Clinical presentation of terbinafine-induced severe liver injury and the value of laboratory monitoring: a critically appraised topic O.N. Kramer BS;1 J. Albrecht MD, PhD2,3 1Medical School, University of Illinois, Chicago, Illinois, USA 2Division of Dermatology, Department of Medicine, J.H. Stroger Hospital of Cook County, Chicago, Illinois, USA 3Department of Dermatology, Rush Medical College, Chicago, Illinois, USA

Introduction Terbinafine causes severe hepatotoxicity - Severe Drug Induced Liver Injury (DILI) It is rare - estimated to occur in 1:50.000 to 1:120.000 prescription Usually within the first 4-6 weeks Idiosyncratic, i.e. are neither predictable nor preventable Transient liver function tests (LFTs) abnormality occur in 1% of patients Etiology is unclear

Introduction II LFTs are recommended at the beginning of terbinafine therapy by the FDA and the British National Formulary (BNF) Only the BNF recommends them every 4-6 weeks during therapy. Characteristics of monitoring tests Needs to be practical Needs to have impact on outcome Needs to identify problems before they are clinically obvious If it does neither, it has no utility Goal was to characterize the clinical presentation of DILI in patients on terbinafine, and to evaluate whether monitoring can be done effectively

Literature search Based on the Liver Tox database of the NIH In addition search of EMBASE and MEDLINE, via PUBMED From origin to 4 April 2016. Any relevant papers identified through the references of collected articles were included through hand search All papers were reviewed by two reviewers (O.K., J.A.)

Selection criteria Papers were screened based on abstract and title Abstracts only were excluded for lack of clinical details All potentially relevant papers were reviewed in full No restrictions on language We included all reports of hepatic dysfunction if they described clinical symptoms, and/or physical findings, or explicitly described the patients as asymptomatic

Results 38 papers - 173 cases of terbinafine DILI - 69 cases with clinical details – often incomplete Dose of terbinafine 250mg daily for all

Results II Mean time until sx 30 days (range 5 – 84 days, n=33) 84 days (12 weeks) - had normal LFTS at week 9 Number of patients Duration of therapy until onset of symptoms in days

Results III Mean 15 days of sx until medical attention (range of 0 – 42 days) Did not include outlier who saw MD after 2 years Jaundice and d/c terbinafine Jaundice subsided, but pruritus persisted

Ascites(n=1), Confusion (n=1), Back pain(n=1) Results IV Symptom(s)* Usually combination n = Jaundice and/or icterus 31 Flu-like symptoms (including fatigue, malaise, myalgias, arthralgias, and anorexia) 30; (anorexia n=14) No listing of specific symptoms provided 22 Dark urine Pruritus 16 Nausea and/or vomiting 12 Acholic stools 9 Abdominal pain and/or discomfort including diarrhea 10 Weight loss 5 Palmar erythema Other symptoms Ascites(n=1), Confusion (n=1), Back pain(n=1)

Discussion DILI is dangerous Rapidly evolving Universally symptomatic Minimum 5 days based on the cases Universally symptomatic Generalized pruritus was common Life threatening Estimated 10% need liver transplant, or die

Discussion II Clusters in the first 6 weeks of treatment At 4 weeks more than half of the patients were clinically sick At 6 weeks the overwhelming majority were symptomatic With minimum of 5 day (even 10 day) time from normal labs to open DILI there is no good time point to monitor Patients took in average of 2 weeks to see physicians after symptoms developed – a number of them for scheduled visits Monitoring visits may give wrong sense of security Monitoring for DILI is controversial at best FDA does not recommend for terbinafine Did not work when recommended for troglitazone

Limitations Serious underreporting in literature Even FDA has likely only 10% of the cases and had more transplants and death in 2001, than we saw in the literature 2017 But 6 of 69 of the patients with severe DILI in our series, died or needed transplant About the number expected, suggesting representative sample Our recommendations are the same as the FDA has made based on their data this is about the proportion of patients who are expected to have poor outcome based on a finding of substantial ALT elevation concurrently with bilirubin >2xULN

Conclusion: There is no good time point for monitoring patients on terbinafine 4-6 weeks makes no sense At 4 weeks the majority is clinically sick – labs are useless At 6 weeks most everyone is sick DILI may take only 5 days thus between 4 and 6 weeks patients may either be healthy, or be waiting for transplant

Conclusion: Baseline labs may be helpful to assess LFTs, and diagnose Gilbert’s disease (elevated bili) Warn patients about symptoms of DILI Sx to warn about are abdominal discomfort, yellow eyes, nausea and malaise as well as generalized itch Tell them to stop therapy and see MD

Thank you