This document summarizes key factors related to drug rechallenge following drug-induced liver injury (DILI). It finds that nearly 50 drugs are associated with positive rechallenge, defined as ALT levels 3-5x upper limits of normal. Drugs that cause mitochondrial impairment or immunoallergic injury in vitro have higher positive rechallenge rates, as do those with a daily dose over 50mg. Personal factors like genetics and environment also influence outcomes. Drugs associated with DILI in clinical trials tend to have higher ALT elevations than placebos. While rechallenge carries risks, it may be considered for critical medications if alternatives are unavailable and patients can be closely monitored. More data is still needed to better understand outcomes and identify re

1. HEP-16-2338: Drug Rechallenge Following Drug-Induced Liver Injury
Christine M. Hunt, MD MPH1,2
Julie I. Papay, PharmD,3
Vid Stanulovic, MD,4,5
Arie Regev, MD6
1
Department of Medicine, Duke University Medical Center, Durham, NC
2
Durham Veterans Administration Medical Center, Durham, NC; email:
Christine.Hunt@va.gov
3
Global Patient Safety, UCB BioSciences, Research Triangle Park, NC; email:
Julie.Papay@ucb.com
4
Accelsiors Clinical Research Organization and Consultancy, Budapest, Hungary; email:
Vid.Stanulovic@gmail.com
5
Semmelweis University School of Pharmacy, Budapest, Hungary
6
Global Patient Safety, Eli Lilly and Company, Indianapolis, IN; email:
REGEV_ARIE@LILLY.COM
Correspondence to: Christine M. Hunt, M.D., M.P.H.
Adjunct Associate Professor of Medicine, Duke University
00550 Hospital South
Durham, NC 27710
Email: Christine.Hunt@va.gov
Phone: 919-389-9617
FAX: 919-416-5839
Conflict of Interest Statement: Christine M. Hunt has received consultancy fees from
Otsuka and Furiex. Julie I. Papay was employed at UCB Biosciences during manuscript
preparation. Vid Stanulovic is employed at Accelsiors Clinical Research Organization and
Consultancy, Budapest, Hungary. Arie Regev is employed at Eli Lilly and Company. The
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/hep.29152
This article is protected by copyright. All rights reserved.

2. 2
views expressed in this paper are those of the authors and do not necessarily represent the
policies or position of, nor imply endorsement from, the FDA, Department of Veterans Affairs,
or U.S. Government.
Sponsor: None (there was no external funding source).
Word Count: 2900
Key Words: hepatotoxicity, immunoallergic, mitochondrial dysfunction, toxicity assessment,
benefit: risk assessment
Prior Data Postings:
1) Data was shared at the March 23 2016 FDA : Critical Path Institute Drug-Induced Liver
Injury Conference XVI in Hyattsville MD. Conference proceedings are posted at AASLD.org
2) Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug
rechallenge after drug‐induced liver injury: A systematic review. Hepatol 2010;52:2216-2222.
Abbreviations: bile salt export pump (BSEP); drug-induced liver injury (DILI); IC50:
concentration of an inhibitor which reduces the rate of an enzymatic reaction by 50%;
Institutional Review Board (IRB); times upper limits of normal (xULN)
Authors’ contributions (all authors can attest to the intellectual content of the paper):
Christine M. Hunt: FDA meeting speaker and discussant, drafted and prepared manuscript
Julie I. Papay: FDA meeting speaker and discussant, manuscript preparation and review
Vid Stanulovic: FDA meeting speaker and discussant, manuscript review
Arie Regev: FDA meeting co-chair and discussant, manuscript review
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Abstract (254 words)
Drug induced hepatocellular injury is identified internationally by ALT 5x upper limits normal
(ULN) appearing within 3 months of drug initiation, after alternative causes are excluded.
Upon withdrawing the suspect drug, ALT generally decreases by 50% or more. With drug
readministration, a positive rechallenge has recently been defined by an ALT 3-5xULN or
greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver
injury (DILI): antimicrobials, central nervous system, cardiovascular and oncology
therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk
factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials,
immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors
interact with personal genetic, immune, and metabolic factors to influence positive
rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is
associated with up to 13% mortality in prospective series of all prescribed drugs. In recent
oncology trials, standardized systems enable safer drug rechallenge with weekly liver
chemistry monitoring during the high risk period and exclusion of patients with
hypersensitivity. Yet, high positive rechallenge rates with other innovative therapeutics
suggest caution with rechallenge of high risk drugs.
Conclusion: For critical medicines, drug rechallenge may be appropriate, when no safer
alternatives are available, the objective benefit exceeds the risk, and patients are fully
informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To
better understand rechallenge outcomes and identify key risk factors for positive rechallenge,
additional data is needed from controlled clinical trials, prospective registries, and large
healthcare databases.
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Introduction
Drug-induced liver injury (DILI) remains a key cause of death from acute liver failure.(1),(2)
In a prospective US registry, 3% of those with drug-induced liver injury progressed to liver-
related death, 4% to liver transplant, and 17% of patients developed chronic liver injury (3).
Up to 5% of patients with drug-induced liver injury also suffer Stevens-Johnson
Syndrome/Toxic Epidermal Necrolysis, with 36% mortality (attributed to anti-epileptic,
antimicrobial, and antiretroviral drugs).(4)
DILI is a common cause of hepatic injury identified by liver chemistry elevations, temporally
related to the initiation and cessation of the suspect drug.(5-8) Serious DILI is most
commonly hepatocellular and is the focus of this review. Hepatocellular DILI is characterized
by predominant ALT elevations of 5 times upper limits normal (xULN) (5, 7), appearing within
90 days of suspect drug initiation, which decrease by half or more within one month of drug
cessation.(5, 6, 8) DILI is further affirmed by excluding other causes (e.g. viral hepatitis,
biliary obstruction, alcoholic hepatitis, or hypotension), reports of suspect drug hepatotoxicity,
and liver injury recurrence upon rechallenge (or readministration) of the suspect drug – which
has traditionally been strongly discouraged (Figure 1).(5, 6, 9) DILI may be misidentified in
clinical practice, with nearly half of DILI reports not representing DILI on expert review.(10)
Designed for clinicians, internationally agreed scoring systems identify the likelihood of DILI
as highly probable, probable, possible, unlikely or excluded – by tallying DILI findings.(5, 6, 8)
Following DILI, most patients fully recover when the suspect medication is stopped. When
liver chemistries normalize with drug cessation, this “positive dechallenge” suggests liver
injury resolution and may implicate the suspect drug in the initial liver injury (Figure 1).(5)
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Following a positive dechallenge, patients receiving benefit from a critical or life-saving
medicine may be considered for drug rechallenge. Increasingly, drug rechallenge has been
incorporated into controlled clinical trials of critical therapeutics. Recent prospective clinical
studies examining hundreds of rechallenge events currently define a positive drug
rechallenge as an ALT 3-5xULN or greater, which generally occurs much more rapidly than
the initial drug-induced liver injury(11-13). This new definition of positive rechallenge has
largely replaced an earlier historic definition of ALT doubling for hepatocellular injury,
empirically defined in 77 cases, which has not been further substantiated (9).
High Risks in Drug Rechallenge
In comparison to the initial DILI, drug rechallenge is associated with even greater risks. For
example, among those rechallenged with halothane within one month of halothane re-
exposure, nearly half died (Figure 2).(14) This resulted in the markedly decreased use of
halothane and a heightened awareness of drug rechallenge-related liver injury. DILI and drug
rechallenge of all prescribed drugs have been prospectively recorded and analyzed in the
Spanish DILI registry for more than 20 years. In this series, 13% of patients exhibiting a
positive drug rechallenge after predominantly hepatocellular DILI either died or underwent
liver transplantation.(15) These positive rechallenge events were also associated with
frequent hospitalization (52%), jaundice (64%), and hypersensitivity (39%).(15) Similarly, in a
retrospective study of 88 positive drug rechallenge events, the highest risk events occurred in
those with severe hepatocellular injury with jaundice, in whom two (2%) died.(16) Further,
most positive rechallenge events occur more rapidly than the initial DILI: a) in less than half
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the time in the prospective study,(15) and b) within one week of rechallenge in nearly half of
those reported retrospectively.(16) There’s very limited published data on negative
rechallenge,(17) suggesting a bias to reporting positive rechallenge. Most drug rechallenge
events are inadvertent (e.g. patients self-medicating months or years after DILI)(16). Hence,
by accurately identifying DILI and communicating with the patient their need to avoid suspect
drug readministration, inadvertent drug rechallenge may be preventable.
A Small Minority of Drugs Account for Most Positive Rechallenge Events
Among the hundreds of drugs associated with hepatotoxicity, 48 drugs have more than 50
published cases each of DILI.(18) These drugs include antimicrobials, central nervous
system (e.g. anti-seizure), cardiovascular and oncology therapeutics.(18) In this high risk
subgroup, more than 90% are associated with at least one fatal liver injury and one positive
rechallenge.(18) In Phase II and III studies, drugs associated with DILI exhibit a higher
incidence of ALT > 3xULN in treated versus placebo groups, particularly when the daily dose
exceeds 50 mg.(19) In contrast, drugs with fewer DILI reports are associated with
progressively lower fatality and positive rechallenge rates.(18) When a similarly low incidence
of ALT elevations in treated versus placebo groups is observed during clinical trials, liver
safety is likely.(19) This suggests that drug characteristics influence the risk of DILI, fatality,
and positive rechallenge, including reactive metabolites, bile salt export pump (BSEP)
inhibition, and mitochondrial impairment.(15, 20, 21) Timely information on a drug’s
association with mitochondrial impairment can be obtained through online search (i.e. drug
name AND mitochondrial impairment). Among drugs withdrawn from the market or labeled
with a black box warning, 38% result in mitochondrial impairment and most inhibit the bile
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salt export pump.(21) An earlier systematic review of drugs with at least 10 well-documented
rechallenge events revealed that the highest rate of positive rechallenge (and fatality) is
observed in drugs associated with: 1) immunoallergic injury and mitochondrial impairment
(with positive rechallenge rates of up to 11% to 51%), 2) hepatocellular injury, and 3) high
daily drug dose (>50 mg).(7, 20, 22) A list of 46 drugs with ten or more events of DILI and at
least one positive rechallenge is provided in Supplementary Table 1. Among these drugs, 40
(87%) have a daily dose range >50 mg (observed in 40% of the most commonly prescribed
US drugs) (22) and half exhibit mitochondrial impairment in vitro.
In summary, in diverse medications, a drug’s mechanism of liver injury, high daily dose, and
clinical profile of injury inform rechallenge risk.
Personal and Environmental Risk Factors Affect Liver Injury
In addition to drug-specific factors, susceptibility to DILI varies by patient. For example,
children with mitochondrial polymorphisms/disorders are highly susceptible to drug-induced
acute liver failure and fatality. (23-25) Further, drug metabolism and immune response are
influenced by concomitant medications, inflammation, and genetics.(26, 27) More than a
dozen HLA markers are associated with an increased risk of DILI, which varies from less
than 2-fold for isoniazid to a more than an 80-fold increase with flucloxacillin.(28) However, in
contrast to the 100% positive predictive value of HLA-B*5701 carriage for abacavir
hypersensitivity,(29) positive predictive values are generally low for DILI HLA markers,
suggesting the importance of other factors.(28)
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Drugs with Fatal or Frequent Positive Rechallenge
Through salient examples, we can examine drugs associated with fatal or frequent positive
rechallenge. Halothane is associated with DILI with jaundice resulting in nearly 50 percent
mortality with rechallenge. Halothane is oxidized to a trifluoroacetyl halide, which forms
protein adducts.(30) Immunoallergic injury occurs rapidly with halothane rechallenge, with
fever, rash, eosinophilia, halothane adduct and auto-antibodies, and an associated HLA A-11
marker.(31) Further, by inhibiting mitochondrial complex I and II,(32) fatty acid and pyruvate
oxidation,(33) halothane impairs mitochondrial function, resulting in critical cellular energy
loss (as mitochondria provide 90% percent of cellular ATP).(34) Mitochondria can
regenerate, yet require one to several weeks for regeneration (34) – leaving the hepatocyte
vulnerable to a “second hit”. Patients rechallenged with halothane within the first month after
halothane liver injury exhibit the highest fatality rate (Figure 2), with nearly half of patients
receiving halothane rechallenge resulting in death.(14) This one month period aligns with the
time required for mitochondrial regeneration, suggesting mitochondrial impairment
contributes to immunoallergic injury in halothane positive rechallenge.
A more contemporary oral drug associated with frequent positive rechallenge (Figure 3),
lapatinib is a dual tyrosine kinase inhibitor effective in breast cancer. Lapatinib is metabolized
in the liver to an electrophilic quinone imine which both generates oxidative stress, resulting
in mitochondrial dysfunction, and forms protein adducts, contributing to immunoallergic
injury.(35) Patients carrying HLA-DQA1*02:01 and HLA-DRB1*07:01 are particularly
susceptible to lapatinib-induced liver injury (odds ratio, 14.0),(36) and account for the majority
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of affected patients. Lapatinib metabolites also inhibit BSEP, blocking bile acid efflux from the
hepatocyte and causing cytotoxicity. While primarily liver metabolized, lapatinib exhibits high
inter-subject variability in its metabolism and fecal elimination, and interacts with multiple
drugs (37) – likely further affecting liver injury. The microbiome also affects drug metabolism
(38) and lipopolysaccharide can affect immune tolerance (39) – further modulating liver
injury. Thus, drug, host, and environmental factors interact to determine an individual’s
response to drug rechallenge – which ranges from asymptomatic adaptation without
apparent liver injury to rapid, severe, and even fatal liver injury.
Drug characteristics influence drug-induced liver injury and positive rechallenge
Specific features identify drugs associated with high rates of DILI and positive rechallenge:
daily dose exceeding 50 mg,(7, 19, 22) predominant hepatic metabolism,(7) hepatocellular
injury, and evidence of immunoallergic injury (40) or mitochondrial impairment in vitro.(41,
42) Hepatotoxicity is evident in most drugs with preclinical testing exhibiting: reactive
metabolites, marked metabolism-dependent CYP inhibition (with >5-fold change in IC50),
covalent protein binding (> 200 pmol eq/mg protein), reactive oxygen species, glutathione
adduct formation, lipophilicity (logP>3), BSEP inhibition, cellular ATP depletion, mitochondrial
toxicity, or cytotoxicity.(21, 43-45) Modeling these preclinical tests in human hepatocyte
culture, the FDA’s National Center for Toxicologic Research has identified two factors most
predictive of serious clinical hepatotoxicity: 1) increases in oxidative stress and 2) decreases
in cellular ATP (i.e. mitochondrial dysfunction).(44) Mirroring these findings, immunoallergic
injury from reactive metabolites and mitochondrial dysfunction were associated with the
highest rates of clinically important positive rechallenge injury(20). Searched through
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PubMed, Google Scholar, FDA.gov and cross-referencing (2010-2016), recent data from
drugs with 10 or more rechallenge events was incorporated with that of an earlier systematic
review to highlight key drug characteristics in a “heat map” fashion (Figure 3). When
compared to drugs with few or no positive rechallenge reports, drugs associated with positive
rechallenge exhibit both immunoallergic (i.e. hypersensitivity, reactive metabolite, and HLA
marker) and mitochondrial injury.
Emphasizing the risks of drug rechallenge, the FDA DILI clinical trial guidance advises
caution (46). Yet, innovative therapeutics efficacious in inhibiting targeted cancer pathways
continue to exhibit hepatotoxicity.(47) Hence, in patients with DILI exhibiting efficacy,
prospective oncology trials are increasingly examining drug rechallenge, using selective
criteria (Table 1)(11). With the rigorous monitoring of prospective clinical trials, we can better
evaluate the efficacy and safety outcomes of drug rechallenge of critical medications(48).
Drug Rechallenge in Controlled Clinical Trials
With early evidence of efficacy and liver injury, pazopanib controlled trials adapted protocols
to enable drug rechallenge with attentive follow-up. Pazopanib is a tyrosine kinase inhibitor
effective in the treatment of renal cell carcinoma and soft tissue sarcoma. During clinical
trials, ALT > 8xULN affected 5% of patients receiving pazopanib.(11) In over 2000 patients in
Phase II and III studies, 103 patients developing pazopanib-induced liver injury were
rechallenged if they derived clinical benefit from pazopanib, exhibited a positive dechallenge
(with ALT’s decreasing to <2.5xULN), and had no evidence of hypersensitivity.(11) Patients
were monitored with weekly liver chemistries for 2 months,(49) and most received an initially
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reduced dose of pazopanib.(49) Among the 103 patients, 62 (60%) displayed a negative
rechallenge (or adaptation), 2 (2%) had incomplete follow-up, and 39 (38%) exhibited a
positive rechallenge with ALT > 3xULN. In the 39 patients with a positive rechallenge, 31/39
(79%) exhibited an ALT < 8xULN and 8/39 (21%) developed an ALT > 8 to 20xULN at a
median of nine days. No patients developed severe liver injury with positive rechallenge. Risk
factors for pazopanib-induced liver injury included older age,(11) concomitant simvastatin
treatment,(49) and carriage of HLA-B*57:01, present in only 10% of patients with ALT >
5xULN.(50) These data support the safety of pazopanib rechallenge with close
monitoring.(49) With pazopanib rechallenge after an event of likely pazopanib-induced liver
injury, most patients exhibit adaptation to liver injury, rather than recurrence.
Critical to public health globally, tuberculosis medications are associated with high rates of
DILI. Two prospective controlled clinical trials evaluated the safety of rechallenging patients
with active tuberculosis following positive dechallenge, many of whom had severe
symptomatic hepatitis or jaundice on initial isoniazid, rifampin, and pyrazinamide
treatment.(12, 13) In 220 patients rechallenged with isoniazid, rifampin, with or without
pyrazinamide or ethambutol, most patients exhibited a negative rechallenge, or clinical
adaptation.(12, 13) From 0-24% of patients experienced nonfatal positive rechallenge (with
negative rechallenge observed when pyrazinamide was excluded). The initial DILI severity
did not increase the risk of positive rechallenge. No difference in rechallenge rates was
observed when all drugs were restarted simultaneously or sequentially.(12) Mechanisms
contributing to positive rechallenge with tuberculosis medications include: isoniazid’s
reactive metabolite, an HLA DQB1*0201 marker associated with liver injury (odds ratio,
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1.9)(51), hypersensitivity, and mitochondrial impairment (52). Patients experiencing liver
injury exhibited increased Th17 cells, anti-isoniazid and anti-CYP P450 antibodies,
hypoalbuminemia, older age, female gender and alcohol use (51, 53).
In contrast to the predominantly negative rechallenge observed with tuberculosis medications
or pazopanib, 55% of patients exhibited a positive rechallenge with lapatinib or tolvaptan in
small retrospective clinical trial reviews (Figure 3)(54, 55). These two compounds are
associated with immunoallergic injury (with HLA marker carriage substantively increasing risk
of lapatinib liver injury), mitochondrial impairment,(35, 56) and BSEP inhibition.(37, 57)
Tolvaptan is a vasopressin V2-receptor antagonist indicated for hyponatremia and evaluated
for autosomal dominant polycystic kidney disease (ADPKD).(55) In ADPKD clinical trials,
ALT >3xULN was reported in 4% of tolvaptan-treated and 1% of those receiving placebo,
with 3 serious events of tolvaptan-induced liver injury (which resolved with treatment
cessation).(55) DILI developed after 3 to 18 months of tolvaptan administration, progressed
for 1 month after treatment cessation, and resolved in a median of 1.5 months.(55) In total,
20 patients were rechallenged with tolvaptan. Nine rechallenged patients exhibited
adaptation, with ALT < 3xULN. Eleven (55%) patients exhibited rapid positive rechallenge
(e.g. ALT 10xULN) prompting tolvaptan cessation, with ALT normalizing in 1 to 4 months.(55)
With immunoallergic injury appearing likely, studies are reportedly underway to search for a
possible HLA marker of tolvaptan-induced liver injury.(55)
Drug rechallenge of critical medications
In prospective national registry studies of all drugs, drug rechallenge was associated with
13% mortality (or liver transplantation), and substantive comorbidity.(15) Hence, drug
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rechallenge should generally be avoided. With innovative drugs targeting cancer or other
critical pathways associated with DILI in development, prospective controlled Phase II/III
clinical trial data on drug rechallenge can inform the safety of targeted therapeutics(48) and
may enable safe rechallenge in clinical practice.(58) In earlier described oncology clinical
trials, drug rechallenge was safely performed in patients deriving a clinical benefit, without
evidence of hypersensitivity, in whom ALT decreased to <2.5xULN prior to rechallenge with a
reduced dose of the suspect drug, and whom completed 2 months of weekly liver chemistry
monitoring.(11) Additional prospective rechallenge data of diverse drugs is needed to better
inform outcomes. These data can be obtained in large healthcare databases, clinicians
reporting rechallenge results to FDA MedWatch,(59) and in prospective national DILI
registries.
In a patient with a likely initial DILI event,(5, 6) a critical medicine providing valuable patient
benefits may be considered for drug rechallenge after DILI if: a) continued treatment is
necessary and there are no safer therapeutic alternatives; b) the patient is receiving a
compelling benefit which exceeds the risk of rechallenge; c) in shared decision making, the
benefits and risks of drug rechallenge are discussed fully with the patient to assure a clear
understanding and informed consent, d) the patient agrees to immediately alert their provider
if hepatitis symptoms arise (e.g. fatigue, nausea, abdominal pain, anorexia, or jaundice) and
adhere to close clinical follow-up (e.g., liver chemistries at one week or less), and e) an
Institutional Review Board (IRB) Chair discussion may be helpful (Table 1). Rechallenge
results are then recorded in the medical record and communicated to the FDA or other health
authorities.(59) While drug desensitization may be used prior to rechallenge,(60) this
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approach may be infeasible for a critical medication requiring a specified therapeutic
exposure threshold or when resistance may develop with subtherapeutic dosing. Dose
reductions have been successfully used in prospective rechallenge studies,(11, 13) yet data
is limited. For patients exhibiting a positive rechallenge and liver failure with mild hepatic
encephalopathy, N-acetylcysteine administration has proven beneficial in a controlled clinical
trial.(27) No other agents have proven efficacious in DILI.
Conclusions
Our broad review reveals that a minority of drugs, administered at daily doses >50 mg,
associated with an increased ALT incidence in clinical trials, immunoallergic injury, and
mitochondrial impairment in vitro, are responsible for the highest rates of DILI and positive
rechallenge. A patient’s immune response, genetics, co-medications, and other factors also
influence positive rechallenge. With up to 13% mortality of drug rechallenge following DILI in
prospective series of all prescribed drugs, drug rechallenge should generally be avoided.
Large controlled studies have demonstrated that drug rechallenge of critical medicines can
be safely performed, using standardized safety algorithms and weekly liver chemistry
monitoring during the high risk period.(11) However, high positive rechallenge rates and
clinically significant liver injury in other recent trials (54, 55) suggest the need for controlled,
cautious rechallenge of high risk drugs. Drug rechallenge can be appropriate for critical
medicines, when no safer alternatives are available and the patient’s objective benefit
exceeds their risk. Patients must be involved in shared decision making, alert providers to
hepatitis symptoms and adhere to close follow-up. Due to the high potential risk of drug
rechallenge, IRB discussion may be appropriate. When DILI affects a critical medication,
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controlled clinical trial assessment of drug rechallenge may afford adequate safety data to
inform clinical practice. Further data from clinical trials, prospective DILI registries, and large
healthcare datasets can inform rechallenge outcomes and identify key risk factors for positive
rechallenge.
Acknowledgements
The authors wish to acknowledge the informed, insightful discussions of participants at the
FDA: Critical Path Institute Drug-Induced Liver Injury Conference XVI on March 23-24, 2016.
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24. Figure Legends
Figure 1. Hepatocellular drug-induced liver injury and rechallenge definitions
Hepatocellular drug-induced liver injury is identified by ALT >5xULN observed within 90
days of suspect drug challenge (or initiation), for which non-drug diagnoses are
excluded.(5,6) With dechallenge, or cessation of the suspect drug, most patients fully
recover from liver injury. When the suspect drug is then rechallenged or readministered
after a drug-induced liver injury event, a positive rechallenge is defined by an ALT >3-
5xULN, while a negative rechallenge remains below this threshold.(8)
Figure 2. High mortality with halothane rechallenge within 4 weeks
In two case series, those rechallenged with halothane anesthetic within one month of
halothane-associated liver injury, nearly half died.(12) Most deaths were observed
when halothane was rechallenged within one month of the original liver injury.
Figure 3. Nonclinical and clinical characteristics of drugs associated or not
associated with drug-induced liver injury and positive rechallenge
In the far left column, drugs are profiled in descending order of positive rechallenge
rates, with the top nine medium gray rows depicting drugs with at least ten published
rechallenge events, the next five light gray rows include drugs associated with non-
serious drug-induced liver injury and low or absent rechallenge, and the bottom 3 white
rows portray drugs which are not associated with either drug-induced liver injury nor
positive rechallenge. The columns to the right of the drug names are profiled in a “heat
map” fashion to reveal drug characteristics: red indicates “severe or fatal”, orange
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25. represents “marked”, yellow profiles “mild to moderate”, green reports “absent,” and
white indicates “no data”. When compared to drugs with few or no positive rechallenge
reports, drugs associated with positive rechallenge exhibit notable immunoallergic (i.e.
hypersensitivity, reactive metabolite, and HLA marker) and mitochondrial injury, with a
modest increase in bile salt export pump inhibition.
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26. Challenge
Drug induced hepatocellular injury with ALT > 5xULN within 90 days of suspect drug initiation
Dechallenge
Recovery from injury with drug discontinuation (e.g. ALT < 2.5xULN)
Rechallenge
Suspect drug readministered
Negative
ALT unchanged or < 3xULN
Positive
ALT > 3-5xULN
Figure 1.
• Exclude viral hepatitis, biliary obstruction, alcoholic hepatitis, hypotension
• Examine suspect drug information, published reports of hepatotoxicity
• Assess concomitant medications for hepatotoxicity
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27. High mortality with halothane rechallenge within 4 weeksFigure 2.
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28. Drug Positive
Rechallenge
Mitochondrial
Dysfunction HLA Marker
Hypersens-
itivity
Reactive
Metabolite
BSEP
Inhibition
halothane (n=141)
51% fatal
lapatinib (n=20)
55%
tolvaptan (n=20) 55%
pazopanib (n=103) 38%
tacrine (n=145) 33%
isoniazid, rifampin,
pyrazinamide (n=220)
11% - 24%
azathioprine (n=14)
lamivudine, didanosine,
stavudine, zidovudine (n=11)
amoxicillin:clavulanate (n=10)
nifedipine
methotrexate
captopril
tetracycline
fenofibrate
bupropion
trazadone
furosemide
Figure 3.
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29. Table 1. Considerations for drug rechallenge after drug-induced liver injury
1. Evaluate role of suspect drug in initial drug-induced liver injury
• Confirm drug-induced liver injury(6) and exclude alternative diagnoses(5, 7)
2. Examine alternatives
• Is treatment continuation necessary?
• Are there safer therapeutic alternatives?
3. Review suspect drug information for increased risk of positive rechallenge
• Higher incidence of ALT elevations in suspect drug vs control groups in
clinical trials
• Reports of hypersensitivity (fever, rash, eosinophilia), HLA marker associated
with liver injury
• Mitochondrial regeneration following injury requires 1 to several weeks
• Reports of suspect drug-induced liver injury with jaundice (i.e. serious liver
injury)
• Severe or fatal liver injury or rechallenge reports in product label or
publications
4. Evaluate drug’s clinical benefit and risks in patient being considered for
rechallenge
• Is the patient receiving a compelling benefit which exceeds the risk of
rechallenge?
• Has the patient exhibited hypersensitivity or drug-specific HLA markers,
putting them at high risk of positive drug rechallenge (i.e. rechallenge to be
avoided)?
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30. • Has the patient experienced jaundice, coagulopathy, or encephalopathy (i.e.
signs of liver failure) with the initial suspect drug-induced liver injury (i.e.
rechallenge to be avoided)?
• Should a reduced dose be administered (or is this inappropriate, due to
subtherapeutic exposure or possible resistance limiting clinical benefit)?
5. Is rechallenge appropriate in this patient?
• Have the benefits and risks of drug rechallenge been discussed fully with the
patient in shared decision making to assure a clear understanding and
informed consent?
• Can the patient promptly report hepatitis symptoms and adhere to the
required clinical follow-up?
• Has rechallenge been discussed with the IRB or Ethics Committee?
6. Report results of rechallenge
• Record results in the medical record and report to the FDA or health
authorities
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31. Supplementary Table 1. Drugs associated with ten or more events of drug-
induced liver injury and at least one positive drug rechallenge event
Allopurinol1
Interferon-alpha/Peginterferon Sulindac1,2
Amiodarone1,2
Interferon-beta Tacrine1,2
Androgenic steroids (n=10)1
Isoniazid1,2
Tolvaptan1,2
Atorvastatin1,2
Ketoconazole1,2
Valproate1,2
Auranofin/Gold products (n=3) Lamivudine/Didanosine/Stavudine/Zidovudine1,2
Azathioprine/Mercaptopurine1,2
Lapatinib1,2
Carbamazepine1,2
Methyldopa1
Chlorpromazine1
Minocycline1,2
Clavulanate with Amoxicillin1
Nevirapine1
Dantrolene1
Nimesulide1
Diclofenac1,2
Nitrofurantoin1,2
Didanosine1,2
Pazopanib1,2
Disulfiram1,2
Phenytoin/Fosphenytoin1
Erythromycin1,2
Propylthiouracil1,2
Estrogens (n=9)/Progestins (n=12) Pyrazinamide1
Flucloxacillin1
Quinidine1
Flutamide Rifampin1,2
Halothane2
Simvastatin2
Hydralazine1
Sulfamethoxazole with Trimethoprim1
Ibuprofen1,2
Sulfasalazine1,2
Infliximab1
Sulfonamides (n=5)1
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32. 1
daily drug dose range > 50 mg 2
mitochondrial toxicity in vitro
[References: 11-13, 15-18, 20, 21, 42-44, 52-56]
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