Abstract
This retrospective medical record review examines the prevalence of laboratory monitoring and laboratory abnormalities during systemic terbinafine therapy in pediatric onychomycosis.
Onychomycosis is a fungal infection of the nail resulting in discoloration, thickening, and separation from the nail bed. Pediatric onychomycosis has a reported incidence of 0.4% to 2.6%. Topical antifungal therapy has been shown to have some efficacy in children compared with adults; however, when the infection involves the nail matrix, systemic therapy is often indicated. Terbinafine is the systemic antifungal of choice, with cure rates as high as 80%. Though terbinafine is well tolerated, hepatotoxic effects have been reported in adults. There are fewer risk factors for liver injury in children and consensus regarding laboratory surveillance during therapy has not been reached, with physician preference varying widely. The aim of our study was to investigate the prevalence of laboratory monitoring and laboratory abnormalities during systemic terbinafine therapy in pediatric patients with onychomycosis.
Methods
We conducted an institutional review board-approved retrospective medical record review of patients seen at Children’s Hospital of Philadelphia for onychomycosis from December 2008 to December 2016. Patients not prescribed systemic terbinafine therapy were excluded. Laboratory abnormalities were graded based on The National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Statistical analyses were performed using Stata statistical software (version 14.2, Stata Corp).
Results
Over an 8-year period, 1302 patients were diagnosed with onychomycosis. Of these, 269 (21%) were prescribed oral terbinafine and were included in analysis (Table 1 and Table 2). A total of 192 (71.4%) patients were treated by pediatricians and 77 (28.6%) were treated by pediatric dermatologists. Mean (SD) age at initial presentation was 11.5 (3.9) years (range, 2-20 years). The male to female ratio of the study population was 1.5:1.0, with 160 (59%) male patients and 109 (41%) female.
Table 1. Demographics of the Study Population and Patients Who Underwent Laboratory Monitoring.
| Overall Demographics of Study Population | Finding |
|---|---|
| Patients prescribed terbinafine, No. | 269 |
| Age, mean (SD), y | 11.5 (3.9) |
| Sex, No. (%) | |
| Female | 109 (41) |
| Male | 160 (59) |
| Nail involved, No. (%) | |
| Toenail(s) | 263 (98) |
| Fingernail(s) | 1 (<1) |
| Unknown | 5 (2) |
| Prescribed daily oral terbinafine dose,a No. (%) | |
| 62.5 mg (<20 kg) | 1 (<1) |
| 125 mg (20-40 kg) | 93 (35) |
| 250 mg (>40 kg) | 174 (65) |
| Other (187.5 mg per tinea capitis dosing) | 1 (<1) |
| Patients with treatment extended beyond typical course duration,b No. (%) | 6 (2) |
| Toenail(s) | 5 |
| Fingernail(s) | 1 |
Weight-based dosing used based on prior studies and clinical practice although no standard dosing guidelines in pediatric patients per drug insert.
Duration of therapy based on adult guidelines of 6 weeks of total therapy for fingernail onychomycosis and 12 weeks of total therapy for toenail onychomycosis.
Table 2. Demographics of Patients With Laboratory Monitoringa.
| Characteristic | Overall | Normal Laboratory Results or Laboratory Abnormality Prior to Therapy | Laboratory Abnormality During Therapy | P Value |
|---|---|---|---|---|
| Patients with laboratory monitoring, No. (%) | 144 (54) | 138 (96) | 6 (4) | |
| Sex, No. (%) | ||||
| Female | 68 (47) | 65 (96) | 3 (4) | .89 |
| Male | 76 (53) | 73 (96) | 3 (4) | |
| Age, No. (%), y | ||||
| <12 | 71 (49) | 68 (96) | 3 (4) | .97 |
| ≥12 | 73 (51) | 70 (96) | 3 (4) |
Demographics of the study population and patients who underwent laboratory monitoring. χ2 tests were performed to evaluate covariates of sex and age assuming a .05 significance level.
Diagnosis of onychomycosis was confirmed by nail culture and/or periodic–acid schiff (PAS) stain in 128 (48%) cases prior to initiation of treatment. Seventy-two (56%) patients had positive culture results, 44 (34%) patients had positive PAS stain results, and 12 (9%) patients had both.
Mean (SD) number of treatment courses was 1.1 (0.3) and mean (SD) duration was 11.8 (2.3) weeks. Mean (SD) time to complete resolution was 5.0 (1.9) months. Cure rates were all determined clinically. A total of 144 (53.5%) patients underwent laboratory monitoring of liver function panels and/or complete blood cell counts. Timing of laboratory monitoring was primarily prior to treatment (34 patients, 23.6%) or prior to treatment and at 6 weeks (102 patients, 70.8%). Whereas 126 (87.5%) patients had normal laboratory results, 18 (12.5%) patients had grade 1 laboratory abnormalities either prior to (12 patients, 8.3%) or during therapy (6 patients, 4.2%). In those with abnormal results during therapy, 3 patients discontinued treatment. Only 1 patient reported an adverse effect (urticaria) at 3 weeks and treatment was stopped.
Discussion
The US Food and Drug Administration (FDA) labeling for systemic terbinafine specifically states that the safety and efficacy in pediatric patients has not been established but in adults recommends pretreatment serum transaminases and laboratory monitoring periodically during therapy. Of the 144 patients prescribed systemic terbinafine who underwent laboratory monitoring, none developed more than a grade 1 laboratory abnormality. In otherwise healthy children, mild liver enzyme elevations are common postinfection. Clinically apparent liver injury from terbinafine treatment occurs in 1 per 50 000 to 120 000 cases. Asymptomatic elevations in serum aminotransferases are found in less than 1% of patients, which typically self-resolve without discontinuing therapy.
We recommend baseline transaminase monitoring. However, routine laboratory monitoring during systemic therapy (12 weeks or less) for onychomycosis in healthy children may be unnecessary owing to low incidence of clinically significant adverse effects, costs of laboratory tests, workup of spurious laboratory abnormalities, and patient discomfort. This study is limited by its generalizability, small sample size, and retrospective nature. Larger, prospective studies evaluating the safety profile in pediatric patients are needed to detect the rare but serious adverse effects that could occur during therapy and work toward FDA label changes for a pediatric onychomycosis indication.
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