OVERVIEW

Introduction

Terbinafine is an orally and topically active allylamine fungicidal agent which is used to treat superficial fungal infections of the skin and nails. Terbinafine has been clearly linked to rare instances of acute liver injury that can be severe and sometimes fatal.

Background

Terbinafine (ter' bin a feen) is a synthetic allylamine derivative that has potent activity against many dermatophytes that affect skin and nails, including Epidermophyton floccosum, Trichophyton mentagrophytes and Trichophyton rubrum. The antifungal activity of terbinafine is believed to be due to the selective inhibition of fungal squalene epoxidase, which increases squalene to toxic levels, thus killing the fungal cell. Terbinafine was approved for use in the United States in a topical form in 1992 and as an oral antifungal agent in 1998. Topical terbinafine is available over-the-counter as a 1% cream or spray for treatment of dermatophyte infections of the skin (tinea pedis, cruris or corporis). Oral terbinafine is available by prescription only in tablets of 250 mg generically and under the brand name of Lamisal. Oral terbinafine is used in the therapy of onychomycosis or fungal infections of the fingernails or toenails (tinea unguium) typically in a dose of 250 mg once daily for 6 weeks (fingernails) or 12 weeks (toenails). The most common side effects of terbinafine include gastrointestinal disturbances, headache, change in taste and rash.

Hepatotoxicity

Drug induced liver injury due to terbinafine was identified shortly after its introduction into medical use. Oral therapy with terbinafine is associated with elevations in serum aminotransferases in less than 1% of patients and the elevations are generally asymptomatic and resolve without stopping therapy. The estimated probability of developing elevated serum aminotransferase levels requiring stopping treatment is about 0.31% for 2 to 6 weeks' treatment and 0.44% for treatment longer than 8 weeks.

Clinically apparent liver injury from terbinafine occurs rarely (1 in 50,000 to 120,000 prescriptions), but many case reports and even case series have been described in the literature. Liver injury usually arises within the first 6 weeks of therapy. The pattern of injury can be either hepatocellular or cholestatic initially, but typically evolves into a cholestatic pattern which can be prolonged (Cases 1 and 2). Some cases may progress to vanishing bile duct syndrome. Signs of hypersensitivity (rash, fever, eosinophilia) are not common and, when present, are generally mild-to-moderate in severity. Autoantibody formation is rare. In addition, cases with severe hepatocellular injury with acute liver failure have been described. These instances are marked by precipitous onset with marked elevations in serum aminotransferase levels and progressive jaundice and hepatic failure. Terbinafine has also been implicated in cases of Stevens-Johnson syndrome, in which case the hepatic injury may be overshadowed by rash and allergic symptoms.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

Mechanism of Injury

The acute hepatotoxicity caused by terbinafine appears to be part of a hypersensitivity reaction, although the mechanism has not been defined. Genome-wide association studies identified polymorphisms within the HLA region of chromosome six to be linked to cholestatic cases of drug induced liver injury, and particularly terbinafine. HLA sequencing has confirmed these associations and shown that most subjects of European ancestry with terbinafine hepatotoxicity are carriers of HLA-A* 33:01 (heterozygosity), an allele found in less than 1% of control populations. The HLA-A* 33:03 allele which shares 99% sequence identity with 33:01 has been linked to terbinafine hepatotoxicity in a small number of Asian subjects. These associations indicate that the injury is immunologically mediated.

Outcome and Management

Most cases of acute hepatic injury from terbinafine resolve within 3 to 6 months of stopping the medication. In some instances, however, the injury is severe and unremitting, leading to acute liver failure and either death or need for liver transplantation. A severe outcome is more likely if terbinafine is continued after the appearance of symptoms and signs of liver injury. Terbinafine has also been implicated in several cases of acute bile duct injury, followed by prolonged cholestasis associated with vanishing bile duct syndrome. There appears to be no cross sensitivity to hepatic injury between terbinafine and griseofulvin, another agent used for onychomycosis.

Drug Class: Antifungal Agents

CASE REPORT

Case 1. Prolonged cholestasis due to terbinafine.

[Modified from: Fernandes NF, Geller SA, Fong TL. Terbinafine hepatotoxicity: case report and review of the literature. Am J Gastroenterol 1998; 93: 459-60. PubMed Citation]

A 24 year old man developed progressive loss of appetite, pruritus and jaundice within days of stopping a 3½ week course of terbinafine (250 mg daily) for onychomycosis of the toe nails. On initial evaluation one week later, he was jaundiced and had excoriations. There was no fever, urticaria or rash. Laboratory tests showed serum bilirubin of 6.6 mg/dL and elevations in both ALT (584 U/L) and alkaline phosphatase (222 U/L). Tests for hepatitis A, B and C were negative, he did not drink alcohol to excess, and he took no other medications. Ultrasound of the abdomen showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis and injury to small bile ducts, with reduction in the number of ducts. Despite having stopped terbinafine, his symptoms and laboratory test abnormalities worsened over the next few weeks. Pruritus was treated with antihistamines and cholestyramine. Six weeks after stopping terbinafine, his symptoms began to improve and 16 weeks after stopping his liver tests were normal (Table).

Key Points

Laboratory Values

*Values estimated from Figure 2.

Comment

This was a typical case of terbinafine hepatotoxicity arising within 4 weeks of starting therapy and worsening for several weeks thereafter despite the prompt discontinuation. The initial laboratory results suggested a hepatocellular pattern of injury, but by the time of peak bilirubin elevation the serum enzyme pattern was clearly cholestatic. The prominence of jaundice and pruritus also argued for a cholestatic injury. A liver biopsy showed evidence of injury to bile ducts and ductopenia, which was clearly severe enough to cause prolonged jaundice, but not severe enough to cause persistence of cholestatic features and qualify as vanishing bile duct syndrome.

Case 2. Terbinafine induced cholestatic hepatitis.

[Modified from a case in the database of the Drug-Induced Liver Injury Network]

A 43 year old man with history of diabetes and onychomycosis developed fatigue and flu-like symptoms one month after starting treatment with terbinafine taken orally once daily. He developed severe itching one week later and stopped terbinafine after a total of 40 days. Several days later he complained of nausea, vomiting and became jaundiced. Laboratory investigations (Table 1) revealed bilirubin of 6.8 mg/dL, ALT 269 U/L and alkaline phosphatase 433 U/L. Tests for hepatitis A, B and C were negative as were autoantibodies. Imaging of the liver showed no evidence of extrahepatic obstruction. Five days after stopping terbinafine, prednisone was started. Prednisone was initially given intravenously and then orally in tapering doses over 4 weeks (60 mg, 40 mg, 20 mg, 10 mg for one week each). The itching and jaundice improved and he became asymptomatic a month after initial presentation. Liver test abnormalities resolved over the next several months.

Key Points

Laboratory Values

Comment

A 43 year old man developed fatigue approximately 5 weeks after starting terbinabine and itching and jaundice one to two weeks later. The symptoms (itching) suggested a cholestatic hepatitis, although the initial pattern of enzyme elevations was “mixed” (R=3.7). While corticosteroids may improve itching and jaundice, they have not been shown to ameliorate or shorten the course of illness. The patient became asymptomatic after 4 weeks, but was lost to follow up. Follow up is important, as terbinafine hepatotoxicity has been linked to cases of chronic cholestasis and vanishing bile duct syndrome, and his liver tests were not normal when he was last seen and prednisone stopped.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Terbinafine – Generic, Lamisil®

DRUG CLASS

Antifungal Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 01 January 2018

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  • Kim B, Jang H, Jwa S, Jang B, Kim M, Oh C, Kwon Y, et al. Generalized pustular psoriasis and hepatic dysfunction associated with oral terbinafine therapy. J Korean Med Sci 2007; 22: 167-9. [PMC free article: PMC2693560] [PubMed: 17297275]
    (61 year old man with psoriasis developed generalized pustular psoriasis 4 days after starting terbinafine with fever, rash, and neutrophilia but no jaundice [bilirubin normal, ALT 376 U/L, Alk P 564 U/L], symptoms and enzyme elevations responding to corticosteroids within 2 weeks).
  • Chang CH, Young-Xu Y, Kurth T, Orav JE, Chan AK. The safety of oral antifungal treatments for superficial dermatophytosis and onychomycosis: a meta-analysis. Am J Med 2007; 120: 791-8. [PubMed: 17765049]
    (The pooled probability of stopping terbinafine because of elevated ALT/AST was 0.31% [95% CI, 0%-0.74%] for 2-6 weeks and 0.44% [95% CI, 0.13%-0.76%] for 8-48 weeks).
  • Perveze Z, Johnson MW, Rubin RA, Sellers M, Zayas C, Jones JL, Cross R, et al. Terbinafine-induced hepatic failure requiring liver transplantation. Liver Transpl 2007; 13: 162-4. [PubMed: 17192859]
    (50 year old man developed jaundice 3 months after starting terbinafine [bilirubin 29 rising to 67.7 mg/dL, ALT 149 U/L, Alk P 497 U/L], with progressive hepatic failure leading to liver transplantation, explant showed severe cholestasis and paucity of bile ducts).
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    (55 year old developed jaundice 6 weeks after starting terbinafine [bilirubin 11.9 mg/dL, ALT 57 U/L, Alk P 590 U/L], jaundice persisting for 3 months and Alk P elevations continuing for more than 6 months, biopsy showing vanishing bile duct syndrome).
  • 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]
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    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 8 were attributed to antifungal agents, including 4 to terbinafine, 2 to fluconazole, 1 each to ketaconazole and itraconazole).
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    (Concise summary of therapy of fungal infections with recommendations on agents, dosage and duration of treatment and safety; because of risk of liver injury from terbinafine, recommends that liver tests be assessed before and periodically during therapy).
  • Gupta AK, Lynch LE, Kogan N, Cooper EA. The use of an intermittent terbinafine regimen for the treatment of dermatophyte toenail onychomycosis. J Eur Acad Dermatol Venereol 2009; 23: 256-62. [PubMed: 19438818]
    (Trial comparing continuous vs intermittent terbinafine for onychomycosis in 142 adults reported no serious adverse events; no mention of liver toxicity).
  • Takahata Y, Hiruma M, Shiraki Y, Tokuhisa Y, Sugita T, Muto M. Treatment of dermatophyte onychomycosis with three pulses of terbinafine (500 mg day for a week). Mycoses 2009; 52: 72-6. [PubMed: 18444971]
    (55 patients with oncychomycosis were treated with 3 one-week courses [pulses] of terbinafine; no patient had “abnormal findings in any of the laboratory tests”).
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    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, voriconazole ranked 21st with 52 cases [odds ratio 10.7] and fluconazole 30th with 42 cases [odds ratio 8.6]; terbinafine was not listed in the top 41 causes).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, of which 6 were due to antifungal agents, including 3 to terbinafine).
  • Tey HL, Tan AS, Chan YC. Meta-analysis of randomized, controlled trials comparing griseofulvin and terbinafine in the treatment of tinea capitis. J Am Acad Dermatol 2011; 64: 663-70. [PubMed: 21334096]
    (Systematic review of trials comparing oral griseofulvin and terbinafine, rates of hepatotoxicity not mentioned, but authors do not recommend routine monitoring of liver tests if terbinafine is given for 4 weeks only).
  • Deng S, Hu H, Abliz P, Wan Z, Wang A, Cheng W, Li R. A random comparative study of terbinafine versus griseofulvin in patients with tinea capitis in western China. Mycopathologia 2011; 172: 365-72. [PubMed: 21701791]
    (88 children with tinea capitis were treated with 2-4 weeks of oral terbinafine or grisefulvin; reported that there were no side effects).
  • Antifungal drugs. Treat Guidel Med Lett 2012; 10 (120): 61-8. [PubMed: 22825657]
    (Concise summary of recommendations and guidelines for use of antifungal drugs including the imidazoles and triazoles, echinocandins, terbinafine, flucytosine, and amphotericin; liver adverse events are mentioned for terbinafine, ketoconazole, fluconazole, itraconazole, posaconazole and voriconazole).
  • Kao WY, Su CW, Huang YS, Chou YC, Chen YC, Chung WH, Hou MC, et al. Risk of oral antifungal 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, only 2 of which were attributed to terbinafine).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to terbinafine or other antifungal agents).
  • Choudhary NS, Kotecha H, Saraf N, Gautam D, Saigal S. Terbinafine induced liver injury: a case report. J Clin Exp Hepatol 2014; 4: 264-5. [PMC free article: PMC4284205] [PubMed: 25755569]
    (55 year old man developed jaundice and pruritus 1 month after starting terbinafine [bilirubin 13.6 mg/dL, ALT 216 U/L, Alk P 202 U/L], resolving within 3 months of stopping and with ursodiol therapy).
  • Kumar K, Gill A, Shafei R, Wright JL. A curious case of cholestasis: oral terbinafine associated with cholestatic jaundice and subsequent erythema nodosum. BMJ Case Rep 2014; 2014. [PMC free article: PMC4265052] [PubMed: 25480138]
    (A 30ish year old woman developed itching and jaundice shortly after completing a 3 week course of terbinafine [bilirubin 8.5 mg/dL, ALT 120 U/L, Alk P 463 U/L] followed by eythema nodosum which was treated with prednisone; 6 weeks later the skin rash had resolved and all liver tests were normal).
  • 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 395 cases of liver injury attributed to terbinafine including 27 cases of acute liver failure, thus ranking first in total number of cases due to antifungal agents).
  • Yan J, Wang X, Chen S. Systematic review of severe acute liver injury caused by terbinafine. Int J Clin Pharm 2014; 36: 679-83. [PubMed: 24986266]
    (Case report and systematic review of the literature on liver injury from terbinafine; 45 year old man developed dark urine 2 weeks after starting terbinafine and was admitted one month later [biliirubin 18.9 mg/dL, ALT 580 U/L, Alk P not provided] with eventual full recovery after treatment with ursodiol and several traditional Chinese medications).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to terbinafine).
  • 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 mulitcenter prospective study between 2004 and 2013, 7 [0.9%] were attributed to terbinafine).
  • 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 discusses terbinafine and its association with both hepatocellular and cholestatic jaundice and which can result in acute liver failure).
  • Kramer ON, Albrecht J. Clinical presentation of terbinafine-induced severe liver injury and the value of laboratory monitoring: a critically appraised topic. Br J Dermatol 2017; 177: 1279-84. [PubMed: 28762471]
    (Among 38 publications describing clinical features of terbinafine induced liver injury, 173 cases were analyzed but only 31 with jaundice, mean age of 54 years [range 24-75], mean latency to onset was 33 days [range 5-84], 3 patients died and 3 underwent liver transplantation; the authors conclude that routine monitoring of liver tests is not justified and is unlikely to be beneficial).
  • Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, et al.; International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology 2017; 152: 1078-89. [PMC free article: PMC5367948] [PubMed: 28043905]
    (A genome-wide association study done on 862 persons of European ancestry with drug induced liver injury demonstrated a highly significant association with a polymorphism on chromosome 6 which was a proxy for HLA-A* 33:01 and most strongly linked to cases of terbinafine, although also with fenofibrate, methyldopa and ticlopidine and possibly other drug causes of cholestatic injury).