Griseofulvin for tinea capitis

Tinea capitis is a common fungal infection in children. Pharmacotherapy with a systemic antifungal agent is necessary for treatment and control. This month’s column is a follow-up to last month’s column on the systemic use of antifungal agents in the pediatric population, with a discussion of the use of griseofulvin and other antifungal agents for the treatment of tinea capitis.

Tinea capitis results from infection with various fungal pathogens. In the United States, Trichophyton tonsurans is a common cause of tinea capitis, and during the past several decades, this fungal species has replaced Microsporum canis as the predominant pathogen in the United States. M. canis continues as a common cause of tinea capitis in some European countries.

Agent of choice

Griseofulvin has long been considered the agent of choice for the pharmacotherapy of tinea capitis. It has an established efficacy and safety profile, and it is relatively inexpensive. Griseofulvin is FDA-labeled for use in children aged 2 years and older, and it is available as an oral suspension (25 mg/mL) and as a tablet, which may be crushed and administered over soft foods without chewing. Oral absorption of griseofulvin differs by product. Absorption of ultramicrosize products (Gris-PEG, 125 mg, 250 mg tablets) is nearly complete, whereas absorption of microsize products (Grifulvin V suspension and 500 mg tablets) is less, approximately 25% to 70%. Administration of microsize griseofulvin products with fatty meals can increase absorption because it is lipophilic. These differences in absorption result in differing dosing: 10 mg/kg per day to 20 mg/kg per day for microsize products and 5 mg/kg per day to 15 mg/kg per day for ultramicrosize products, both given for 6 to 8 weeks’ duration. Some experts recommend that treatment durations of up to 12 weeks may be necessary.

Griseofulvin may be given in one or two divided doses per day. Some experts recommend griseofulvin dosages as high as 25 mg/kg per day (microsize), as anecdotal evidence indicates that higher doses may be necessary. The 2009 AAP Red Book recommends that treatment be continued for 2 additional weeks beyond clinical resolution.

Adverse effects

Griseofulvin is a relatively safe antifungal agent, and this contributes to its favorable profile. When used for treatment durations of up to 8 weeks, laboratory monitoring is not necessary. Adverse effects may include gastrointestinal upset (which may be reduced by administration with food) and headache. Griseofulvin may also cause photosensitivity reactions, and sunscreen should be used when users are exposed to sunlight. Griseofulvin has the potential to interact with other medications, although the list of interacting medications is small. There is some evidence to indicate that griseofulvin may be teratogenic. It is labeled as a Pregnancy Category C.

Although griseofulvin has a favorable treatment profile, anecdotal evidence of increasing dermatophyte resistance, resulting in higher recommended dosing or treatment durations, has led to investigations of other suitable pharmacotherapies. Several azole antifungal medications, including terbinafine (Lamisil, Novartis), itraconazole, ketoconazole and fluconazole have been investigated in prospective controlled trials for tinea capitis in children.

Of the azole agents investigated for the treatment of tinea capitis, only terbinafine is FDA-labeled for this use. Terbinafine is labeled for use in children aged 4 years and older for 6-week treatment durations and is available in tablet and oral granule formulations.

Oral granules should not be chewed and should be administered with soft, non-acidic foods (ie, not fruits), such as pudding. Terbinafine has been investigated in several clinical trials, with the largest published study comparing it to griseofulvin in more than 1,500 children (aged 4 to 12 years). In this study (Elewski), terbinafine oral granules (5 mg/kg to 8 mg/kg once daily) were compared with griseofulvin oral suspension (10 mg/kg to 20 mg/kg once daily) for 6 weeks in a randomized, single blinded manner.

The primary endpoint was end-of-study complete cure rate (mycologic and clinical cure) with modified intent-to-treat analysis. Complete cure rate was higher in children receiving terbinafine (45.1%) vs. children receiving griseofulvin (39.2%). The mycologic cure, a secondary endpoint, was also greater in children receiving terbinafine vs. griseofulvin (61.5% vs. 55.5%, respectively). The clinical cure rate at study end was not significantly different among the treatment groups (58.8% to 63%). Approximately 50% of the participants were infected with T. tonsurans, and in these children, terbinafine was statistically superior to griseofulvin for mycologic and clinical cure. Griseofulvin was superior to terbinafine when M. canis was the causative pathogen. Both medications were well tolerated in this study.

Potential limitations of terbinafine include an increased potential for drug-drug interactions, as compared with griseofulvin, and the labeled recommendation for monitoring of hepatic enzymes (ALT, AST) before initiation of therapy (and again if treatment duration is 6 weeks). Terbinafine is a strong inhibitor of the drug-metabolizing enzyme CYP2D6 and a weak inhibitor of CYP3A4. These hepatic drug-metabolizing enzymes contribute to the metabolism of numerous medications. Another more practical limitation of terbinafine is its cost. Terbinafine granules (labeled dose of 125 mg granules for children weighing 25 kg; 187.5 mg for children 25 kg to 35 kg) are available only as Lamisil, at a cost of more than $500 for a 6-week treatment course.

Conclusion

Although several pharmacotherapeutic agents have been investigated for the treatment of tinea capitis in children, only two are FDA-labeled for this use: griseofulvin and terbinafine. Both agents have been shown to be safe and effective, with some recent evidence from a large controlled trial indicating that terbinafine may have superior efficacy.

Griseofulvin is likely to be more effective if the causative pathogen is M. canis. Advantages of griseofulvin include a longer history of proven efficacy and safety, less potential for drug-drug interactions and significantly less cost. It is also labeled for use in children aged younger than 4 years, as compared with terbinafine, which is labeled for use in children aged 4 years and older. Griseofulvin does not require laboratory monitoring before use, unlike terbinafine. Anecdotal evidence suggests that labeled dosing for griseofulvin may be too low for some strains of T. tonsurans, and higher doses (20 mg/kg) may be necessary. Griseofulvin should remain the drug of choice for most children with tinea capitis. Terbinafine can be useful for children who do not respond to, or do not tolerate, griseofulvin, although its cost can be limiting.

For more information:

• Bennett ML. Pediatr Dermatol. 2000;17:304-309.
• Elewski BE. J Am Acad Dermatol. 2008;59:41-54.
• Fleece D. Pediatrics. 2004;114:1312-1315.
• Kakourou T. Pediatr Dermatol. 2010;27:226-228.
• Lorch Dauk KC. Clin Pediatr (Phila). 2010;49:280-286.

Edward A. Bell, PharmD, BCPS, is professor of clinical sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. Bell is also a member of the Infectious Diseases in Children Editorial Board. Disclosure: Dr. Bell reports no relevant financial disclosures.

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