Overview

Griseofulvin is a fungistatic antifungal agent indicated for the treatment of fungal infections caused by Epidermophyton, Microsporum, and Trichophyton species.¹ It inhibits fungal cell mitosis by interfering with the function of microtubules. Griseofulvin is rapidly excreted from the body, necessitating a prolonged course of treatment for weeks to months to achieve therapeutic efficacy. In Malaysia, there are currently six (6) griseofulvin-containing tablet products registered with the Drug Control Authority (DCA).²

Severe cutaneous adverse reactions (SCARs) are idiosyncratic, severe, and potentially life-threatening forms of skin reactions that are most often induced by drugs.^3-6 These include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP).

Background of the Safety Issue

During the course of local signal detection activities, the National Pharmaceutical Regulatory Agency (NPRA) became aware of cases of SJS following the administration of oral griseofulvin.⁷ This prompted the NPRA to initiate a safety review, and further investigation into the local pharmacovigilance database revealed the presence of other types of SCARs reports, including TEN and AGEP, suspected to be related to griseofulvin use.

The pathophysiology of how drugs, including griseofulvin, induce SCARs is still not completely understood.⁵ All types of SCARs belong to delayed type IV hypersensitivity reactions triggered by a T-cell-mediated drug-specific immune response, while their clinical heterogeneity could be attributed to the activation of different effector or regulatory cells that produce specific cytokines.^5-6 The reported time-to-onset of SCAR symptoms following griseofulvin use ranged from days to weeks.^8-10 Patient recoveries were documented following cessation of griseofulvin and supportive treatment.

Based on the review of the local situation, scientific literature, global post-marketing reports, package inserts (PIs) from reference regulatory agencies, reported positive dechallenges as well as inconsistent information across PIs and consumer medication information leaflets (RiMUPs) for all locally registered products that contain griseofulvin,^2,8-13 the NPRA has concluded that there is a need to revise and harmonise the information pertaining to the risk of SCARs in the local PIs and RiMUPs for all griseofulvin-containing products.

Adverse Drug Reaction Reports⁷

To date, the NPRA has received 257 reports with 507 adverse events suspected to be related to griseofulvin-containing products. Of these, 220 reports involved 331 events classified under System Organ Class (SOC) Skin and subcutaneous tissue disorders. Among the SCARs reported locally following the use of griseofulvin were Stevens-Johnson syndrome (12 reports), toxic epidermal necrolysis (2), and acute generalised exanthematous pustulosis (3).

Advice for Health Care Professionals

• Be aware of the risk of potentially life-threatening SCARs in patients receiving griseofulvin therapy.
• Educate patients to seek urgent medical attention if they encounter severe skin reactions, including bumps under the skin, blisters, redness and peeling with or without fever, and swollen glands.
• If a SCAR is suspected, discontinue griseofulvin and immediately refer patients to a dermatologist for diagnosis and treatment.
• Report all suspected adverse events associated with griseofulvin-containing products to the NPRA.

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: 600-1/9/13 (22) Jld. 1] had been issued for all registration holders of products containing griseofulvin to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. Olson JM, Troxell T. Griseofulvin. [Updated 2023 Jan 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan [cited on 2023 Feb 8]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537323/
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2023 [cited 2023 Apr 10]. Available from: https://www.npra.gov.my
3. Medical Dictionary for Regulatory Activities Terminology (MedDRA). Severe cutaneous adverse reactions (SMQ). MedDRA 25.1. 2022 Sep [cited on 2023 Feb 8]. Available from: https://www.meddra.org/ (access restricted)
4. Roujeau JC, Allanore L, Liss Y, et al. Severe cutaneous adverse reactions to drug (SCAR): definitions, diagnostic criteria, genetic predisposition. Dermatol Sinica. 2009 Dec 1;27(2):203-9. Available from: https://doi.org/4103/0378-6323.74963
5. Bellón T. Mechanisms of severe cutaneous adverse reactions: recent advances. Drug Safety. 2019 Aug;42(8):973-992. Available from: https://doi.org/10.1007/s40264-019-00825-2
6. Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O. Severe cutaneous adverse reactions to drugs. Lancet. 2017 Oct 28;390(10106):1996-2011. Available from: http://dx.doi.org/10.1016/S0140-6736(16)30378-6
7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2023 [cited on 2023 Feb 8]. Available from: https://www.npra.gov.my (access restricted)
8. Disky A, Zouhair K, Khadir K, Benchikhi H. Stevens-Johnson syndrome and griseofulvin. Revue française d'allergologie et d'immunologie clinique. 2007 Dec 1;47(8):484-6. Available from: https://doi.org/10.1016/j.allerg.2007.08.013
9. Le Guern A, Kerrad I, Oehler E. Severe cutaneous drug reactions to misused griseofulvin: 2 cases. InAnnales de Dermatologie et de Venereologie 2016 Jan 29 (Vol. 143, No. 3, pp. 219-222). Available from: http://dx.doi.org/10.1016/j.annder.2015.12.012
10. Maiolo C, Ross C, Ibbetson J, Kearney D. Griseofulvin associated with drug reaction with eosinophilia and systemic symptoms (DRESS). JAAD Case Reports. 2016 Jul 1;2(4):315-6. Available from: http://dx.doi.org/10.1016/j.jdcr.2016.05.018
11. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2023 [cited 2023 Feb 8]. Available from: https://www.vigilyze.who-umc.org  (access restricted)
12. United States Food and Drug Administration (US FDA). GRISEOFULVIN (griseofulvin tablet; Sandoz Inc) [Package Insert]. FDALabel. 2016 Dec [cited 2023 Feb 8]. Available from: https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/98829d90-b289-4bec-a625-7af412a5cb2d/spl-doc?hl=griseofulvin.
13. Australian Therapeutic Goods Administration (TGA). GRISOVIN (griseofulvin) tablet [Package Insert]. TGA eBusinesses Services. 2022 Sep 14 [cited 2023 Feb 8]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2022-PI-02452-1&d=20230426172310101

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgment. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Wo Wee Kee
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Lee Sing Chet, Noor'ain Shamsuddin, Norleen Mohamed Ali