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. Introduction
Terbinafine causes severe hepatotoxicity - Severe Drug Induced Liver Injury (DILI)
It is rare - estimated to occur in 1: to 1: 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

3. 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

4. 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.)

5. 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

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

8. 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

9. 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

10. 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)

11. 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

12. 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

13. 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

14. 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

15. 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

16. Thank you