Int J Clin Pharm (2014) 36:679–683 DOI 10.1007/s11096-014-9969-y
REVIEW ARTICLE
Systematic review of severe acute liver injury caused by terbinafine Jun Yan • Xiaolin Wang • Shengli Chen
Received: 6 November 2013 / Accepted: 4 June 2014 / Published online: 2 July 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background Terbinafine is an effective antimicrobial agent against dermatophytes, cryptococcus and other fungi. It is the preferred drug to treat onychomycosis. However, severe acute hepatitis from oral terbinafine administration has been recently reported. Aim To describe a representative case, and review the literature regarding the best evidence on treatment and prognosis of severe acute hepatitis caused by oral terbinafine. Methods The literature was searched for publications on severe hepatitis caused by terbinafine using MEDLINE, China Biology Medicine Disc, and the VIP Medical Information Resource System. Related references were searched manually. Results Seventeen English and three Chinese references of case reports were included after eliminating duplicate publications. No randomized control studies were found. Liver enzyme levels were found to have been increased significantly. Abdominal ultrasound demonstrated cholestasis. Conclusions Severe acute liver injury is a known, but unusual complication of terbinafine exposure. The prognosis is often good with appropriate treatment. Liver function assessment before treatment and periodic monitoring 4–6 weeks after initiation of treatment is recommended. Keywords Adverse reactions Hepatitis Systematic review Terbinafine
Impacts on practice •
•
Several case reports indicate that terbinafine can be associated with acute severe liver injury. But with appropriate treatment the prognosis is usually good. Clinicians should obtain liverfunction tests before and after initiation of treatment with terbinafine.
Introduction Terbinafine is an effective antimicrobial agent against dermatophytes, cryptococcus and other fungi. It is generally well-tolerated. Oral ingestion of the agent has been reported to cause liver damage, but this is uncommon with an estimated incidence of between 1/120,000 as reported by Hay et al. [1], and 1/45,000–1/54,000 according to Gupta et al. [2]. As of April 2001, the FDA had received reports of 16 cases of hepatic failure related to terbinafine including 11 deaths, 2 cases that required liver transplantation, and 8 cases of liver failure [3]. As of January 2008, the Australian monitoring committee on adverse drug reactions had received 722 reports on terbinafine including 3 cases of liver failure [4]. The package insert for the use of terbinafine in Japan was revised in 2004, to include a warning of the possibility of liver damage [5]. Reports of severe liver damage due to terbinafine in China have been rare.
J. Yan X. Wang Jinan City Hospital for Skin Diseases Prevention and Treatment, Jinan 250001, China
Aim of the study
S. Chen (&) Shandong Provincial Institute of Dermatology and Venereology, Shandong Acdemy of Medical Sciences, Jinan 250022, China e-mail: [email protected]
To describe a representative case, and to review the literature regarding the best evidence on treatment and prognosis of severe acute hepatitis caused by oral terbinafine.
123
680
Methods Inclusion criteria Patients with a recent history of oral terbinafine administration, and with signs or symptoms drug-induced liver damage. The primary outcomes were liver enzyme levels. Secondary outcomes were abdominal ultrasound and liver biopsy findings. Literature search A computer search of MEDLINE (1966–2012) was performed using the terms: terbinafine AND (hepatic injury OR injury of liver) with language limited to English. China Biology Medicine disc (CBM 1978–2012) and VIP medical information resource system (1989–2012) were searched with the terms: terbinafine AND (liver OR liver injury) with language limited to Chinese. Related references were searched manually. Data included clinical symptoms, laboratory tests, imaging, and therapy. Data extraction A meta-analysis model was used in this study, as reported previously by Moher et al. [6]. Two investigators assessed the quality of trials, independently. Any disagreements on validity assessment were resolved through discussion or consultation with the third author. Quality analysis of methodology was evaluated according to the Jadad scale, including randomization, blinding and discontinuation of medication. The Jadad scale scores ranged from 1 to 5, where 1 or 2 indicates poor in quality and 3–5 indicates high quality [7]. Case reports were included in accordance with the inclusion criteria. Statistical analysis Statistical analysis was performed with Review Manager Software (RevMan 5, Cochrane Collaboration). Heterogeneity of results between each trial was tested by the Chi squared test (p [ 0.1, I2 \ 50 %). Meta-analyses was done using the fixed effect model if there was no heterogeneity among subgroups. Otherwise, the randomized effect model was used. Comparison of the effects between the two groups was expressed by odds ratio (OR) and its 95 % confidence interval (95 % CI).
Int J Clin Pharm (2014) 36:679–683
daily, and developed anorexia and dark urine after 2 weeks of taking terbinafine. A diagnosis of terbinafine-induced hepatitis was made a month later. He denied a history of having other medications, alcohol consumption, previous hepatitis, tuberculosis or other infections. Physical examination revealed a body temperature of 36.8 C, pulse of 80 beats/min, respiratory rate of 20 per min, and blood pressure of 130/90 mmHg. The patient was conscious, and obviously jaundiced. There were no petechiae, ecchymoses, palmar erythema, spider nevi. The abdominal wall was soft without tenderness. The liver and spleen were not palpable and there was no shifting dullness. Laboratory tests revealed ALT 580 U/L (n \ 40), AST 324.7 U/L (n \ 40). ALB 40 G/L (n: 35-55), GGT 499.9 U/L (n \ 85), TBil 322.7 lmol/L (n \ 19), DBil 170.9 lmol/L (n \ 8), and IBil 151.8 lmol/L (n \ 12). Hepatitis A, B, C, D and E serologies were negative. The white cell count was 3.41 9 109/L (n range 4-10) with granulocytes at 53.40 % (n range 50–70 %) and lymphocytes at 29 % (n range 20–40 %). Abdominal ultrasound showed a normal liver with no abnormal densities, an obscure gall bladder, and a normal pancreas, spleen and kidneys. The common bile duct was 0.4 cm in diameter. A diagnosis of drug-induced hepatitis was made. The patient was started on hemodialysis, and was given an (unknown) oral medicine in a local hospital. After 12 days, he was transferred to a hospital specialized in the treatment of liver diseases, and was started on plasmapheresis. However, the effects were unsatisfactory, and liver transplantation was recommended. At the local hospital, liver transplantation was recommended. We recommended supportive therapy, not liver transplantation based on the searched evidence and the patient’s condition. The patient was given glycyrrhizin injections (Eisai China Inc.) injection 160 mg/d for 1 w, and oral ursodesoxycholic acid (Shanghai Sine Pharmaceutical Co. Ltd.) 0.15 g tid, and Wuzhi capsule (a traditional Chinese medicine schisandra alcohol extract) (Sichuan HYGIEN Pharmaceutical Co. Ltd.) at 0.5 g bid for 3 months. The patient improved, and the appetite and physical strength returned to normal. Results of laboratory tests were ALT 45 U/L, AST 29 U/L, ALB 39.6 G/L, GGT 332 U/L, TBil 35 lmol/L, and DBil 22.9 lmol/L. Followup 6 months after treatment revealed that all laboratory tests results had returned to normal. Search results
Results A representative case A 45 year-old man came to our hospital because of onychomycosis. He had been treated with 250 mg terbinafine
123
Thirty-one English references and four Chinese references were found, of which 14 were rejected because of lack of relation to the current problem. Inclusion was determined by reading the abstracts, and full texts of 21 studies. No randomized control studies were found. Finally, 17 English
Int J Clin Pharm (2014) 36:679–683
681
Table 1 Patient characteristics of previously reported cases of terbinafine hepatotoxicity Gender
ALT (U/1)
AST (U/1)
ALP (U/1)
c-glutamyltranspeptidase (U/1)
References
Patient Age
Bilirubin (lmol/l)
Lowe [8]
52
M
930
/
193
143
29
van’tWout [9]
63
M
194
82
440
201
182
52
F
446
136
296
/
124
Lazoros [10]
58
F
470
164
934
1,200
285
Dwyer [11]
40
M
165
/
256
215
95
Mallat [12]
75
F
227
242
375
321
89
Fernandes [13]
24
M
584
296
222
318
529
Gupta [2]
54
M
407
/
273
/
153
42
F
521
225
214
/
91
74
F
333
308
157
/
180
Gupta [14] Agarwal [15]
66 48
M F
154 /
147 /
72 /
/ /
9 /
Conjeevaram [16]
63
M
1,073
/
597
/
79
Chambers [17]
41
M
49
124
568
/
583
Ajit [18]
65
M
313
179
1,040
/
188
Agca [19]
56
F
425
676
384
406
340
244
18.8
Xin [20]
73
M
267
Lv [21]
49
F
500
/
290
/
/
Perveze [22]
50
M
225
584
874
/
Kim [23]
61
M
Paredes [24]
57
M
376
219
564
/
1,044
1,282
/
Gendre [25]
55
/
101
F
461
257
393
1,313
422
Jing [26] This case
44
M
102.7
24.6
/
/
156.5
45
M
580
324.7
1,158
499.9
ALT Alanine aminotransferase, AST aspartate aminotransferase, ALP alkaline phosphatase
and 3 Chinese references of case reports were included after eliminating duplicate publications. Characteristics of selected tests Clinical symptoms, laboratory test results are shown in Table 1. The literature showed that liver injury caused by terbinafine has been reported to involve usually in patients above the age of 40 years of age [2, 8–26]. Patients with terbinafine-induced hepatitis recovered after withdrawal of the agent without additional treatment if the duration of exposure had been less than 2 weeks [8, 16, 21, 23]. Patients who took the terbinafine for over 3 weeks have been reported to require medical treatment in order to have a good outcome [12, 17–20]. Only two patients required liver transplantation, one took the terbinafine for 3 months [22], the other took three medications including terfinabine [15].
Discussion The incidence of oral terbinafine-induced serious liver damage is very low. Previous meta-analyses and systematic
reviews [31–39] mainly reported on the efficacy and cost of oral terbinafine. Some RCTs reported that terbinafine could affect the liver causing enzyme elevations, and abnormal liver function [27–30]. Follow up after early withdrawal of drug showed no further development of severe liver damage. In order to obtain information on adverse reactions, specific test results had to be searched such as liver enzyme levels, and liver function abnormalities. Most cases recovered after discontinuation of the drug, and/or medical treatment. There were no reports of serious chronic liver damage. Only two patients required liver transplantation, one had been exposed to terfinabine for [3 mo, the other took the combination of three medications including terfinabine. While the timing and clinical picture appear to be most consistent with terbinafine-induced liver damage, other etiologies are possible. These include other medications not reported by the patient, or infection by an undetected virus. In Europe, the package insert for terbinafine states clearly that hepatotoxicity may occur in patients with and without pre-existing liver disease. Therefore, periodic monitoring (after 4–6 weeks of treatment) of liver function is recommended. Terbinafine tablets should be immediately
123
682
Int J Clin Pharm (2014) 36:679–683
discontinued in case of elevation of liver tests. In the Chinese package insert for terbinafine, it is stated that cases of liver dysfunction may occur very rarely, but a causal association with the intake of terbinafine tablets is uncertain. Our research and the current case report supports the association of terfinabine administration with acute severe liver damage, and the package insert recommendations that liver function assessment be performed before treatment and 4–6 weeks after treatment.
Conclusions Oral terbinafine is a known cause acute liver injury. Individuals who are [40 years old treated with terfinabine for 3–4 weeks were at highest risk. There are no reports of randomized controlled trials which somewhat reduces the credibility of the results. Acknowledgments Lei CUI, Xiaodan LV: Jinan Infectious Disease Hospital, Liver Disease Diagnosis and Treatment Center of Shandong Province, Jinan, 250013 China. Funding
No funding was received to support this work.
Conflicts of interest
The authors have no conflicts of interest.
References 1. Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol. 1993;29:S50–4. 2. Gupta AK, del Rosso JQ, Lynde CW, Brown GH, Shear NH. Hepatitis associated with terbinafine therapy: three case reports and a review of the literature. Clin Exp Dermatol. 1998;23:64–7. 3. Itraconazole, terbinafine possibly linked to liver failure. Am J Health Syst Pharm. 2001; 58: 1076. 4. Hepatic reactions with terbinafine. Aust Adverse Drug React Bull. 2008;27:2. 5. Xiao Z, Yanqing LI. Japan revised terbinafinewarning. Chin Pharmacist. 2004;7:479. 6. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 7. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. 8. Lowe G, Green C, Jennings P. Hepatitis associated with terbinafine treatment. BMJ. 1993;306:248. 9. van ‘t Wout JW, Herrmann WA, De Vries RA, Stricker BH. Terbinafine-associated hepatic injury. J Hepatol. 1994;21:115–7. 10. Lazaros GA, Papatheodoridis GV, Delladetsima JK, Tassopoulos NC. Terbinafine-induced cholestatic liver disease. J Hepatol. 1996;24:753–6. 11. Dwyer CM, White MI, Sinclair TS. Cholestatic jaundice due to terbinafine. Br J Dermatol. 1997;136:976–7. 12. Mallat A, Zafrani ES, Metreau JM, Dhumeaux D. Terbinafineinduced prolonged cholestasis with reduction of interlobular bile ducts. Dig Dis Sci. 1997;42:1486–8.
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13. Fernandes NF, Geller SA, Fong TL. Terbinafine hepatotoxicity: case report and review of the literature. Am J Gastroenterol. 1998;93:459–60. 14. Gupta AK, Porges AJ. Hypersensitivity syndrome reaction to oral terbinafine. Australas J Dermatol. 1998;39(3):171–2. 15. Agarwal K, Manas DM, Hudson M. Terbinafine and fulminant hepatic failure. N Engl J Med. 1999;340:1292–3. 16. Conjeevaram G, Vongthavaravat V, Sumner R, Koff RS. Terbinafine-induced hepatitis and pancytopenia. Dig Dis Sci. 2001;46:1714–6. 17. Chambers WM, Millar A, Jain S, Burroughs AK. Terbinafineinduced hepatic dysfunction. Eur J Gastroenterol Hepatol. 2001;13:1115–8. 18. Ajit C, Suvannasankha A, Zaeri N, Munoz SJ. Terbinafineassociated hepatotoxicity. Am J Med Sci. 2003;32:292–5. 19. Agca E, Akcay A, Simsek H. Ursodeoxycholic acid for terbinafine-induced toxic hepatitis. Ann Pharmacother. 2004;38:1088–9. 20. Xin S. Terbinafine hydrochloride caused by drug hepatic damage. Clin Med Chin. 2004;20:515. 21. Xiaoqin LV, Zhang X. Terbinafine cause cholestasis hepatitis one case. Herald Med. 2006;25:593. 22. Perveze Z, Johnson MW, Rubin RA, Sellers M, Zayas C, Jones JL, et al. Terbinafine-induced hepatic failure requiring liver transplantation. Liver Transpl. 2007;13:162–4. 23. Kim BS, Jang HS, Jwa SW, Jang BS, Kim MB, Oh CK, et al. Generalized pustular psoriasis and hepatic dysfunction associated with oral terbinafine therapy. J Korean Med Sci. 2007;22:167–9. 24. Paredes AH, Lewis JH. Terbinafine-induced acute autoimmune hepatitis in the setting of hepatitis B virus infection. Ann Pharmacother. 2007;41:880–4. 25. Gendre G, Buclin T, Morard I, Fontannaz J, Berney JL. Terbinafine induced hepatitis with persistent cholestasis. Rev Med Suisse. 2008;4:736–9. 26. Jing B, Yang Y. Terbinafine cause cholestasis hepatitis. ADRJ. 2008;10:284. 27. Tausch I, Bra¨utigam M, Weidinger G, Jones TC. Evaluation of 6 weeks treatment of terbinafine in tinea unguium in a doubleblind trial comparing 6 and 12 weeks therapy. The Lagos V Study Group. Br J Dermatol. 1997;136(5):737–42. 28. Gupta AK, Lynde CW, Konnikov N. Single-blind, randomized, prospective study of sequential itraconazole and terbinafine pulse compared with terbinafine pulse for the treatment of toenail onychomycosis. J Am Acad Dermatol. 2001;44(3):485–91. 29. Baran R, Feuilhade M, Combernale P, Datry A, Goettmann S, Pietrini P, et al. A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycoses affecting the matrix region. Br J Dermatol. 2000;142(6):1177–83. 30. De Backer M, De Vroey C, Lesaffre E, Scheys I, De Keyser P. Twelve weeks of continuous oral therapy for toenail onychomycosis caused by dermatophytes: a double-blind comparative trial of terbinafine 250 mg/day versus itraconazole 200 mg/day. J Am Acad Dermatol. 1998;38(5 Pt 3):S57–63. 31. 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. 32. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004;150:537–44. 33. Krob AH, Fleischer AB Jr, D’Agostino R Jr, Feldman SR. Terbinafine is more effective than itraconazole in treating toenail onychomycosis: results from a meta-analysis of randomized controlled trials. J Cutan Med Surg. 2003;7:306–11. 34. Casciano J, Amaya K, Doyle J, Arikian S, Shear N, Haspel M, Kahler K. Economic analysis of oral and topical therapies for
Int J Clin Pharm (2014) 36:679–683 onychomycosis of the toenails and fingernails. Manag Care. 2003;12:47–54. 35. Haugh M, Helou S, Boissel JP, Cribier BJ. Terbinafine in fungal infections of the nails: a meta-analysis of randomized clinical trials. Br J Dermatol. 2002;147:118–21. 36. Gupta AK. Treatment of dermatophyte toenail onychomycosis in the United States. A pharmacoeconomic analysis. J Am Podiatr Med Assoc. 2002;92:272–86.
683 37. Gupta AK, Lambert J. Pharmacoeconomic analysis of the new oral antifungal agents used to treat toenail onychomycosis in the USA. Int J Dermatol. 1999;38:S53–64. 38. De Doncker P. Itraconazole and terbinafine in perspective: from petri dish to patient. J Eur Acad Dermatol Venereol. 1999;12:S10–6. 39. Marchetti A, Piech CT, McGhan WF, Neugut AI, Smith BT. Pharmacoeconomic analysis of oral therapies for onychomycosis: a US model. Clin Ther. 1996;18:757–77.
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REVIEW ARTICLE
Systematic review of severe acute liver injury caused by terbinafine Jun Yan • Xiaolin Wang • Shengli Chen
Received: 6 November 2013 / Accepted: 4 June 2014 / Published online: 2 July 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background Terbinafine is an effective antimicrobial agent against dermatophytes, cryptococcus and other fungi. It is the preferred drug to treat onychomycosis. However, severe acute hepatitis from oral terbinafine administration has been recently reported. Aim To describe a representative case, and review the literature regarding the best evidence on treatment and prognosis of severe acute hepatitis caused by oral terbinafine. Methods The literature was searched for publications on severe hepatitis caused by terbinafine using MEDLINE, China Biology Medicine Disc, and the VIP Medical Information Resource System. Related references were searched manually. Results Seventeen English and three Chinese references of case reports were included after eliminating duplicate publications. No randomized control studies were found. Liver enzyme levels were found to have been increased significantly. Abdominal ultrasound demonstrated cholestasis. Conclusions Severe acute liver injury is a known, but unusual complication of terbinafine exposure. The prognosis is often good with appropriate treatment. Liver function assessment before treatment and periodic monitoring 4–6 weeks after initiation of treatment is recommended. Keywords Adverse reactions Hepatitis Systematic review Terbinafine
Impacts on practice •
•
Several case reports indicate that terbinafine can be associated with acute severe liver injury. But with appropriate treatment the prognosis is usually good. Clinicians should obtain liverfunction tests before and after initiation of treatment with terbinafine.
Introduction Terbinafine is an effective antimicrobial agent against dermatophytes, cryptococcus and other fungi. It is generally well-tolerated. Oral ingestion of the agent has been reported to cause liver damage, but this is uncommon with an estimated incidence of between 1/120,000 as reported by Hay et al. [1], and 1/45,000–1/54,000 according to Gupta et al. [2]. As of April 2001, the FDA had received reports of 16 cases of hepatic failure related to terbinafine including 11 deaths, 2 cases that required liver transplantation, and 8 cases of liver failure [3]. As of January 2008, the Australian monitoring committee on adverse drug reactions had received 722 reports on terbinafine including 3 cases of liver failure [4]. The package insert for the use of terbinafine in Japan was revised in 2004, to include a warning of the possibility of liver damage [5]. Reports of severe liver damage due to terbinafine in China have been rare.
J. Yan X. Wang Jinan City Hospital for Skin Diseases Prevention and Treatment, Jinan 250001, China
Aim of the study
S. Chen (&) Shandong Provincial Institute of Dermatology and Venereology, Shandong Acdemy of Medical Sciences, Jinan 250022, China e-mail: [email protected]
To describe a representative case, and to review the literature regarding the best evidence on treatment and prognosis of severe acute hepatitis caused by oral terbinafine.
123
680
Methods Inclusion criteria Patients with a recent history of oral terbinafine administration, and with signs or symptoms drug-induced liver damage. The primary outcomes were liver enzyme levels. Secondary outcomes were abdominal ultrasound and liver biopsy findings. Literature search A computer search of MEDLINE (1966–2012) was performed using the terms: terbinafine AND (hepatic injury OR injury of liver) with language limited to English. China Biology Medicine disc (CBM 1978–2012) and VIP medical information resource system (1989–2012) were searched with the terms: terbinafine AND (liver OR liver injury) with language limited to Chinese. Related references were searched manually. Data included clinical symptoms, laboratory tests, imaging, and therapy. Data extraction A meta-analysis model was used in this study, as reported previously by Moher et al. [6]. Two investigators assessed the quality of trials, independently. Any disagreements on validity assessment were resolved through discussion or consultation with the third author. Quality analysis of methodology was evaluated according to the Jadad scale, including randomization, blinding and discontinuation of medication. The Jadad scale scores ranged from 1 to 5, where 1 or 2 indicates poor in quality and 3–5 indicates high quality [7]. Case reports were included in accordance with the inclusion criteria. Statistical analysis Statistical analysis was performed with Review Manager Software (RevMan 5, Cochrane Collaboration). Heterogeneity of results between each trial was tested by the Chi squared test (p [ 0.1, I2 \ 50 %). Meta-analyses was done using the fixed effect model if there was no heterogeneity among subgroups. Otherwise, the randomized effect model was used. Comparison of the effects between the two groups was expressed by odds ratio (OR) and its 95 % confidence interval (95 % CI).
Int J Clin Pharm (2014) 36:679–683
daily, and developed anorexia and dark urine after 2 weeks of taking terbinafine. A diagnosis of terbinafine-induced hepatitis was made a month later. He denied a history of having other medications, alcohol consumption, previous hepatitis, tuberculosis or other infections. Physical examination revealed a body temperature of 36.8 C, pulse of 80 beats/min, respiratory rate of 20 per min, and blood pressure of 130/90 mmHg. The patient was conscious, and obviously jaundiced. There were no petechiae, ecchymoses, palmar erythema, spider nevi. The abdominal wall was soft without tenderness. The liver and spleen were not palpable and there was no shifting dullness. Laboratory tests revealed ALT 580 U/L (n \ 40), AST 324.7 U/L (n \ 40). ALB 40 G/L (n: 35-55), GGT 499.9 U/L (n \ 85), TBil 322.7 lmol/L (n \ 19), DBil 170.9 lmol/L (n \ 8), and IBil 151.8 lmol/L (n \ 12). Hepatitis A, B, C, D and E serologies were negative. The white cell count was 3.41 9 109/L (n range 4-10) with granulocytes at 53.40 % (n range 50–70 %) and lymphocytes at 29 % (n range 20–40 %). Abdominal ultrasound showed a normal liver with no abnormal densities, an obscure gall bladder, and a normal pancreas, spleen and kidneys. The common bile duct was 0.4 cm in diameter. A diagnosis of drug-induced hepatitis was made. The patient was started on hemodialysis, and was given an (unknown) oral medicine in a local hospital. After 12 days, he was transferred to a hospital specialized in the treatment of liver diseases, and was started on plasmapheresis. However, the effects were unsatisfactory, and liver transplantation was recommended. At the local hospital, liver transplantation was recommended. We recommended supportive therapy, not liver transplantation based on the searched evidence and the patient’s condition. The patient was given glycyrrhizin injections (Eisai China Inc.) injection 160 mg/d for 1 w, and oral ursodesoxycholic acid (Shanghai Sine Pharmaceutical Co. Ltd.) 0.15 g tid, and Wuzhi capsule (a traditional Chinese medicine schisandra alcohol extract) (Sichuan HYGIEN Pharmaceutical Co. Ltd.) at 0.5 g bid for 3 months. The patient improved, and the appetite and physical strength returned to normal. Results of laboratory tests were ALT 45 U/L, AST 29 U/L, ALB 39.6 G/L, GGT 332 U/L, TBil 35 lmol/L, and DBil 22.9 lmol/L. Followup 6 months after treatment revealed that all laboratory tests results had returned to normal. Search results
Results A representative case A 45 year-old man came to our hospital because of onychomycosis. He had been treated with 250 mg terbinafine
123
Thirty-one English references and four Chinese references were found, of which 14 were rejected because of lack of relation to the current problem. Inclusion was determined by reading the abstracts, and full texts of 21 studies. No randomized control studies were found. Finally, 17 English
Int J Clin Pharm (2014) 36:679–683
681
Table 1 Patient characteristics of previously reported cases of terbinafine hepatotoxicity Gender
ALT (U/1)
AST (U/1)
ALP (U/1)
c-glutamyltranspeptidase (U/1)
References
Patient Age
Bilirubin (lmol/l)
Lowe [8]
52
M
930
/
193
143
29
van’tWout [9]
63
M
194
82
440
201
182
52
F
446
136
296
/
124
Lazoros [10]
58
F
470
164
934
1,200
285
Dwyer [11]
40
M
165
/
256
215
95
Mallat [12]
75
F
227
242
375
321
89
Fernandes [13]
24
M
584
296
222
318
529
Gupta [2]
54
M
407
/
273
/
153
42
F
521
225
214
/
91
74
F
333
308
157
/
180
Gupta [14] Agarwal [15]
66 48
M F
154 /
147 /
72 /
/ /
9 /
Conjeevaram [16]
63
M
1,073
/
597
/
79
Chambers [17]
41
M
49
124
568
/
583
Ajit [18]
65
M
313
179
1,040
/
188
Agca [19]
56
F
425
676
384
406
340
244
18.8
Xin [20]
73
M
267
Lv [21]
49
F
500
/
290
/
/
Perveze [22]
50
M
225
584
874
/
Kim [23]
61
M
Paredes [24]
57
M
376
219
564
/
1,044
1,282
/
Gendre [25]
55
/
101
F
461
257
393
1,313
422
Jing [26] This case
44
M
102.7
24.6
/
/
156.5
45
M
580
324.7
1,158
499.9
ALT Alanine aminotransferase, AST aspartate aminotransferase, ALP alkaline phosphatase
and 3 Chinese references of case reports were included after eliminating duplicate publications. Characteristics of selected tests Clinical symptoms, laboratory test results are shown in Table 1. The literature showed that liver injury caused by terbinafine has been reported to involve usually in patients above the age of 40 years of age [2, 8–26]. Patients with terbinafine-induced hepatitis recovered after withdrawal of the agent without additional treatment if the duration of exposure had been less than 2 weeks [8, 16, 21, 23]. Patients who took the terbinafine for over 3 weeks have been reported to require medical treatment in order to have a good outcome [12, 17–20]. Only two patients required liver transplantation, one took the terbinafine for 3 months [22], the other took three medications including terfinabine [15].
Discussion The incidence of oral terbinafine-induced serious liver damage is very low. Previous meta-analyses and systematic
reviews [31–39] mainly reported on the efficacy and cost of oral terbinafine. Some RCTs reported that terbinafine could affect the liver causing enzyme elevations, and abnormal liver function [27–30]. Follow up after early withdrawal of drug showed no further development of severe liver damage. In order to obtain information on adverse reactions, specific test results had to be searched such as liver enzyme levels, and liver function abnormalities. Most cases recovered after discontinuation of the drug, and/or medical treatment. There were no reports of serious chronic liver damage. Only two patients required liver transplantation, one had been exposed to terfinabine for [3 mo, the other took the combination of three medications including terfinabine. While the timing and clinical picture appear to be most consistent with terbinafine-induced liver damage, other etiologies are possible. These include other medications not reported by the patient, or infection by an undetected virus. In Europe, the package insert for terbinafine states clearly that hepatotoxicity may occur in patients with and without pre-existing liver disease. Therefore, periodic monitoring (after 4–6 weeks of treatment) of liver function is recommended. Terbinafine tablets should be immediately
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discontinued in case of elevation of liver tests. In the Chinese package insert for terbinafine, it is stated that cases of liver dysfunction may occur very rarely, but a causal association with the intake of terbinafine tablets is uncertain. Our research and the current case report supports the association of terfinabine administration with acute severe liver damage, and the package insert recommendations that liver function assessment be performed before treatment and 4–6 weeks after treatment.
Conclusions Oral terbinafine is a known cause acute liver injury. Individuals who are [40 years old treated with terfinabine for 3–4 weeks were at highest risk. There are no reports of randomized controlled trials which somewhat reduces the credibility of the results. Acknowledgments Lei CUI, Xiaodan LV: Jinan Infectious Disease Hospital, Liver Disease Diagnosis and Treatment Center of Shandong Province, Jinan, 250013 China. Funding
No funding was received to support this work.
Conflicts of interest
The authors have no conflicts of interest.
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