OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Griseofulvin	126-07-8	C17-H17-Cl-O6

ANNOTATED BIBLIOGRAPHY

References updated: 14 March 2018

• Zimmerman HJ. Antifungal agents. Hormonal derivatives and related drugs. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 609-11.

  (Expert review of hepatotoxicity of antifungal agents published in 1999 mentions that griseofulvin is an interesting experimental hepatoxin [causing Mallory body formation in rats], but produces little hepatic injury in humans).
• Moseley RH. Antifungal agents. Hepatoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 470-3.

  (Review of hepatotoxicity of antifungal agents mentions that griseofulvin causes a variety of acute and chronic effects in rodents, but hepatotoxicity is rare in humans; individual case reports have been published of cholestatic jaundice and precipitation of acute intermittent porphyria).
• Bennett JE. Antifungal agents. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1571-92.

  (Textbook of pharmacology and therapeutics; griseofulvin is fungistatic against several species of dermatophytes, but has no effect on bacteria or other fungi).
• Osment LS. The many effects of griseofulvin. Ala J Med Sci 1969; 6: 392-8. [PubMed: 4903304]

  (Review of griseofulvin structure, mechanism of action, efficacy and safety; griseofulvin is fungistatic, it induces hepatic microsomal enzymes and can trigger acute attacks of porphyria in susceptible patients, common side effects are gastrointestinal upset, headache and rash; it rarely causes liver injury).
• Redeker AG, Sterling RE, Bronow RS. Effect of griseofulvin in acute intermittent porphyria. JAMA 1964; 188: 466-8. [PubMed: 14125225]

  (Two patients with acute intermittent porphyria were given griseofulvin [1 g/day]; urine pyrole excretion increased within 2-5 days and one developed severe abdominal and leg pain, tachycardia and hypertension with elevation of ALT from 38 to 129 U/L).
• Berman A, Franklin RL. Precipitation of acute intermittent porphyria by griseofulvin therapy. JAMA 1968; 192: 1005-7. [PubMed: 14290427]

  (43 year old woman developed attack of acute porphyria [abdominal pain, nausea and restlessness] 7 days after starting griseofulvin [500 mg/day], with bilirubin 0.7 mg/dL, ALT 29 U/L, Alk P normal, and urine porphobilinogen positive).
• Brienstrup H, Sogaard-Andersen J. Intrahepatic cholestasis after griseofulvin treatment. Ugeskr Laeger 1966; 128: 145-6. Danish. [PubMed: 5914466]

  (14 year old boy developed jaundice 4 months after starting griseofulvin [bilirubin 6.1 mg/dL, ALT 312 U/L, Alk P ~3 times ULN], with recovery over next few months).
• Chiprut RD, Viteri A, Jamroz C, Dyck WP. Intrahepatic cholestasis after griseofulvin administration. Gastroenterology 1976; 70: 1141-3. [PubMed: 131731]

  (63 year old man developed fatigue and pruritus 3 weeks after starting griseofulvin [bilirubin 3.4 mg/dL, AST 75 U/L and Alk P ~3 times ULN], resolving within few months of stopping: Case 1).
• Gotz H, Reichenberger M. Ergebnisse einer Fragebogenaktion bei 1670 Dermatologen der Bundes-Republik Deutschland uber Nebenwirkungen dei der Griseofulvintherapie. [Results of questionnaires of 1670 dermatologists in West Germany concerning the side effects of griseofulvin therapy]. Hautarzt 1975; 11: 485-92. [PubMed: 4655974]

  (1670 German dermatologists answered a questionnaire regarding griseofulvin; only 5% reported having seen liver injury during therapy, the majority of which was serum aminotransferase elevations without jaundice or symptoms).
• Smith AG, De Matteis F. Drugs and the hepatic porphyrias. Clin Haematol 1980; 9: 399-425. [PubMed: 7398153]

  (Extensive review of the effects of drugs on heme metabolism and porphyria; griseofulvin appears to inhibit hepatic ferrochelatase, leading to accumulation of protoporphyrin).
• Simon N, Berko G, Polay A, Kocsis G. Der Einflus der Griseofulvintherapie auf die Leber function und den Porphyrin-Stofwechsel. [Influence of griseofulvin treatment on liver function and porphyrine metabolism]. Arch Dermatol Forsch 1981; 241: 148-55. [PubMed: 4255210]

  (Griseofulvin therapy in humans leads to transient increase in serum AST and erythrocyte porphyrin levels, but this effect is highly variable and abnormalities usually return to normal within a few weeks).
• Hay RJ, Clayton YM, Griffiths WA, Dowd PM. A comparative double blind study of ketoconazole and griseofulvin in dermatophytosis. Br J Dermatol 1985; 112: 691-6. [PubMed: 3890924]

  (Controlled trial of ketoconazole vs griseofulvin for up to one year in 74 patients with dermatophytoses; similar efficacy; side effects were mild and there was no evidence of liver toxicity in either group “as assessed clinically or by liver function tests.”).
• Lambert DR, Siegle RJ, Camisa C. Griseofulvin and ketoconazole in the treatment of dermatophyte infections. Int J Dermatol 1989; 28: 300-4. [PubMed: 2666321]

  (Review of efficacy and safety of griseofulvin and ketoconazole for superficial mycoses; rate of hepatotoxicity of ketoconazole ranges from 1:10,000 to 1:15,000, and is more common among women and in persons over 40 years of age; recommends routine monitoring of liver enzymes; in contrast, griseofulvin is “remarkably safe” and no deaths have been attributed directly to the drug).
• Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol 1993; 29: S50-4. [PubMed: 8315062]

  (Review article on hepatotoxicity of antifungal agents, griseofulvin, ketoconazole, fluconazole, itraconazole and terbinafine; does not recommend routine monitoring, but stresses need to discontinue agent for hepatic injury with symptoms).
• Watanabe M, Akagi S, Kohge N, Uchida Y, Jguyen TX, Hirakawa K, Fukumoto S. Laparoscopy of griseofulvin-induced liver injury presenting a wide depression. Endoscopy 1994; 26: 514-5. [PubMed: 7956975]

  (42 year old man developed abnormal liver tests 4 months after starting griseofulvin [bilirubin 1.2 mg/dL, ALT 170 rising to 369 U/L despite stopping alcoholic intake]; liver biopsy showed mild inflammation without fibrosis, abnormalities resolved with stopping griseofulvin).
• Polo CF, Buzalh AM, Vazquez ES, Afonso SG, Navone NM, del Carmen Battle AM. Griseofulvin-induced hepatopathy due to abnormalities in heme pathway. Gen Pharmac 1997; 29: 207-10. [PubMed: 9251900]

  (In mice, griseofulvin inhibits ferrocheletase which is responsible for inserting iron into the protoporphyrin ring and can induce attacks of protoporphyria).
• Wingfield AB, Fernandez-Obregon AC, Wignall FS, Greer DL. Treatment of tinea imbricate: a randomized clinical trial using griseofulvin, terbinafine, itraconazole and fluconazole. Br J Dermatol 2004; 150: 119-26. [PubMed: 14746625]

  (Randomized trial of four antifungals for 4 weeks for tinea imbricate in 86 patients in New Guinea; griseofulvin and terbinafine were effective; itraconazole and fluconazole were not; only one patient had ALT elevation [3-fold: terbinafine]).
• Song J, Deresinski S. Hepatotoxicity of antifungal agents. Curr Opin Investig Drugs 2005; 6: 170-7. [PubMed: 15751740]

  (Extensive review of hepatotoxicity of antifungal agents; although griseofulvin is rarely associated with hepatotoxicity, it has been linked to rare cases of cholestatic hepatitis arising after 1-4 months of therapy).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 8 cases were attributed to antifungal agents, but no cases were attributed to griseofulvin).
• Elewski BE, Cáceres HW, DeLeon L, El Shimy S, Hunter JA, Korotkiy N, Rachesky IJ, et al. Terbinafine hydrochloride oral granules versus oral griseofulvin suspension in children with tinea capitis: results of two randomized, investigator-blinded, multicenter, international, controlled trials. J Am Acad Dermatol 2008; 59: 41-54. [PubMed: 18378354]

  (Controlled trial of 6 weeks of terbinafine vs griseofulvin in 1549 children with tinea capitis; side effects were similar; low rate of serum biochemistry abnormalities, although 2 patients on griseofulvin stopped therapy because of serum aminotransferase elevations).
• Kao WY, Su CW, Huang YS, Chou YC, Chen YC, Chung WH, Hou MC, et al. Risk of oral anti-fungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol 2014; 77: 180-9. [PMC free article: PMC3895359] [PubMed: 23750489]

  (Analysis of Taiwan national health Insurance database from 2002-2008 identified 52 patients with drug induced liver injury among 90,847 users of oral antifungal agents, rates were were 4.3 per 10,000 persons taking griseofulvin [8 cases], but none were fatal).
• Raschi E, Poluzzi E, Koci A, Caraceni P, Ponti FD. Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database. World J Hepatol 2014; 6: 601-12. [PMC free article: PMC4163743] [PubMed: 25232453]

  (Analysis of spontaneous reports of drug induced liver injury to the FDA between 2004 and 2011 identified 1964 cases attributed to antifungal agents, only 3 of which were linked to griseofulvin, none of which were fatal).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 14 cases [1.6%] were attributed to antifungal agents including 7 due to terbinafine, 6 triazoles [4 fluconazole, 1 ketoconazole and 1 voriconazole], 1 micafungin, but none due to griseofulvin).
• Smith RJ, Boos MD, McMahon P. Probable griseofulvin-induced drug reaction with eosinophilia and systemic symptoms in a child. Pediatr Dermatol 2016; 33: e290-1. (9 year old boy developed fever, rash, adenopathy and liver test abnormalities 3 weeks after starting griseofulvin [bilirubin not provided, ALT 31 rising to 282 U/L, Alk P 170 rising to 285 U/L, eosinophils 310/µ. [PubMed: 27397873]

  L], rash, fever and laboratory abnormalities resolving within 2-4 weeks of starting prednisone therapy).
• Kyriakidis I, Tragiannidis A, Munchen S, Groll AH. Clinical hepatotoxicity associated with antifungal agents. Expert Opin Drug Saf 2017; 16: 149-65. [PubMed: 27927037]

  (Review of the hepatotoxicity of antifungal agents states that all antifungal agents may cause hepatic toxicity, mentions that griseofulvin has been linked to rare cases of transient liver injury, but not to acute liver failure).