Microtubule Assembly Inhibitors (Griseofulvin)

Article Author:
Jazmine Olson
Article Editor:
Neil Shah
Updated:
12/25/2018 12:02:27 PM
PubMed Link:
Microtubule Assembly Inhibitors (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] Among antifungal therapies for tinea capitis, griseofulvin and terbinafine were found to have the highest clinical and complete cure rates.[2] In the same study, griseofulvin more effectively treated Microsporum than Trichophyton. However, it is important 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Griseofulvin is also indicated in onychomycosis, although it has largely been replaced by newer antifungals such as terbinafine, itraconazole, and fluconazole.[3] The cause of the majority of onychomycosis is by T. rubrum and T. interdigitale.[4] There is high-quality evidence that compared to placebo it is an effective treatment for onychomycosis with regards to both clinical and mycologic cure. Treatment is partly dependent on the rate of nail growth. Toenails grow at a slower rate than fingernails, sometimes taking as long as 12-18 months to grow in its entirety, and have a decreased rate of treatment success.[5][6] Nail debridement may assist in the success of treatment.[4]

Additionally, griseofulvin is used to 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. It can also be used 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 not effective 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 ultramicrosize (125 and 250 mg tablets) forms. Ultramicrosize tablets are absorbed better than microsize. Griseofulvin is poorly water soluble. 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., 6-12 weeks for tinea capitis) which may lead to noncompliance. It is also available in a liquid suspension formulation. In tinea capitis, recommended doses are 20-25 mg/kg/day for microsize and 10-15 mg/kg/day for ultramicrosize. Each of these medications should be taken daily for 6 or more weeks and continued until the patient is clinically asymptomatic.

Adverse Effects

Overall, griseofulvin has few adverse effects. It most commonly causes gastrointestinal issues of nausea, vomiting, and diarrhea as well as headache 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.

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.[7] Additionally, griseofulvin increases the effects of alcohol and may cause a disulfiram-like reaction.[8]

In 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. Cases of conjoined twins have also been reported 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.[9] Do not use griseofulvin in a person who has a hypersensitivity to any portion of the medication. It is also contraindicated in patients with hepatic failure and those with a diagnosis of porphyria cutanea tarda.[10]

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.[11]

Enhancing Healthcare Team Outcomes

When considering superficial fungal infections, it is essential to make an accurate diagnosis to prevent treatment failure. However, it is also important to treat the infection in a timely manner to prevent the spread of infection and its sequelae. In particular, tinea capitis can lead to permanent baldness. This can have a serious psychosocial effect on children. For this reason, 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 (I).

It merits mention that griseofulvin is not effective 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 causes frustration and disappointment for patients as well as a delay in 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 (I).

Finally, as mentioned above under "Monitoring," 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 been shown to be of benefit in patients taking griseofulvin for dermatophyte infections (III).


References

[1] Tinea Capitis in Children and Trichoscopic Criteria., Elghblawi E,, International journal of trichology, 2017 Apr-Jun     [PubMed PMID: 28839385]
[2] Tinea capitis in children: a systematic review of management., Gupta AK,Mays RR,Versteeg SG,Piraccini BM,Shear NH,Piguet V,Tosti A,Friedlander SF,, Journal of the European Academy of Dermatology and Venereology : JEADV, 2018 May 24     [PubMed PMID: 29797669]
[3] Oral antifungal medication for toenail onychomycosis., Kreijkamp-Kaspers S,Hawke K,Guo L,Kerin G,Bell-Syer SE,Magin P,Bell-Syer SV,van Driel ML,, The Cochrane database of systematic reviews, 2017 Jul 14     [PubMed PMID: 28707751]
[4] Gupta AK,Foley KA,Versteeg SG, New Antifungal Agents and New Formulations Against Dermatophytes. Mycopathologia. 2017 Feb     [PubMed PMID: 27502503]
[5] Gupta AK,Cooper EA, Update in antifungal therapy of dermatophytosis. Mycopathologia. 2008 Nov-Dec     [PubMed PMID: 18478357]
[6] Gupta AK,Daigle D,Foley KA, Topical therapy for toenail onychomycosis: an evidence-based review. American journal of clinical dermatology. 2014 Dec     [PubMed PMID: 25257931]
[7] Blank H, The actions and interactions of drugs: the therapeutic significance of enzyme induction. Transactions of the St. John's Hospital Dermatological Society. 1967     [PubMed PMID: 4867271]
[8] Katz HI, Systemic antifungal agents used to treat onychomycosis. Journal of the American Academy of Dermatology. 1998 May     [PubMed PMID: 9594937]
[9] Smith EB, The treatment of dermatophytosis: safety considerations. Journal of the American Academy of Dermatology. 2000 Nov     [PubMed PMID: 11044286]
[10] Spiro JM,Demis DJ, The effects of griseofulvin on porphyria cutanea tarda. The Journal of investigative dermatology. 1968 Mar     [PubMed PMID: 5644892]
[11] Stolmeier DA,Stratman HB,McIntee TJ,Stratman EJ, Utility of Laboratory Test Result Monitoring in Patients Taking Oral Terbinafine or Griseofulvin for Dermatophyte Infections. JAMA dermatology. 2018 Oct 17     [PubMed PMID: 30347032]