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

Dr Owen Kramer

Introduction What’s already known? Terbinafine induced hepatotoxicity is a rare idiosyncratic event Severe, usually idiosyncratic drug-induced liver injury (DILI) due to terbinafine is universally symptomatic and can lead to liver transplantation and death Liver function tests (LFTs) are recommended at the beginning of terbinafine therapy by the Food and Drug Administration (FDA) and the British National Formulary (BNF), but only the BNF recommends them every 4-6 weeks during therapy

Introduction What’s already known? Terbinafine causes severe hepatotoxicity - Severe DILI Occurs in 1:50,000 to 1:120,000 prescriptions Usually within the first 4-6 weeks Idiosyncratic, i.e. neither predictable nor preventable Transient LFTs abnormality occur in 1% of patients Aetiology unclear

Methods CASE SCENARIO A 47-year-old healthy male patient without significant past medical history desires treatment for Periodic acid-Schiff (PAS) confirmed onychomycosis He lives far from the clinic, does not have sick days, and wonders whether laboratory monitoring of liver function tests is necessary during terbinafine treatment

Methods Clinical Question: Can terbinafine therapy be safely monitored with clinical observation only, rather than with laboratory testing? Objective: Evaluate the symptoms of published cases of terbinafine associated severe DILI (Drug Induced Liver Injury) to assess the utility of laboratory monitoring

Methods Data sources: Study selection: Data extraction: Liver Tox database of the National Institute of Health, PUBMED and EMBASE Hand search of references of the papers identified Study selection: All reports of patients with DILI on terbinafine and reported clinical symptoms, or absence thereof Data extraction: Two reviewers assessed articles for eligibility of inclusion, collected and evaluated the data

Methods Data extracted on to a standard proforma on Study design, sample size, and the number of hepatotoxic events reported in the article For each event the following data was recorded Gender, age, dosage, symptoms, duration of therapy until symptom onset, duration of symptoms until seeking medical attention, duration of symptoms until discontinuing drug and/or receiving an intervention, intervention received, lab abnormalities, physical exam findings, follow up, and outcome

Results

Results 38 papers fulfilled the inclusion criteria with reports of 69 symptomatic patients Mean duration of terbinafine treatment until onset of symptoms was 30.20 days (range 5 – 84) Symptoms in order of frequency were jaundice, flu-like symptoms, dark urine, and pruritus Patients experienced symptoms for a mean and median of 14.78 and 16 days, respectively, (range of 0 -42) until seeking medical attention

Mean time until sx 30 days (range 5 – 84 days, n=33) Results 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

Ascites(n=1), Confusion (n=1), Back pain(n=1) Symptom(s)* Usually combination n = Jaundice and/or icterus 31 Flu-like symptoms (including fatigue, malaise, myalgia, 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) Results

Discussion Majority affected in the first 6 weeks of treatment At 4 weeks over half of the patients were clinically sick At 6 weeks the majority were symptomatic With a minimum of 5 days from normal investigations to DILI there is no good time point to monitor Patients took an average of 2 weeks to see physicians after symptoms developed – a number of them for scheduled visits Monitoring visits may confer a false sense of security Monitoring for DILI is controversial FDA does not recommend for terbinafine

Limitations Serious underreporting in literature Only 10% cases are reported More transplants and deaths reported in 2001, than in the literature in 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: Baseline monitoring may be helpful to assess LFTs, and diagnose Gilbert’s syndrome Warn patients about symptoms of DILI Abdominal discomfort Yellow eyes Nausea Malaise Generalized itch Tell patients to stop therapy and seek medical attention

Discussion What does this study add? No reports of terbinafine induced liver injury in an asymptomatic patient identified through laboratory screening A number of patients did not seek medical attention and continued treatment until routine clinical visits were due in spite of significant clinical symptoms Based on our data, we could not identify a specific time point for laboratory monitoring that would not miss the majority of patients, or be at a point when affected patients are already systemically unwell

Discussion What does this study add? All reported cases of terbinafine-induced hepatotoxicity were clinically symptomatic, most commonly presenting with jaundice, flu-like symptoms, abdominal discomfort, and pruritus Laboratory monitoring is not safe, if it conveys the belief to patients that it has clinical utility and is protective of symptomatic Drug Induced Liver Injury (DILI)

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