections is 200 mg orally four times daily (QD) for 12 weeks. Fingernail infections may be treated with a six-week course of therapy. Effective drug concentrations remain present in the nail for months after therapy. Therefore, pulse therapy (200 mg orally twice daily for one week per month) is approved to treat fingernail infections. It has also proven to be effective in toenail infections but has not been approved by the FDA for this indication.

Similar efficacy of continuous and pulse therapies has been demonstrated. The efficacy and safety of itraconazole pulse therapy was compared with daily therapy in a multicenter, double-blind, randomized study. The study included 129 men and women between 18 and 60 years old with distal subungual onychomycosis of the toenail. Patients received itraconazole 200 mg QD for three months or 400 mg QD for one week per month for three months. Primary outcomes were the clinical response and mycological cure. Patients were assessed every month during the three-month treatment phase and every three months thereafter during the nine-month follow-up period. There were no statistical differences between the groups at any point. At 12 months, clinical response rates in the continuous and pulse groups were 69% and 81% respectively. Complete clinical cure was obtained in 44% of patients in both groups at 12 months. Mycologic cure rates were 66 and 69%.

---Onychomycosis due to Trychophyton rubrum, right and left great toe.
SOURCE: CDC/Dr. Edwin P. Ewing Jr.

Between September 1992 and April 2001, the FDA received 94 reports of the spontaneous development of congestive heart failure (HF) in patients receiving itraconazole therapy. Fifty-eight of these cases occurred in the U.S. The median age of the patients was 57 years (data for 50 out of 58 patients. Most patients were women (36 of 55). The most common indication for the use of itraconazole was the treatment of onychomycosis, followed by systemic fungal infections and prophylaxis or other indications. Data available for 48 patients indicated that the median dose of itraconazole was 300 mg/day with a range of 100 mg-800 mg daily. Of the 58 patients, 28 were hospitalized. Thirteen deaths were reported. It is difficult to identify a causal relationship between itraconazole and these deaths secondary to confounding factors, including 10 patients with serious underlying conditions. There have also been unpublished studies associating IV itraconazole administration with a negative inotropic effect in anesthetized dogs and healthy human subjects.

The FDA has added information to the black box warning for itraconazole. The previous black box warning included information regarding cardiac-related adverse events caused by drug interactions. The revised warning states that administration of itraconazole for the treatment of onychomycosis in patients who have left ventricular dysfunction or a history of HF is not recommended. It also recommends discontinuing itraconazole if signs or symptoms of heart failure appear during treatment of onychomycosis. For indications other than onychomycosis, benefits of treatment should outweigh the risks.

As of March 2001, the FDA has reviewed 24 cases of liver failure possibly related to the use of itraconazole, including 11 deaths. Hepatotoxicity has been reported in patients with and without pre-existing liver disease and medical conditions. Caution should be used when administering itraconazole to patients with hepatic insufficiency. Baseline liver function tests are recommended in all patients. Periodic liver function tests should be performed in patients who receive therapy for more than one month. Additionally, liver function tests should be performed at any time if a patient develops any signs and symptoms of dysfunction.

Terbinafine

Terbinafine, an allylamine, inhibits the biosynthesis of ergosterol through its inhibition of squalene epoxidase. The resulting accumulation of the toxic squalene destroys the fungal cell. Terbinafine binds strongly to plasma proteins, lipids and keratin. High concentrations are achieved in the stratum corneum, sebum, hair and breast milk. Therapeutic concentrations are present in the nail for nine months after discontinuing therapy. A dose of 250 mg/day for 12 weeks is FDA approved for toenail infections, and for six weeks in fingernail infections. Published studies have demonstrated mycologic cure rates of 71%-82% and a clinical cure rate of 60%-70%.

The transient elevations of serum transaminases, cholestatic jaundice, hepatitis and fatal hepatic failure have been observed in patients taking terbinafine. Symptoms generally develop within three to six weeks of use and usually resolve within two weeks of stopping terbinafine. As of April 2001, the FDA had received 16 reports of liver failure associated with the use of terbinafine, including 11 deaths and two liver transplants. Patients were being treated with terbinafine for a variety of dermatologic indications including onychomycosis. Subsequently, an FDA advisory statement was issued in May 2001 to alert prescribers to the danger of liver toxicity associated with terbinafine. Although the potential for liver toxicity was already included in the package labeling, the FDA felt it important to note that hepatotoxicity may occur in patients with or without pre-existing liver disease. Baseline liver function tests are recommended in all patients before initiating therapy with terbinafine. Patients with symptoms of liver toxicity, including persistent nausea, vomiting, anorexia, right upper abdominal pain and jaundice, should discontinue therapy and have liver function tests evaluated immediately. Concerns of liver toxicity do not apply to those patients being treated with topical terbinafine.

As a result of postmarketing reports concerning their safety, the package labeling for itraconazole and terbinafine have been revised. It is now recommended that physicians obtain nail specimens for laboratory analysis to confirm the diagnosis of fungal nail infections prior to prescribing these agents. The risks associated with the systemic treatment of onychomycosis must be weighed against the potential benefits. The FDA advisory serves to remind us that these therapies are not benign. In addition to serious adverse events, they are associated with multiple drug-drug interactions, high cost and less than optimal cure rates.

For more information:

• Cribeier BJ, Paul C. Long-term efficacy of antifungals in toenail onychomycosis: a critical review. British Journal of Dermatology. 2001;145:446-452.
• FDA Public Health Advisory. May 9, 2001. www.fda.gov/bbs/topics/answers/2001/ans01083.html.
• Havu V, Brandt H, Heikkila H, et al. A double-blind, randomized study comparing itraconazole pulse therapy with continuous dosing for the treatment of toenail onychomycosis. British Journal of Dermatology. 1997;136(2):230-234.
• Ahmad S, Singer B, Leissa B. Congestive heart failure associated with itraconazole. Lancet. 2001;357(9270):1766-1767.
• Rodgers P, Bassler M. Treating onychomycosis. Am Fam Physician. 2001;63:663-672,677-678.
• Micromedex Healthcare Series. Terbinafine: Drug Evaluation. Micromedex, Inc., 2002.