1. 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

2. Dr Owen Kramer

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. Results

10. Results
38 papers fulfilled the inclusion criteria with reports of 69 symptomatic patients
Mean duration of terbinafine treatment until onset of symptoms was 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 and 16 days, respectively, (range of ) until seeking medical attention

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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)

18. Call for correspondence
Why not join the debate on this article through our correspondence section?
Rapid responses should not exceed 350 words, four references and one figure
Further details can be found here