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The efficacy and safety of terbinafine in children
Dermatol Clin 21 (2003) 511 – 520
The efficacy and safety of terbinafine in children Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Elizabeth A. Cooper, HBSc, BEScb, Charles W. Lynde, MD, FRCP(C)c a
Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Division of Dermatology, Department of Medicine, University Health Network (Toronto Western site) and the University of Toronto, 3 Ovida Boulevard, Toronto, Ontario L3P 7N8, Canada
Terbinafine is an allylamine antifungal agent, which has been used effectively to treat both superficial and systemic mycoses in the adult population. Terbinafine use in pediatric superficial fungal infection, particularly tinea capitis, has also been effective, and is summarized in this article. Tinea capitis is the most common fungal infection among the pediatric population, occurring mainly in prepubescent children. The incidence of tinea capitis has been increasing over the last several years. Lobato et al [1] found that the rate of prescriptions have increased by 209.7% for black children, by 140.4% for white children, and by 84.2% for all children. Since its availability in 1991, terbinafine has been approved for the management of tinea capitis in many countries including Australia, New Zealand, China, Japan, most South American countries, India, Sri Lanka, many African counties, and several European nations. Terbinafine has also been used successfully in pediatric cases of onychomycosis, and other superficial fungal infections.
Terbinafine Terbinafine is a lipophilic allylamine compound that is well absorbed ( > 70%) and binds strongly and nonspecifically to plasma proteins (99%) [2,3]. Ab-
* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).
sorption is not altered when terbinafine is taken with food [3,4]. Terbinafine penetrates keratinized tissues, and enters the stratum corneum and sebum by direct diffusion through the dermis and living epidermis [5,6]. Terbinafine accumulates in skin rapidly, to higher concentrations than in the plasma; plasma concentrations are poor indicators of concentrations in target organs [5]. The elimination half-life of terbinafine is about 17 to 36 hours [2,3]. Radiolabeled terbinafine exhibits a triphasic plasma concentrationtime profile of elimination with a component that has an even longer half-life [7]. The excretion of terbinafine in the urine and feces is 80% and 20%, respectively [8,9]. Terbinafine reduces the conversion of squalene to squalene epoxide by inhibiting the enzyme squalene epoxidase. Ultimately, the reduction in squalene epoxide leads to a decrease in ergosterol, which is an essential component of fungal cell membranes [10]. The excess of squalene may also damage cellular membranes, causing the release of lytic enzymes from vacuoles. These actions may be responsible for the fungicidal in vitro action of terbinafine [10]. Terbinafine is highly selective for fungal squalene epoxidase, which may be caused by differences in amino acid sequences compared with mammalian squalene epoxidases [11]. The concentration ratio for the inhibition of mammalian cholesterol synthesis versus fungal ergosterol synthesis is 4000:1 [7], and it is unlikely that terbinafine affects the synthesis of cholesterol in animals and humans [12]. The minimum inhibitory concentration of terbinafine is extremely low in vitro against both dermato-
0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00029-9
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phyte species (0.001 to < 0.06 mg/mL) and a spectrum of nondermatophytes [13]. Organisms include Aspergillus species, Scopulariopsis brevicaulis, Sporothrix schenckii, Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Cryptococcus neoformans, Fonsecaea, Phialophora, Madurella, Acremonium, certain Candida species, and dimorphic fungi. Terbinafine is metabolized extensively by a wide range of cytochrome P-450 (CYP) enzymes, including CYP1A2, CYP3A4, and CYP2C9 [14]. Terbinafine inhibits CYP2D6 [14,15]. Drugs metabolized by CYP2D6 may be affected by terbinafine usage, including monoamine oxidase inhibitors, b-blockers, selective serotonin reuptake inhibitors, and tricyclic antidepressants [8]. Cyclosporine clearance is increased [3,16]. Other possible interactions include rifampin (100% increase in terbinafine clearance) and cimetidine (33% decrease in terbinafine clearance) [3]. No effects on antipyrine or digoxin metabolism were noted [3]. There are no drugs that are contraindicated with terbinafine.
Tinea capitis In the 1940s and early 1950s Microsporum audouinii was the most common organism responsible for tinea capitis in North America; however, since the late 1980s to 1990s, in North America, there has been a shift in causative agents, with Trichophyton tonsurans largely replacing M audouinii. Gupta and Summerbell [17] noted that in 1985, T tonsurans was responsible for 9% of confirmed cases of tinea capitis in Ontario, Canada, whereas in 1996 it was responsible for 76% of cases. Wilmington and Frieden [18] indicated that between 1974 and 1978, T tonsurans caused 41.7% of the cases of tinea capitis in the San Francisco Bay area, and increased to 87.5% between 1986 and 1993. Terbinafine use in tinea capitis has been discussed in many studies and case reports, for both Trichophyton and Microsporum infections [12,19 – 52]. The use of terbinafine to treat tinea capitis is summarized in Tables 1 and 2. Terbinafine is generally found to be effective in Trichophyton-caused tinea capitis over shorter dosage periods than for Microsporum tinea capitis. Studies are underway to determine more optimal treatment schedules using terbinafine for Microsporum tinea capitis. The standard dosing regimen (62.5 mg/d for body weight 10 to 20 kg; 125 mg/d for body weight 20 to 40 kg; 250 mg/d for body weight more than 40 kg) may be insufficient in some infections, and it has been suggested that dosing
be considered on a milligram per kilogram per day basis instead. Tinea capitis caused by Trichophyton species Table 1 summarizes studies involving treatment of Trichophyton species with terbinafine [12,21,29, 35,36,46]. Studies were excluded when the description of the study methodology or results was not detailed enough to provide data with adequate points of comparison for Table 1. Most studies used the standard dosing regimen of terbinafine: 62.5 mg/d for body weight 10 to 20 kg, 125 mg/d for body weight 20 to 40 kg, 250 mg/d for body weight greater than 40 kg. High rates of efficacy have been observed when the standard regimen is used to treat tinea capitis for a duration of 2 to 4 weeks, with cure rates of 65% to 100% when evaluated 12 weeks from the start of therapy. Improvement in the disease state continues in patients followed-up for a few weeks after active terbinafine therapy is stopped. Friedlander et al [29] noted that better rates of complete cure were obtained in patients using doses amounting to more than 4.5 mg/kg/d, regardless of treatment duration. Tinea capitis caused by Microsporum species Table 1 summarizes studies involving treatment of Microsporum species with terbinafine [23,27,35, 47,48,50]. Studies were excluded when the description of the study methodology or results was not detailed enough to provide data with adequate points of comparison for Table 1. Most studies used the standard dosing regimen of terbinafine: 62.5 mg/d (for body weight of 10 to 20 kg); 125 mg/d (20 to 40 kg); 250 mg/d (more than 40 kg). The duration of treatment generally ranges from 2 to 8 weeks. When the standard terbinafine dosing regimen is used and active therapy administered for 6 to 8 weeks the efficacy of therapy when evaluated at follow-up (complete cure or effective cure) has ranged from 71.4% to 77.6% [23,47]. Romero et al [53] obtained clinical cure in 22 (84%) of 26 patients with Microsporum tinea capitis after 6 to 8 weeks of standard-dose terbinafine treatment [53]. When complete cure was considered in relation to dosages on a per kilogram basis, all patients who received greater than 7 mg/kg/d were clinically cured. Of the four failures, the mean dose was only 5.4 mg/kg/d. The authors suggested that effective treatment of Microsporum tinea capitis required 7.5 mg/kg/d for 6 weeks. Other papers have also noted that higher doses of terbinafine were
Table 1 Cure rates produced by standard terbinafine dosing of children with Trichophyton or Microsporum tinea capitis
Microsporum species treated with terbinafine Authors Hamm et al [35] No. of patients 7 Duration of active 1 therapy (wk) Assessment week from 12 start of therapy Complete cure 0% 0/7 Effective cure 14% 1/7 Mycologic cure
Friedlander et al [29] 50 1
Haroon et al [12] 51 2
Hamm et al [35] 14 2
Friedlander et al [29] 55 2
de Freitas et al [24] 20 4
Haroon et al [12] 57 4
Friedlander et al [29] 54 4
12
12
12
12
12
12
12
42% 21/50 56% 28/50
60.8% 31/51 80.4% 41/51
64% 9/14 86% 12/14
49% 27/55 69% 38/55
95% 19/20
66.7% 38/57 85.9% 49/57
56% 30/54 65% 35/54
Haroon et al [36] 10 6 8
80% 8/10 90% 9/10
100% 20/20 Schwinn et al [50] 12 1–2
Pierini et al [48] 11 4
Schwinn et al [50] 6 5 – 6 (1 – 2, then 4)
Dragos and Lunder [27] 22 6
Peharda et al [47] 15 8
12
NR
12
NR
14
12
0% 0/7 8.3% 1/12
8
100% 11/11
100% 11/11
Hamm et al [35] 5 2
0% 0/5 0% 0/5
Nejjam et al [46] 11 6
Crespi [23] 140 8 8 77.6% 83/107
66.7% 4/6 32% 7/22
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Trichophyton species treated with terbinafine Authors Haroon Hamm et al [12] et al [35] No. of patients 53 9 Duration of active 1 1 therapy (wk) Assessment week 12 12 from start of therapy Complete cure 49.1% 44% 26/53 4/9 Effective cure 73.6% 56% 39/53 5/9 Mycologic cure
71.4% 10/14 78.6% 11/14
Std dose regimen used = Terbinafine capsule/tablet by weight: 62.5 mg/d (10 – 19 kg), 125 mg/d (20 – 40 kg), 250 mg/d (> 40 kg). Complete cure = mycology (KOH and culture) negative and no clinical signs. Effective cure = mycology (KOH and culture) negative and minimal to no clinical signs. Mycologic cure = mycology (KOH and culture) negative. 513
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Table 2 Comparative studies of terbinafine and griseofulvin for the treatment of tinea capitis Terbinafine versus griseofulvin
Reference
Mean Study No. of pts age (y) description
Terba Duration (wk)
Grisb Duration (wk)
Organisms
Terbinafine Follow-up Cure Rate (weeks) Outcome Observed
Griseofulvin Cure Rate Observed
Statistics: Significance
Terb:56 Gris: 49
8.9
Randomized, double-blind
4 (capsules)
8 (capsules)
Trichophyton sp.
12
EC
93% 79.6% P = .0840 52/56 39/49 CI:89.4 – 96.3 CI: 73.8 – 85.3
Terb:25 Gris: 25
6.8
Randomized, double-blind
4 (tablets)
8 (tablets)
T tonsurans, M canis
12
CC
Memisoglu et al 1999 Turkey [44] Gupta et al 2001 Canada/South Africa [33] Fuller et al 2001 UK [30]
Terb:32 Gris:35 Terb:50 Gris:50
6.8
Double- blind 4 (capsules)
8 (capsules)
EC
5.75
Randomized, single-blind
Trichophyton sp. and 12 Microsporum sp Trichophyton sp. 12
76% 19/25 CI:67.5 – 84.5 78% 25/32 94% 47/50
44% P < .05 11/25 CI:34.1 – 53.9 74% NR 26/35 92% Not significantd 46/50
5.8
Randomized, 4 (tablets) open, parallelgroup, ITT
10 mg/kg/d, 8 (suspension)
Randomized, double-blind, ITT
6:35 pts 8:33 10:33 12:32
20 mg/kg/d, Microsporum sp. 12 (suspension)
63%(41/65) 65%(42/65) 9%(1/11) 18%(2/11) 62.1%(18/29) 60%(18/30) 48.1%(13/27) 43.5%(10/23)
47%(27/58) 53%(31/58) 50%(5/10) 70%(7/10) 84% 21/25
Terba Duration
Itrac Duration
2
2
Lipozencic et al Multicenter [43]
Terb:77 Gris:70
Terb:133 Gris:30
7.7
2 – 3 (capsules) 20 mg/kg/d, 6 (capsules)
Trichophyton sp. Microsporum sp.
8 12 8 12 16
CC
EC EC
CC
P = .07 NR P = .06 NR P = 0.121 (Armitage trend test)
Terbinafine versus itraconazole
Reference
No. of pts
Jahangir et al 1998 Pakistan [39]
Terb:27 Itra: 28
Gupta et al 2001 Canada/South Africa [33]
Terb:50 Itra:50
7.85
5.4
Randomized, double-blind
Randomized, single-blind
2–3
5 mg/kg/d, 2–3
Organisms
Terbinafine Follow-up Cure Rate (wk) Outcome Observed
Itraconazole Cure Rate Observed
Trichophyton sp.
12
CC
12
EC
12
CC
64.3% 18/28 85.7% 24/28 CI:79.1 – 92.3 82% 41/50s
Trichophyton sp.
59.3% 16/27 77.8% 21/27 CI:69.8 – 85.8 94% 47/50
Significance Not significant P > .05 Not significant P > .05 Not significantd
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Alvi et al 1993 Pakistan [19] (also Haroon et al [37]) Ca´ceres-Rı´os et al 2000 Peru [22]
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required to produce adequate cure rates in Microsporum tinea capitis [43,54].
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the terbinafine group; however, logistic regression did not determine any significant difference in effective therapy rates for the two treatments.
Tinea capitis: terbinafine versus griseofulvin Terbinafine treatment for 4 weeks produced similar cure rates of Trichophyton tinea capitis compared with 8 weeks of griseofulvin capsules or suspension in the comparative studies (see Table 2) [19,22,30, 33,44]. These studies used the standard dosing regimen of terbinafine: 62.5 mg/d (10 to 20 kg); 125 mg/d (20 to 40 kg); 250 mg/d (> 40 kg). The dosage of griseofulvin was 10 mg/kg/d; 20 mg/kg/d; or a regimen of 125 mg/d (10 to 20 kg), 250 mg/d (20 to 40 kg), and 500 mg/d (> 40 kg). Lipozencic et al [43] performed a randomized, double-blind study on the effectiveness of terbinafine for 6 to 12 weeks using the standard dosage regimen, compared against griseofulvin suspension 20 mg/kg/d given for 12 weeks on the treatment of Microsporum tinea capitis (see Table 2). At the 16-week follow-up assessment the complete cure (negative mycology and no clinical signs) was terbinafine (6 weeks), 62.1% (N = 29 patients); terbinafine (8 weeks), 84% (N = 30 patients); and griseofulvin, 84% (N = 25 patients) ( P = not significant). Tinea capitis: terbinafine versus itraconazole Terbinafine for 2 to 3 weeks produced cure rates, which were similar to 2 to 3 weeks use of itraconazole for Trichophyton tinea capitis (see Table 2) [33,39]. Tinea capitis: terbinafine versus fluconazole In a comparative study where patients had Trichophyton tinea capitis, terbinafine for 2 to 3 weeks produced rates of effective therapy similar to 2 to 3 weeks of fluconazole (94% and 84%, respectively; intention to treat analysis) [33]. The fluconazole group had more severe cases of tinea capitis than
Onychomycosis Although onychomycosis is relatively uncommon in children, it has been observed to be increasing in prevalence [55]. There is no approved treatment for onychomycosis in children in North America; however, the recommended dosage regimen for terbinafine is 62.5 mg/d (for body weight of < 20 kg); 125 mg/d (20 to 40 kg); and 250 mg/d (> 40 kg). The duration of treatment should be daily for 6 weeks for fingernail onychomycosis and for 12 weeks for toenail onychomycosis [56]. Ungpakorn et al [57] reported a case of a 2-yearold boy treated with terbinafine, 62.5 mg/d for 6 weeks [57]. The cultures became negative at the end of the fourth week, with no clinical or mycologic evidence of onychomycosis when evaluated 36 weeks after therapy. The side effect of acute urticaria, which appeared after 4 weeks of treatment, subsided after antihistamines were administered. Terbinafine was not discontinued and there were no other side effects or instances of urticaria reported. Goulden and Goodfield [58] reported onychomycosis in three children, ages 5, 8, and 13 years old treated with terbinafine, 250 mg/d. All three had previously failed to respond to griseofulvin. One patient needed 6 months of treatment, whereas the other two required 3 months of therapy to achieve clinical and mycologic cure. No side effects were seen in any of the patients during the course of treatment or following the end of therapy. Gupta et al [55,59] treated five patients, ages 4 to 9 years, with terbinafine for toenail onychomycosis. Terbinafine, 62.5 to 125 mg/d, was administered for 4 to 12 weeks. Four (80%) of five patients were clinically and mycologically cured.
Notes to Table 2: Abbreviations: NR, not reported; CC, complete cure (mycology negative and no clinical signs); EC, effective cure (mycology negative and minimal to no clinical signs); MC, mycologic cure (KOH negative and culture negative). a Terbinafine capsule/tablet dosage by weight: 62.5 mg/d (10 – 20 kg); 125 mg/d (20 – 40 kg); 250 mg/d (> 40 kg), unless otherwise specified. b Griseofulvin capsule/tablet dosage: 125 mg/d (10 – 20 kg); 250 mg/d (20 – 40 kg); 500 mg/d (> 40 kg), unless otherwise specified. c Itraconazole capsules: 50 mg/d (< 20kg); 100 mg/d (20 – 40 kg); 200 mg/d (> 40kg), unless otherwise specified. d Analysis performed as part of a larger study comparing terbinafine treatment with itraconazole, fluconazole, and griseofulvin.
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Other pediatric fungal infections Two patients treated with a combination of oral terbinafine and oral itraconazole were cleared of Scopulariopsis brevicaulis skin infection. One patient was treated for 2 months and remained completely cleared after 6 months [60]. The second patient was treated for over 11 months before a complete cure was noted, but relapsed 10 months after stopping treatment [61]. A 7 year old with phaeohyphomycosis caused by Exophiala spinifera was administered terbinafine, 500 mg/d for 2 months [62]. He exhibited moderate improvement compared with previously unsuccessful responses with amphotericin B, ketoconazole, and flucytosine. A 2 year old with facial infection caused by Pythium insidiosum responded to terbinafine, 60 mg twice daily, and itraconazole, 125 mg twice daily given for over 12 months. No adverse effects were associated with treatment, and no recurrence was observed after a year and a half [63]. Terbinafine has shown some efficacy in the treatment of cutaneous leishmaniasis [64]. The treatment group studied included some pediatric patients, and no adverse effects were noted.
Safety of oral terbinafine use in children In summarizing the data from the papers reviewed here, 989 children in 20 studies were given terbinafine and monitored for adverse effects [12,21,22,24, 25,27,29,30,34 – 36,39,41 – 43,46,52,57,58,65]. Tinea capitis was the infection in 99.5% of the cases, with most adjusting dosage of terbinafine by weight. Only eight studies reported regular monitoring of liver enzymes and blood; these included over 500 children [12,27,35,36,41,42,46,52]. In total, 106 (10.7%) of 989 children experienced adverse events; however, only eight patients (0.8%) discontinued terbinafine treatment [29,30,43,52]. Table 3 displays the list of specific adverse events that were reported in 93 of 106 children experiencing adverse events, and six of eight children who discontinued terbinafine. These adverse events involved the gastrointestinal system (2.8% patients); cutaneous system (1.2%); and nervous system (0.9%). Abnormalities in hepatic enzymes and hematologic parameters were observed in 1.8% and 1.3% of children, respectively. The adverse events noted in children are within the spectrum noted for adults treated with terbinafine [62,66]. Most events were mild and transient. Terbinafine seems safe for use in children.
Some rare cases of hepatic failure have been noted in treatment of onychomycosis in adults. Most of these were in patients with serious underlying systemic conditions, and had uncertain causal relation to terbinafine use [3].
Discussion Terbinafine has demonstrated a good record of efficacy and safety in treatment of pediatric superficial fungal infections. Terbinafine has been most effective in treating Trichophyton tinea capitis, when using standard dosage regimen. One-week treatments have displayed effective cure rate of 50%, whereas 2- to 4-week durations have provided effective cure rates from 80% to 100%. Treatment duration of 6 weeks or more may be required with Microsporum tinea capitis. Terbinafine is equally as effective as griseofulvin and itraconazole in comparative trials with Trichophyton tinea capitis. The duration of therapy with terbinafine is substantially shorter compared with griseofulvin, and may be associated with fewer adverse effects and higher compliance. Increasing the dosage above what has been used in some studies (eg, 125 mg/d for children 10 to 15 kg body weight, 187.5 mg/d for 16 to 25 kg, and 250 mg/d for > 25 kg) has enabled higher efficacy to be achieved in treatment of Microsporum tinea capitis; in fact, efficacy in a subset of patients treated with this higher dosing over 2 to 4 weeks (complete cure 77.3%) was similar to that obtained using the standard dosage regimen administered over 8 weeks (see Table 1) [48]. The optimal terbinafine dosage for both Microsporum and Trichophyton infection may need to be given on a milligram per kilogram per day basis rather than milligram per day basis. One study of Microsporum infection indicated that patients who received terbinafine doses greater than 7 mg/kg/d were clinically cured, whereas failures averaged a dose of 5.4 mg/kg/d [53]. Data from studies where terbinafine has been used to treat tinea capitis caused by Trichophyton [29] and Microsporum [43] suggest there is a linear relationship between the terbinafine dose and observed cure rates, independent of duration of treatment [67]. The clearance of terbinafine is about 40% higher in children compared with adults [67]. A dose that is approximately the double of the median dose results in a systemic exposure that is comparable with the standard adult dose of 250 mg/d. Modeling conducted by Friedlander et al [29,43,67] suggests that cure rates may approach 80% if a dose of 9 mg/kg/d were to be used, twice the actual median
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Table 3 Summary of adverse events noted in children administered oral terbinafine for the treatment of superficial fungal infections
System affected
Total number of events reported (%)
Gastrointestinal events
28 (2.8)
Cutaneous events
Nervous system events
Hepatic enzyme abnormalities
12 (1.2)
9 (0.9)
18 (1.8)
Hematologic parameter abnormalities
13 (1.3)
Other laboratory parameter abnormalities Other
10 (1)
Total
93 / 989 (9.4)
3 (0.3)
Adverse event Unspecified gastrointestinal effects Stomach upset Abdominal pain Anorexia Taste loss Nausea Vomiting Diarrhea Obstipation Weight loss Unspecified skin effects Urticaria Pruritis Rash Headaches Somnolence Hyperesthesia Vertigo Unspecified elevation of liver enzymes Abnormal bilirubin Abnormal alkaline phosphatase Eosinophilia Granulocytopenia Leukopenia Elevation of triglycerides Body ache Fever
dose (approximately 4.5 mg/kg/d) used in the studies. Future investigation into the efficacy and safety of higher doses of terbinafine may provide further guidance regarding the optimal treatment regimen for Trichophyton and Microsporum tinea capitis. In the United States, the use of terbinafine for tinea capitis has increased in response to the gradual increase in daily dosage of griseofulvin [68]. Griseofulvin may also have a higher frequency of adverse effects compared with terbinafine. Griseofulvin is available in an oral suspension, however, whereas terbinafine is only available in a tablet form. Oral suspensions or solutions may be required for young children who are unable to swallow capsules or tablets. To help, the pharmacist may break the terbinafine tablet in smaller pieces when the child may be too young to swallow the tablet [69].
Number of children experiencing AE (%)
Number of children discontinuing due to AE (%)
9 (0.9) 3 2 4 1 4 1 1 2 1 4 5 2 1 4 2 1 2 8
(0.3) (0.2) (0.4) (0.1) (0.4) (0.1) (0.1) (0.2) (0.1) (0.4) (0.5) (0.2) (0.1) (0.4) (0.2) (0.1) (0.2) (0.8)
1 (0.1)
1 (0.1) 2 (0.2)
1 (0.1)
2 (0.2) 8 (0.8) 11 (1.1) 1 (0.1) 1 (0.1) 10 (1.0) 1 (0.1) 2 (0.2) 93/ 989 (9.4)
1 (0.1)
6 / 989 (0.6)
From a pharmacoeconomic viewpoint, a 4-week treatment course of terbinafine for a 30-kg child with Trichophyton tinea capitis in the United States costs US $116.9 (one half of a 250-mg tablet given for 4 weeks; [ie, a total of 14 terbinafine 250-mg tablets each costing average wholesale price US $8.35 per 250 mg tablet] [70]). In contrast, a 6-week course of griseofulvin suspension, 125 mg/5 mL administered at 20 mg/kg/d, costs US $261.3 (average wholesale price of griseofulvin suspension is US $31.11 for a 120 mL bottle [70]) for the same child. There is a substantial cost savings to consider terbinafine in such a clinical situation. There are no guidelines for laboratory monitoring before initiating and during therapy with terbinafine for tinea capitis. It is the author’s practice (AKG) to get blood work based on the medical history and
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examination of the infected child. Baseline blood work and intratherapy monitoring are not performed on a regular basis. Studies where tinea capitis in children has been treated with terbinafine suggest that it is generally a safe agent. Children with systemic mycoses have more adverse effects, depending on underlying illness and types of concomitant medications given. The United States package insert advises pretreatment serum transaminases (alanine transaminase and aspartate transaminase) before starting on terbinafine for the treatment of onychomycosis in adults [9]. It remains to be seen what guidelines physicians will adopt as this agent becomes more widely used for the treatment of tinea capitis in children. Treatment efficacy may be reduced by reinfection from asymptomatic carriers of the infecting organism. Investigations had difficulty establishing the rate of asymptomatic carriage of tinea capitis organisms among family members and schoolmates of infected children, and the treatment course to be used, if any, for asymptomatic carriers [71 – 76]. It has been suggested that the entire family should use a sporicidal shampoo, such as ketoconazole shampoo, when treating Trichophyton tinea capitis to reduce the carrier stage [75].
Summary In summary, terbinafine is a broad-spectrum allylamine, which has been used to treat superficial fungal infections including onychomycosis, and some systemic mycoses in adults. With a fungicidal activity, low minimum inhibitory concentration value, and high selectivity for fungal squalene epoxidase, terbinafine has demonstrated good efficacy in superficial fungal infections. Its lipophilic nature provides excellent, widespread absorption into hair, skin, and nails where it can eradicate fungal infection. Terbinafine has been shown to be effective and safe in several studies of the treatment of tinea capitis and onychomycosis in children. When treating Trichophyton tinea capitis the length of therapy may be 2 or 4 weeks. Microsporum tinea capitis may require somewhat higher or longer doses of terbinafine for adequate efficacy. These regimens still tend to be shorter than treatment with griseofulvin, and terbinafine may provide a higher compliance and a more cost-effective means of managing tinea capitis. It is possible that even higher cure rates and a shorter duration of therapy may be achieved following further optimization of treatment regimens that use a higher daily dosage of terbinafine than is currently recommended. The evidence is strongly in
favor of using terbinafine to treat superficial fungal infections in children.
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The efficacy and safety of terbinafine in children Aditya K. Gupta, MD, PhD, FRCP(C)a,b,*, Elizabeth A. Cooper, HBSc, BEScb, Charles W. Lynde, MD, FRCP(C)c a
Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada b Mediprobe Laboratories Inc., 490 Wonderland Road South, Suite 6, London, Ontario N6K 1L6, Canada c Division of Dermatology, Department of Medicine, University Health Network (Toronto Western site) and the University of Toronto, 3 Ovida Boulevard, Toronto, Ontario L3P 7N8, Canada
Terbinafine is an allylamine antifungal agent, which has been used effectively to treat both superficial and systemic mycoses in the adult population. Terbinafine use in pediatric superficial fungal infection, particularly tinea capitis, has also been effective, and is summarized in this article. Tinea capitis is the most common fungal infection among the pediatric population, occurring mainly in prepubescent children. The incidence of tinea capitis has been increasing over the last several years. Lobato et al [1] found that the rate of prescriptions have increased by 209.7% for black children, by 140.4% for white children, and by 84.2% for all children. Since its availability in 1991, terbinafine has been approved for the management of tinea capitis in many countries including Australia, New Zealand, China, Japan, most South American countries, India, Sri Lanka, many African counties, and several European nations. Terbinafine has also been used successfully in pediatric cases of onychomycosis, and other superficial fungal infections.
Terbinafine Terbinafine is a lipophilic allylamine compound that is well absorbed ( > 70%) and binds strongly and nonspecifically to plasma proteins (99%) [2,3]. Ab-
* Corresponding author. Suite 6, 490 Wonderland Road, London, Ontario, N6K 1L6, Canada. E-mail address: [email protected] (A.K. Gupta).
sorption is not altered when terbinafine is taken with food [3,4]. Terbinafine penetrates keratinized tissues, and enters the stratum corneum and sebum by direct diffusion through the dermis and living epidermis [5,6]. Terbinafine accumulates in skin rapidly, to higher concentrations than in the plasma; plasma concentrations are poor indicators of concentrations in target organs [5]. The elimination half-life of terbinafine is about 17 to 36 hours [2,3]. Radiolabeled terbinafine exhibits a triphasic plasma concentrationtime profile of elimination with a component that has an even longer half-life [7]. The excretion of terbinafine in the urine and feces is 80% and 20%, respectively [8,9]. Terbinafine reduces the conversion of squalene to squalene epoxide by inhibiting the enzyme squalene epoxidase. Ultimately, the reduction in squalene epoxide leads to a decrease in ergosterol, which is an essential component of fungal cell membranes [10]. The excess of squalene may also damage cellular membranes, causing the release of lytic enzymes from vacuoles. These actions may be responsible for the fungicidal in vitro action of terbinafine [10]. Terbinafine is highly selective for fungal squalene epoxidase, which may be caused by differences in amino acid sequences compared with mammalian squalene epoxidases [11]. The concentration ratio for the inhibition of mammalian cholesterol synthesis versus fungal ergosterol synthesis is 4000:1 [7], and it is unlikely that terbinafine affects the synthesis of cholesterol in animals and humans [12]. The minimum inhibitory concentration of terbinafine is extremely low in vitro against both dermato-
0733-8635/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00029-9
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phyte species (0.001 to < 0.06 mg/mL) and a spectrum of nondermatophytes [13]. Organisms include Aspergillus species, Scopulariopsis brevicaulis, Sporothrix schenckii, Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Cryptococcus neoformans, Fonsecaea, Phialophora, Madurella, Acremonium, certain Candida species, and dimorphic fungi. Terbinafine is metabolized extensively by a wide range of cytochrome P-450 (CYP) enzymes, including CYP1A2, CYP3A4, and CYP2C9 [14]. Terbinafine inhibits CYP2D6 [14,15]. Drugs metabolized by CYP2D6 may be affected by terbinafine usage, including monoamine oxidase inhibitors, b-blockers, selective serotonin reuptake inhibitors, and tricyclic antidepressants [8]. Cyclosporine clearance is increased [3,16]. Other possible interactions include rifampin (100% increase in terbinafine clearance) and cimetidine (33% decrease in terbinafine clearance) [3]. No effects on antipyrine or digoxin metabolism were noted [3]. There are no drugs that are contraindicated with terbinafine.
Tinea capitis In the 1940s and early 1950s Microsporum audouinii was the most common organism responsible for tinea capitis in North America; however, since the late 1980s to 1990s, in North America, there has been a shift in causative agents, with Trichophyton tonsurans largely replacing M audouinii. Gupta and Summerbell [17] noted that in 1985, T tonsurans was responsible for 9% of confirmed cases of tinea capitis in Ontario, Canada, whereas in 1996 it was responsible for 76% of cases. Wilmington and Frieden [18] indicated that between 1974 and 1978, T tonsurans caused 41.7% of the cases of tinea capitis in the San Francisco Bay area, and increased to 87.5% between 1986 and 1993. Terbinafine use in tinea capitis has been discussed in many studies and case reports, for both Trichophyton and Microsporum infections [12,19 – 52]. The use of terbinafine to treat tinea capitis is summarized in Tables 1 and 2. Terbinafine is generally found to be effective in Trichophyton-caused tinea capitis over shorter dosage periods than for Microsporum tinea capitis. Studies are underway to determine more optimal treatment schedules using terbinafine for Microsporum tinea capitis. The standard dosing regimen (62.5 mg/d for body weight 10 to 20 kg; 125 mg/d for body weight 20 to 40 kg; 250 mg/d for body weight more than 40 kg) may be insufficient in some infections, and it has been suggested that dosing
be considered on a milligram per kilogram per day basis instead. Tinea capitis caused by Trichophyton species Table 1 summarizes studies involving treatment of Trichophyton species with terbinafine [12,21,29, 35,36,46]. Studies were excluded when the description of the study methodology or results was not detailed enough to provide data with adequate points of comparison for Table 1. Most studies used the standard dosing regimen of terbinafine: 62.5 mg/d for body weight 10 to 20 kg, 125 mg/d for body weight 20 to 40 kg, 250 mg/d for body weight greater than 40 kg. High rates of efficacy have been observed when the standard regimen is used to treat tinea capitis for a duration of 2 to 4 weeks, with cure rates of 65% to 100% when evaluated 12 weeks from the start of therapy. Improvement in the disease state continues in patients followed-up for a few weeks after active terbinafine therapy is stopped. Friedlander et al [29] noted that better rates of complete cure were obtained in patients using doses amounting to more than 4.5 mg/kg/d, regardless of treatment duration. Tinea capitis caused by Microsporum species Table 1 summarizes studies involving treatment of Microsporum species with terbinafine [23,27,35, 47,48,50]. Studies were excluded when the description of the study methodology or results was not detailed enough to provide data with adequate points of comparison for Table 1. Most studies used the standard dosing regimen of terbinafine: 62.5 mg/d (for body weight of 10 to 20 kg); 125 mg/d (20 to 40 kg); 250 mg/d (more than 40 kg). The duration of treatment generally ranges from 2 to 8 weeks. When the standard terbinafine dosing regimen is used and active therapy administered for 6 to 8 weeks the efficacy of therapy when evaluated at follow-up (complete cure or effective cure) has ranged from 71.4% to 77.6% [23,47]. Romero et al [53] obtained clinical cure in 22 (84%) of 26 patients with Microsporum tinea capitis after 6 to 8 weeks of standard-dose terbinafine treatment [53]. When complete cure was considered in relation to dosages on a per kilogram basis, all patients who received greater than 7 mg/kg/d were clinically cured. Of the four failures, the mean dose was only 5.4 mg/kg/d. The authors suggested that effective treatment of Microsporum tinea capitis required 7.5 mg/kg/d for 6 weeks. Other papers have also noted that higher doses of terbinafine were
Table 1 Cure rates produced by standard terbinafine dosing of children with Trichophyton or Microsporum tinea capitis
Microsporum species treated with terbinafine Authors Hamm et al [35] No. of patients 7 Duration of active 1 therapy (wk) Assessment week from 12 start of therapy Complete cure 0% 0/7 Effective cure 14% 1/7 Mycologic cure
Friedlander et al [29] 50 1
Haroon et al [12] 51 2
Hamm et al [35] 14 2
Friedlander et al [29] 55 2
de Freitas et al [24] 20 4
Haroon et al [12] 57 4
Friedlander et al [29] 54 4
12
12
12
12
12
12
12
42% 21/50 56% 28/50
60.8% 31/51 80.4% 41/51
64% 9/14 86% 12/14
49% 27/55 69% 38/55
95% 19/20
66.7% 38/57 85.9% 49/57
56% 30/54 65% 35/54
Haroon et al [36] 10 6 8
80% 8/10 90% 9/10
100% 20/20 Schwinn et al [50] 12 1–2
Pierini et al [48] 11 4
Schwinn et al [50] 6 5 – 6 (1 – 2, then 4)
Dragos and Lunder [27] 22 6
Peharda et al [47] 15 8
12
NR
12
NR
14
12
0% 0/7 8.3% 1/12
8
100% 11/11
100% 11/11
Hamm et al [35] 5 2
0% 0/5 0% 0/5
Nejjam et al [46] 11 6
Crespi [23] 140 8 8 77.6% 83/107
66.7% 4/6 32% 7/22
A.K. Gupta et al / Dermatol Clin 21 (2003) 511–520
Trichophyton species treated with terbinafine Authors Haroon Hamm et al [12] et al [35] No. of patients 53 9 Duration of active 1 1 therapy (wk) Assessment week 12 12 from start of therapy Complete cure 49.1% 44% 26/53 4/9 Effective cure 73.6% 56% 39/53 5/9 Mycologic cure
71.4% 10/14 78.6% 11/14
Std dose regimen used = Terbinafine capsule/tablet by weight: 62.5 mg/d (10 – 19 kg), 125 mg/d (20 – 40 kg), 250 mg/d (> 40 kg). Complete cure = mycology (KOH and culture) negative and no clinical signs. Effective cure = mycology (KOH and culture) negative and minimal to no clinical signs. Mycologic cure = mycology (KOH and culture) negative. 513
514
Table 2 Comparative studies of terbinafine and griseofulvin for the treatment of tinea capitis Terbinafine versus griseofulvin
Reference
Mean Study No. of pts age (y) description
Terba Duration (wk)
Grisb Duration (wk)
Organisms
Terbinafine Follow-up Cure Rate (weeks) Outcome Observed
Griseofulvin Cure Rate Observed
Statistics: Significance
Terb:56 Gris: 49
8.9
Randomized, double-blind
4 (capsules)
8 (capsules)
Trichophyton sp.
12
EC
93% 79.6% P = .0840 52/56 39/49 CI:89.4 – 96.3 CI: 73.8 – 85.3
Terb:25 Gris: 25
6.8
Randomized, double-blind
4 (tablets)
8 (tablets)
T tonsurans, M canis
12
CC
Memisoglu et al 1999 Turkey [44] Gupta et al 2001 Canada/South Africa [33] Fuller et al 2001 UK [30]
Terb:32 Gris:35 Terb:50 Gris:50
6.8
Double- blind 4 (capsules)
8 (capsules)
EC
5.75
Randomized, single-blind
Trichophyton sp. and 12 Microsporum sp Trichophyton sp. 12
76% 19/25 CI:67.5 – 84.5 78% 25/32 94% 47/50
44% P < .05 11/25 CI:34.1 – 53.9 74% NR 26/35 92% Not significantd 46/50
5.8
Randomized, 4 (tablets) open, parallelgroup, ITT
10 mg/kg/d, 8 (suspension)
Randomized, double-blind, ITT
6:35 pts 8:33 10:33 12:32
20 mg/kg/d, Microsporum sp. 12 (suspension)
63%(41/65) 65%(42/65) 9%(1/11) 18%(2/11) 62.1%(18/29) 60%(18/30) 48.1%(13/27) 43.5%(10/23)
47%(27/58) 53%(31/58) 50%(5/10) 70%(7/10) 84% 21/25
Terba Duration
Itrac Duration
2
2
Lipozencic et al Multicenter [43]
Terb:77 Gris:70
Terb:133 Gris:30
7.7
2 – 3 (capsules) 20 mg/kg/d, 6 (capsules)
Trichophyton sp. Microsporum sp.
8 12 8 12 16
CC
EC EC
CC
P = .07 NR P = .06 NR P = 0.121 (Armitage trend test)
Terbinafine versus itraconazole
Reference
No. of pts
Jahangir et al 1998 Pakistan [39]
Terb:27 Itra: 28
Gupta et al 2001 Canada/South Africa [33]
Terb:50 Itra:50
7.85
5.4
Randomized, double-blind
Randomized, single-blind
2–3
5 mg/kg/d, 2–3
Organisms
Terbinafine Follow-up Cure Rate (wk) Outcome Observed
Itraconazole Cure Rate Observed
Trichophyton sp.
12
CC
12
EC
12
CC
64.3% 18/28 85.7% 24/28 CI:79.1 – 92.3 82% 41/50s
Trichophyton sp.
59.3% 16/27 77.8% 21/27 CI:69.8 – 85.8 94% 47/50
Significance Not significant P > .05 Not significant P > .05 Not significantd
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Alvi et al 1993 Pakistan [19] (also Haroon et al [37]) Ca´ceres-Rı´os et al 2000 Peru [22]
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required to produce adequate cure rates in Microsporum tinea capitis [43,54].
515
the terbinafine group; however, logistic regression did not determine any significant difference in effective therapy rates for the two treatments.
Tinea capitis: terbinafine versus griseofulvin Terbinafine treatment for 4 weeks produced similar cure rates of Trichophyton tinea capitis compared with 8 weeks of griseofulvin capsules or suspension in the comparative studies (see Table 2) [19,22,30, 33,44]. These studies used the standard dosing regimen of terbinafine: 62.5 mg/d (10 to 20 kg); 125 mg/d (20 to 40 kg); 250 mg/d (> 40 kg). The dosage of griseofulvin was 10 mg/kg/d; 20 mg/kg/d; or a regimen of 125 mg/d (10 to 20 kg), 250 mg/d (20 to 40 kg), and 500 mg/d (> 40 kg). Lipozencic et al [43] performed a randomized, double-blind study on the effectiveness of terbinafine for 6 to 12 weeks using the standard dosage regimen, compared against griseofulvin suspension 20 mg/kg/d given for 12 weeks on the treatment of Microsporum tinea capitis (see Table 2). At the 16-week follow-up assessment the complete cure (negative mycology and no clinical signs) was terbinafine (6 weeks), 62.1% (N = 29 patients); terbinafine (8 weeks), 84% (N = 30 patients); and griseofulvin, 84% (N = 25 patients) ( P = not significant). Tinea capitis: terbinafine versus itraconazole Terbinafine for 2 to 3 weeks produced cure rates, which were similar to 2 to 3 weeks use of itraconazole for Trichophyton tinea capitis (see Table 2) [33,39]. Tinea capitis: terbinafine versus fluconazole In a comparative study where patients had Trichophyton tinea capitis, terbinafine for 2 to 3 weeks produced rates of effective therapy similar to 2 to 3 weeks of fluconazole (94% and 84%, respectively; intention to treat analysis) [33]. The fluconazole group had more severe cases of tinea capitis than
Onychomycosis Although onychomycosis is relatively uncommon in children, it has been observed to be increasing in prevalence [55]. There is no approved treatment for onychomycosis in children in North America; however, the recommended dosage regimen for terbinafine is 62.5 mg/d (for body weight of < 20 kg); 125 mg/d (20 to 40 kg); and 250 mg/d (> 40 kg). The duration of treatment should be daily for 6 weeks for fingernail onychomycosis and for 12 weeks for toenail onychomycosis [56]. Ungpakorn et al [57] reported a case of a 2-yearold boy treated with terbinafine, 62.5 mg/d for 6 weeks [57]. The cultures became negative at the end of the fourth week, with no clinical or mycologic evidence of onychomycosis when evaluated 36 weeks after therapy. The side effect of acute urticaria, which appeared after 4 weeks of treatment, subsided after antihistamines were administered. Terbinafine was not discontinued and there were no other side effects or instances of urticaria reported. Goulden and Goodfield [58] reported onychomycosis in three children, ages 5, 8, and 13 years old treated with terbinafine, 250 mg/d. All three had previously failed to respond to griseofulvin. One patient needed 6 months of treatment, whereas the other two required 3 months of therapy to achieve clinical and mycologic cure. No side effects were seen in any of the patients during the course of treatment or following the end of therapy. Gupta et al [55,59] treated five patients, ages 4 to 9 years, with terbinafine for toenail onychomycosis. Terbinafine, 62.5 to 125 mg/d, was administered for 4 to 12 weeks. Four (80%) of five patients were clinically and mycologically cured.
Notes to Table 2: Abbreviations: NR, not reported; CC, complete cure (mycology negative and no clinical signs); EC, effective cure (mycology negative and minimal to no clinical signs); MC, mycologic cure (KOH negative and culture negative). a Terbinafine capsule/tablet dosage by weight: 62.5 mg/d (10 – 20 kg); 125 mg/d (20 – 40 kg); 250 mg/d (> 40 kg), unless otherwise specified. b Griseofulvin capsule/tablet dosage: 125 mg/d (10 – 20 kg); 250 mg/d (20 – 40 kg); 500 mg/d (> 40 kg), unless otherwise specified. c Itraconazole capsules: 50 mg/d (< 20kg); 100 mg/d (20 – 40 kg); 200 mg/d (> 40kg), unless otherwise specified. d Analysis performed as part of a larger study comparing terbinafine treatment with itraconazole, fluconazole, and griseofulvin.
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Other pediatric fungal infections Two patients treated with a combination of oral terbinafine and oral itraconazole were cleared of Scopulariopsis brevicaulis skin infection. One patient was treated for 2 months and remained completely cleared after 6 months [60]. The second patient was treated for over 11 months before a complete cure was noted, but relapsed 10 months after stopping treatment [61]. A 7 year old with phaeohyphomycosis caused by Exophiala spinifera was administered terbinafine, 500 mg/d for 2 months [62]. He exhibited moderate improvement compared with previously unsuccessful responses with amphotericin B, ketoconazole, and flucytosine. A 2 year old with facial infection caused by Pythium insidiosum responded to terbinafine, 60 mg twice daily, and itraconazole, 125 mg twice daily given for over 12 months. No adverse effects were associated with treatment, and no recurrence was observed after a year and a half [63]. Terbinafine has shown some efficacy in the treatment of cutaneous leishmaniasis [64]. The treatment group studied included some pediatric patients, and no adverse effects were noted.
Safety of oral terbinafine use in children In summarizing the data from the papers reviewed here, 989 children in 20 studies were given terbinafine and monitored for adverse effects [12,21,22,24, 25,27,29,30,34 – 36,39,41 – 43,46,52,57,58,65]. Tinea capitis was the infection in 99.5% of the cases, with most adjusting dosage of terbinafine by weight. Only eight studies reported regular monitoring of liver enzymes and blood; these included over 500 children [12,27,35,36,41,42,46,52]. In total, 106 (10.7%) of 989 children experienced adverse events; however, only eight patients (0.8%) discontinued terbinafine treatment [29,30,43,52]. Table 3 displays the list of specific adverse events that were reported in 93 of 106 children experiencing adverse events, and six of eight children who discontinued terbinafine. These adverse events involved the gastrointestinal system (2.8% patients); cutaneous system (1.2%); and nervous system (0.9%). Abnormalities in hepatic enzymes and hematologic parameters were observed in 1.8% and 1.3% of children, respectively. The adverse events noted in children are within the spectrum noted for adults treated with terbinafine [62,66]. Most events were mild and transient. Terbinafine seems safe for use in children.
Some rare cases of hepatic failure have been noted in treatment of onychomycosis in adults. Most of these were in patients with serious underlying systemic conditions, and had uncertain causal relation to terbinafine use [3].
Discussion Terbinafine has demonstrated a good record of efficacy and safety in treatment of pediatric superficial fungal infections. Terbinafine has been most effective in treating Trichophyton tinea capitis, when using standard dosage regimen. One-week treatments have displayed effective cure rate of 50%, whereas 2- to 4-week durations have provided effective cure rates from 80% to 100%. Treatment duration of 6 weeks or more may be required with Microsporum tinea capitis. Terbinafine is equally as effective as griseofulvin and itraconazole in comparative trials with Trichophyton tinea capitis. The duration of therapy with terbinafine is substantially shorter compared with griseofulvin, and may be associated with fewer adverse effects and higher compliance. Increasing the dosage above what has been used in some studies (eg, 125 mg/d for children 10 to 15 kg body weight, 187.5 mg/d for 16 to 25 kg, and 250 mg/d for > 25 kg) has enabled higher efficacy to be achieved in treatment of Microsporum tinea capitis; in fact, efficacy in a subset of patients treated with this higher dosing over 2 to 4 weeks (complete cure 77.3%) was similar to that obtained using the standard dosage regimen administered over 8 weeks (see Table 1) [48]. The optimal terbinafine dosage for both Microsporum and Trichophyton infection may need to be given on a milligram per kilogram per day basis rather than milligram per day basis. One study of Microsporum infection indicated that patients who received terbinafine doses greater than 7 mg/kg/d were clinically cured, whereas failures averaged a dose of 5.4 mg/kg/d [53]. Data from studies where terbinafine has been used to treat tinea capitis caused by Trichophyton [29] and Microsporum [43] suggest there is a linear relationship between the terbinafine dose and observed cure rates, independent of duration of treatment [67]. The clearance of terbinafine is about 40% higher in children compared with adults [67]. A dose that is approximately the double of the median dose results in a systemic exposure that is comparable with the standard adult dose of 250 mg/d. Modeling conducted by Friedlander et al [29,43,67] suggests that cure rates may approach 80% if a dose of 9 mg/kg/d were to be used, twice the actual median
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Table 3 Summary of adverse events noted in children administered oral terbinafine for the treatment of superficial fungal infections
System affected
Total number of events reported (%)
Gastrointestinal events
28 (2.8)
Cutaneous events
Nervous system events
Hepatic enzyme abnormalities
12 (1.2)
9 (0.9)
18 (1.8)
Hematologic parameter abnormalities
13 (1.3)
Other laboratory parameter abnormalities Other
10 (1)
Total
93 / 989 (9.4)
3 (0.3)
Adverse event Unspecified gastrointestinal effects Stomach upset Abdominal pain Anorexia Taste loss Nausea Vomiting Diarrhea Obstipation Weight loss Unspecified skin effects Urticaria Pruritis Rash Headaches Somnolence Hyperesthesia Vertigo Unspecified elevation of liver enzymes Abnormal bilirubin Abnormal alkaline phosphatase Eosinophilia Granulocytopenia Leukopenia Elevation of triglycerides Body ache Fever
dose (approximately 4.5 mg/kg/d) used in the studies. Future investigation into the efficacy and safety of higher doses of terbinafine may provide further guidance regarding the optimal treatment regimen for Trichophyton and Microsporum tinea capitis. In the United States, the use of terbinafine for tinea capitis has increased in response to the gradual increase in daily dosage of griseofulvin [68]. Griseofulvin may also have a higher frequency of adverse effects compared with terbinafine. Griseofulvin is available in an oral suspension, however, whereas terbinafine is only available in a tablet form. Oral suspensions or solutions may be required for young children who are unable to swallow capsules or tablets. To help, the pharmacist may break the terbinafine tablet in smaller pieces when the child may be too young to swallow the tablet [69].
Number of children experiencing AE (%)
Number of children discontinuing due to AE (%)
9 (0.9) 3 2 4 1 4 1 1 2 1 4 5 2 1 4 2 1 2 8
(0.3) (0.2) (0.4) (0.1) (0.4) (0.1) (0.1) (0.2) (0.1) (0.4) (0.5) (0.2) (0.1) (0.4) (0.2) (0.1) (0.2) (0.8)
1 (0.1)
1 (0.1) 2 (0.2)
1 (0.1)
2 (0.2) 8 (0.8) 11 (1.1) 1 (0.1) 1 (0.1) 10 (1.0) 1 (0.1) 2 (0.2) 93/ 989 (9.4)
1 (0.1)
6 / 989 (0.6)
From a pharmacoeconomic viewpoint, a 4-week treatment course of terbinafine for a 30-kg child with Trichophyton tinea capitis in the United States costs US $116.9 (one half of a 250-mg tablet given for 4 weeks; [ie, a total of 14 terbinafine 250-mg tablets each costing average wholesale price US $8.35 per 250 mg tablet] [70]). In contrast, a 6-week course of griseofulvin suspension, 125 mg/5 mL administered at 20 mg/kg/d, costs US $261.3 (average wholesale price of griseofulvin suspension is US $31.11 for a 120 mL bottle [70]) for the same child. There is a substantial cost savings to consider terbinafine in such a clinical situation. There are no guidelines for laboratory monitoring before initiating and during therapy with terbinafine for tinea capitis. It is the author’s practice (AKG) to get blood work based on the medical history and
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examination of the infected child. Baseline blood work and intratherapy monitoring are not performed on a regular basis. Studies where tinea capitis in children has been treated with terbinafine suggest that it is generally a safe agent. Children with systemic mycoses have more adverse effects, depending on underlying illness and types of concomitant medications given. The United States package insert advises pretreatment serum transaminases (alanine transaminase and aspartate transaminase) before starting on terbinafine for the treatment of onychomycosis in adults [9]. It remains to be seen what guidelines physicians will adopt as this agent becomes more widely used for the treatment of tinea capitis in children. Treatment efficacy may be reduced by reinfection from asymptomatic carriers of the infecting organism. Investigations had difficulty establishing the rate of asymptomatic carriage of tinea capitis organisms among family members and schoolmates of infected children, and the treatment course to be used, if any, for asymptomatic carriers [71 – 76]. It has been suggested that the entire family should use a sporicidal shampoo, such as ketoconazole shampoo, when treating Trichophyton tinea capitis to reduce the carrier stage [75].
Summary In summary, terbinafine is a broad-spectrum allylamine, which has been used to treat superficial fungal infections including onychomycosis, and some systemic mycoses in adults. With a fungicidal activity, low minimum inhibitory concentration value, and high selectivity for fungal squalene epoxidase, terbinafine has demonstrated good efficacy in superficial fungal infections. Its lipophilic nature provides excellent, widespread absorption into hair, skin, and nails where it can eradicate fungal infection. Terbinafine has been shown to be effective and safe in several studies of the treatment of tinea capitis and onychomycosis in children. When treating Trichophyton tinea capitis the length of therapy may be 2 or 4 weeks. Microsporum tinea capitis may require somewhat higher or longer doses of terbinafine for adequate efficacy. These regimens still tend to be shorter than treatment with griseofulvin, and terbinafine may provide a higher compliance and a more cost-effective means of managing tinea capitis. It is possible that even higher cure rates and a shorter duration of therapy may be achieved following further optimization of treatment regimens that use a higher daily dosage of terbinafine than is currently recommended. The evidence is strongly in
favor of using terbinafine to treat superficial fungal infections in children.
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