Continuing Education Activity

Griseofulvin is FDA approved for and the drug of choice in tinea capitis. Other indications include onychomycosis as well as superficial fungal infections resistant to topical antifungal medications. This activity will highlight the mechanism of action, adverse event profile, monitoring, and relevant interactions of griseofulvin, pertinent for members of the interprofessional team in the treatment of patients with the conditions mentioned above when using griseofulvin.

Objectives:

• Describe the therapeutic mechanism of action of griseofulvin.
• Summarize the organisms for which griseofulvin is an indicated therapy.
• Outline the contraindications and adverse events associated with griseofulvin therapy.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with griseofulvin.

Indications

Griseofulvin is FDA approved for and also the drug of choice in tinea capitis, although itraconazole and terbinafine have come to be more common choices than griseofulvin for tinea capitis in adults.[1] It is the most commonly prescribed medication for tinea capitis treatment in children due to its cost-effectiveness and easy accessibility.[2] Researchers found that among antifungal therapies for tinea capitis, griseofulvin and terbinafine had the highest clinical and complete cure rates.[2] In the same study, griseofulvin more effectively treated Microsporum than Trichophyton. However, it is essential to note that in the United States, the most common causative agent of tinea capitis is Trichophyton tonsurans. The efficacy of griseofulvin is improved when used in combination with selenium sulfide shampoo.

Griseofulvin is also indicated in onychomycosis, although newer antifungals such as terbinafine, itraconazole, and fluconazole have largely replaced it.[3] The cause of the majority of onychomycosis is T. rubrum and T. interdigitale.[4] There is high-quality evidence that compared to placebo, it is an effective treatment for onychomycosis regarding both clinical and mycologic cures. Treatment is partly dependent on the rate of nail growth. Toenails grow at a slower rate than fingernails, sometimes taking as long as 12 to 18 months to achieve full growth, and therefore demonstrate a decreased rate of treatment success.[5][6] Nail debridement may assist in the success of treatment.[4]

Additionally, griseofulvin can treat superficial fungal infections that are resistant to treatment with topical antifungal medications, with the exception being tinea capitis, for which it is first-line, as mentioned above. It is usually the first-line choice for this purpose in children. Practitioners can use it for severe and diffuse superficial fungal infections. Examples of such infections include tinea manuum, tinea unguium, tinea corporis, and tinea cruris.

Mechanism of Action

Griseofulvin is a microtubule assembly inhibitor. It interacts with microtubules to affect the formation of the mitotic spindle. This interference ultimately inhibits mitosis in dermatophytes. With this mechanism, griseofulvin serves as a fungistatic agent against Trichophyton, Microsporum, and Epidermophyton species.[2] It is noteworthy that it is ineffective in treating dimorphic fungi, yeast (Malassezia, Candida), or chromomycosis. Griseofulvin is quickly eliminated from the body and thus must be taken over an extended period to have efficacy.[2]

Administration

Griseofulvin is an oral medication. It comes in microsize (250 and 500 mg tablets) and ultra micro-size (125 and 250 mg tablets) forms. Ultra micro-size tablets are absorbed better than microsize. Griseofulvin is poorly soluble in water. Griseofulvin is best taken with a high-fat meal to increase absorption from the GI tract.[2] The duration of therapy is long (e.g., 6 to 12 weeks for tinea capitis), potentially leading to non-compliance. It is also available in a liquid suspension formulation. Each of these medications should be taken daily for the indicated duration and continued until the patient is clinically asymptomatic.

Microsize Dosing

• Onychomycosis: 1000 mg daily divided from once to 4 times daily. Duration is 4 months for fingernails and 6 months for toenails.
• Tinea pedis: 1000 mg daily divided from once to four times a day for 4 to 8 weeks, in conjunction with a topical antifungal.
• Tinea corporis/cruris: 500 mg daily divided from once to four times a day for 2 to 4 weeks.
• Tinea capitis: 500 mg daily divided from once to four times a day for 4 to 6 weeks.
• Tinea barbae: 500 mg daily divided from once to four times a day for 4 to 8 weeks.

Ultramicrosize Dosing

• Tinea capitis, barbae, corporis, or cruris: 375 mg daily divided from once to three times a day for 2 to 4 weeks (tinea barbae, corporis, cruris) or 4 to 6 weeks (tinea capitis).

Griseofulvin requires no dose adjustment in renal impairment but is contraindicated in hepatic failure.

Adverse Effects

Overall, griseofulvin has few adverse effects. It most commonly causes gastrointestinal issues of nausea, vomiting, and diarrhea, as well as headaches and allergic reactions.[3] Other adverse effects include photosensitivity, fixed drug eruption, petechiae, pruritus, and urticaria. It may cause a worsening of lupus or porphyria.[7]

Griseofulvin is an inducer of cytochrome P-450 and thus interacts with medications that metabolize via the P-450 system. One such drug is warfarin. When taken with griseofulvin, warfarin's anticoagulation effect decreases.[8] Additionally, griseofulvin increases the effects of alcohol and may cause a disulfiram-like reaction.[9]

A study involving 295 children, 79 (or 26.8%) experienced mild to moderate adverse effects, with the most common being gastrointestinal. These included elevated triglycerides (1/79), anemia (2/79), SGOT (serum glutamic-oxaloacetic transaminase; 1/79), rash (1/79), abdominal pain (10/79), diarrhea (7/79), dyspepsia (3/79), fever (1/79), headache (12/79), nausea (9/79), weight gain (3/79), vomiting (12/79), and other unspecified events (17/79).[2] All of these adverse effects were transient, and none were considered severe.

Contraindications

Griseofulvin is a pregnancy Category C medication. It should not be prescribed to pregnant women due to its reports of causing fetal abnormalities in rats and dogs. There are also reports of conjoined twins in women taking griseofulvin during their first trimester of pregnancy. Patients should wait at least a month after completion of treatment with griseofulvin before becoming pregnant.[10] Clinicians should not use griseofulvin in a person who has a hypersensitivity to any portion of the medication. Contraindications also include patients with hepatic failure and those with a diagnosis of porphyria cutanea tarda.[11]

Monitoring

Whether there is a benefit to monitoring alanine aminotransferase (ALT), aspartate aminotransferase (AST), and complete blood count (CBC) with differential is a concern for some providers prescribing griseofulvin. A large retrospective study performed in adults and children taking griseofulvin or terbinafine for dermatophyte infections provided clarity on this question. There was a low rate of laboratory test result abnormalities. Most of these were low-grade and did not require discontinuation of the medication or repeat laboratory evaluation. Elevations in ALT, elevations in AST, anemia, lymphopenia, and neutropenia were all infrequent and comparable to baseline rates of abnormalities. With these results, it appears unnecessary in both adults and children to perform interval laboratory tests in patients taking griseofulvin for dermatophyte infections.[12]

Enhancing Healthcare Team Outcomes

Griseofulvin is an antifungal prescribed by clinicians (MDs, DOs, NPs, PAs), but therapy is best managed by an interprofessional healthcare team. For example, patient education by the pharmacist is critical if one wants to achieve good therapeutic results. Griseofulvin is not water-soluble, and hence, patients should ingest it with a fatty diet. It has a very slow mode of action, and most treatments require 6 to 10 weeks; therefore, patient compliance is vital.

The pharmacist should also tell the patient that the minor abdominal side effects will resolve within a short time. Pharmacists should also perform a complete medication reconciliation to verify drug-drug interactions that could pose an issue with griseofulvin. Nursing can promptly monitor treatment effectiveness, patient compliance, and adverse effects from medication and report any concerns to the healthcare team. A course with griseofulvin requires collaboration and communication from every member of the interprofessional healthcare team for effective results and minimal adverse effects. [Level 5]

When considering superficial fungal infections, it is essential to make an accurate diagnosis to prevent treatment failure. However, it is also necessary to treat the infection promptly to prevent the spread of infection and its sequelae. In particular, tinea capitis can lead to permanent baldness, which can have a serious psychosocial effect on children. Therefore, it is important to diagnose and treat tinea capitis early in its course. Providers should be aware that current doses of griseofulvin are effective and safe to use for tinea capitis in children. [Level 1]

It merits mentioning that griseofulvin is ineffective in treating dimorphic fungi, yeast (Malassezia, Candida), or chromomycosis. It has been incorrectly prescribed to treat diseases caused by these organisms, such as candidal intertrigo, for which it is ineffective. This situation causes frustration and disappointment for patients, as well as a delay in the resolution of infection and increased risk of spread to others. Providers should be aware that griseofulvin is only effective against Trichophyton, Microsporum, and Epidermophyton species and not against the organisms noted above. [Level 1]

Finally, as mentioned above in the "Monitoring" section, it appears unnecessary to perform interval laboratory test monitoring, including AST, ALT, and CBC, in patients taking griseofulvin. Providers are often hesitant to provide these oral medications to patients with superficial dermatophyte infections. Because laboratory tests are costly to the healthcare system and both inconvenient and stressful for patients, providers should be aware that interval laboratory test monitoring has not demonstrated benefit in patients taking griseofulvin for dermatophyte infections. [Level 3]