Hospital Pharmacy - February 2018 - 57

57

Rose et al
Table 1. RUCAM Causality Assessment Tool Assessment for Hepatocellular Injury (R Ratio = 33).
Assessment
Time of onset from cessation of the drug
Course after stopping drug (decrease in
ALT between peak value and ULN)
Risk factors (alcohol and age ≥55)
Concomitant drugs
Exclusion of other causes of liver injury

Previous information on hepatotoxicity
of the drug
Response to readministration
Total score: 9

Descriptor

Score

≤15 d
Decrease by ≥50% within 8 d

+1
+3

Patient denies alcohol use and is <55
Both amiodarone and sotalol stopped >15 d prior to event.
Warfarin use has suggestive time of onset but is typically associated
with cholestatic injury.
Group I causes: Hepatitis A, B, and C; biliary obstruction, alcoholism,
and recent history of hypotension/shock/ischemia ruled out.
Group II causes: Complications of underlying autoimmune hepatitis,
sepsis, chronic HBV or HCV, primary biliary cirrhosis, sclerosing
cholangitis, CMV, EBV, and HSV ruled out.
All causes in groups I and II ruled out
Reaction labeled in product characteristics

0
0
+2

+2

Compatible, dofetilide readministered on day 2 following labs being
+1
taken for that day. ALT proceeds to increase and peak on day 5.
Interpretation: Scores of 9 or greater imply dofetilide is a "highly probable" cause of
liver injury.

Note. The Roussel Uclaf Causality Assessment Method (RUCAM) for drug-induced liver injury (DILI). R ratio calculated from alanine aminotransferase
(ALT) and alkaline phosphatase (ALK P) values on hospital day 5. Calculation: R ratio = (ALT / ALT ULN) ÷ (ALK P / ALK P ULN), where ALT ULN =
40 and ALK P ULN = 130. CMV = cytomegalovirus; EBV = Epstein-Barr virus; HBV = Hepatitis B Virus; HCV = Hepatitis C Virus; HSV = herpes simplex
virus; ULN = Upper Limit of Normal.

Several diagnostic tests to evaluate hepatic failure etiology were performed during this admission. An abdominal
ultrasound was performed on hospital day 3 which revealed
all veins to be patent with a small amount of right upper
quadrant ascites and borderline hepatomegaly. The gallbladder was found to be thickened but no presence of
stones or sludge. Alpha-1 antitrypsin testing was negative.
Normal viral hepatitis serology tests were performed and
negative.
On hospital day 6, hepatic transaminases began to improve
and total bilirubin continued to trend downward which continued until discharge. On hospital day 11, the patient noticed
a diffuse maculopapular rash on his chest and back which
may have been an immune-related reaction. On hospital day
13, the patient was discharged following resolution of his
dyspnea and acute liver injury.

Discussion
This case report is unique in that DILI from dofetilide has
been previously poorly characterized. While the potential for
hepatotoxicity from dofetilide has been found in manufacturer studies, it is unclear as to the exact nature of how these
reactions have occurred.2 Chemically similar sotalol has
been described in 1 case as a potential causative agent for
chronic hepatits.3 The Roussel Uclaf Causality Assessment
Method (RUCAM) is one of the scoring tools used to assess
the likelihood of DILI.4 An assessment of the RUCAM score
specific to this case is described above (Table 1). All of these
factors add up to a RUCAM score of 9 which may be

interpreted as dofetilide being a "highly probable" cause of
this patient's hepatocellular injury.
DILI has been described to occur by a variety of mechanisms. The most apparent mechanism of hepatotoxicity is the
production of reactive metabolites typically through phase I
metabolism via the cytochrome P450 (CYP450) pathway.5
Another mechanism of hepatotoxicity is parent drug or
metabolite interaction with the bile salt export pump (BSEP)
leading to cholelithiasis and hepatocellular damage. Finally,
idiosyncratic mechanisms have been proposed for immunemediated reactions with parent drug or metabolite acting as a
hapten and binding to a hepatic protein such as a CYP450
isoenzyme eliciting an adaptive immune response leading to
cytotoxic T-cell activation and hepatocellular death. This
idiosyncratic mechanism allows for the explanation of hepatotoxicity that occurs without other apparent cause such as
production of reactive oxygen species.
Dofetilide is chemically classified as a methanesulfonanilide that is primarily excreted unchanged by renal elimination with hepatic metabolism accounting for 20% to 30% of
total drug disposition.1,6 Of the hepatic metabolites, dofetilide is primarily metabolized by CYP3A4 via N-demethylation
to N-desethyl dofetilide. Hepatic metabolites of dofetilide
have shown 20-fold decreased potency to the parent compound and are not relevant in the pharmacologic action of
dofetilide given at therapeutic doses.6 It is not known whether
these metabolites are reactive oxygen species; however, this
may be a theoretical cause of DILI from dofetilide.
Other common causes of hepatocellular liver injury were
ruled out in this case. Viral hepatitis was extensively ruled



Table of Contents for the Digital Edition of Hospital Pharmacy - February 2018

Ed Board
TOC
Editorial
The Evolving Frontier of Digital Health: Opportunities for Pharmacists on the Horizon
Letter to the Editor
Immediate Attention Required: Another Shortage
ISMP Adverse Drug Reactions
ISMP Adverse Drug Reactions
Current FDA-Related Drug Information
Summaries of Safety Labeling Changes Approved By FDA: Boxed Warnings Highlights July-September 2017
ISMP Medication Error Report Analysis
Common Missteps With Medication Safety: Rolling a Single Dice, Ineffective Strategies, and Unexecuted Action Plans
Formulary Drug Reviews
Betrixaban
Pharmaceutical Pipeline Update
Antibiotics in Development for the Treatment of Resistant Bacterial Disease
Articles
Evaluation of the Incidence of Ibuprofen Administration in Alcohol and Opioid Detoxification Patients With Concomitant Thrombocytopenia
Antimicrobial Utilization Pattern in Pediatric Patients in Tertiary Care Hospital, Eastern Ethiopia: The Need for Antimicrobial Stewardship
Acute Hepatocellular Jaundice After Dofetilide Initiation: A Case Report
Outcomes From a Pharmacist: Led Proton Pump Inhibitor Stewardship Program at a Single Institution
Corrigendum
Hospital Pharmacy - February 2018 - Cover1
Hospital Pharmacy - February 2018 - Cover2
Hospital Pharmacy - February 2018 - 1
Hospital Pharmacy - February 2018 - 2
Hospital Pharmacy - February 2018 - 3
Hospital Pharmacy - February 2018 - Ed Board
Hospital Pharmacy - February 2018 - TOC
Hospital Pharmacy - February 2018 - Editorial
Hospital Pharmacy - February 2018 - The Evolving Frontier of Digital Health: Opportunities for Pharmacists on the Horizon
Hospital Pharmacy - February 2018 - 8
Hospital Pharmacy - February 2018 - 9
Hospital Pharmacy - February 2018 - 10
Hospital Pharmacy - February 2018 - Letter to the Editor
Hospital Pharmacy - February 2018 - Immediate Attention Required: Another Shortage
Hospital Pharmacy - February 2018 - 13
Hospital Pharmacy - February 2018 - ISMP Adverse Drug Reactions
Hospital Pharmacy - February 2018 - ISMP Adverse Drug Reactions
Hospital Pharmacy - February 2018 - 16
Hospital Pharmacy - February 2018 - Current FDA-Related Drug Information
Hospital Pharmacy - February 2018 - Summaries of Safety Labeling Changes Approved By FDA: Boxed Warnings Highlights July-September 2017
Hospital Pharmacy - February 2018 - 19
Hospital Pharmacy - February 2018 - 20
Hospital Pharmacy - February 2018 - 21
Hospital Pharmacy - February 2018 - 22
Hospital Pharmacy - February 2018 - 23
Hospital Pharmacy - February 2018 - ISMP Medication Error Report Analysis
Hospital Pharmacy - February 2018 - Common Missteps With Medication Safety: Rolling a Single Dice, Ineffective Strategies, and Unexecuted Action Plans
Hospital Pharmacy - February 2018 - 26
Hospital Pharmacy - February 2018 - 27
Hospital Pharmacy - February 2018 - Formulary Drug Reviews
Hospital Pharmacy - February 2018 - Betrixaban
Hospital Pharmacy - February 2018 - 30
Hospital Pharmacy - February 2018 - 31
Hospital Pharmacy - February 2018 - 32
Hospital Pharmacy - February 2018 - 33
Hospital Pharmacy - February 2018 - 34
Hospital Pharmacy - February 2018 - 35
Hospital Pharmacy - February 2018 - 36
Hospital Pharmacy - February 2018 - Pharmaceutical Pipeline Update
Hospital Pharmacy - February 2018 - Antibiotics in Development for the Treatment of Resistant Bacterial Disease
Hospital Pharmacy - February 2018 - 39
Hospital Pharmacy - February 2018 - Articles
Hospital Pharmacy - February 2018 - Evaluation of the Incidence of Ibuprofen Administration in Alcohol and Opioid Detoxification Patients With Concomitant Thrombocytopenia
Hospital Pharmacy - February 2018 - 42
Hospital Pharmacy - February 2018 - 43
Hospital Pharmacy - February 2018 - Antimicrobial Utilization Pattern in Pediatric Patients in Tertiary Care Hospital, Eastern Ethiopia: The Need for Antimicrobial Stewardship
Hospital Pharmacy - February 2018 - 45
Hospital Pharmacy - February 2018 - 46
Hospital Pharmacy - February 2018 - 47
Hospital Pharmacy - February 2018 - 48
Hospital Pharmacy - February 2018 - 49
Hospital Pharmacy - February 2018 - 50
Hospital Pharmacy - February 2018 - 51
Hospital Pharmacy - February 2018 - 52
Hospital Pharmacy - February 2018 - 53
Hospital Pharmacy - February 2018 - 54
Hospital Pharmacy - February 2018 - Acute Hepatocellular Jaundice After Dofetilide Initiation: A Case Report
Hospital Pharmacy - February 2018 - 56
Hospital Pharmacy - February 2018 - 57
Hospital Pharmacy - February 2018 - 58
Hospital Pharmacy - February 2018 - Outcomes From a Pharmacist: Led Proton Pump Inhibitor Stewardship Program at a Single Institution
Hospital Pharmacy - February 2018 - 60
Hospital Pharmacy - February 2018 - 61
Hospital Pharmacy - February 2018 - 62
Hospital Pharmacy - February 2018 - 63
Hospital Pharmacy - February 2018 - 64
Hospital Pharmacy - February 2018 - 65
Hospital Pharmacy - February 2018 - 66
Hospital Pharmacy - February 2018 - 67
Hospital Pharmacy - February 2018 - Corrigendum
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