Drug rechallenge following drug-induced liver injury.

Drug-induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3-5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials; and 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 have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high-risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high-risk drugs. CONCLUSION: For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) 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 are needed from controlled clinical trials, prospective registries, and large health care databases. (Hepatology 2017;66:646-654).

An automated causality assessment algorithm to detect drug-induced liver injury in electronic medical record data.

PURPOSE: The aim of this study was to develop an automated causality assessment algorithm to identify drug-induced liver injury. METHODS: The Roussel Uclaf Causality Assessment Method (RUCAM) is an algorithm for determining the causal association between a drug and liver injury. In collaboration with hepatology experts, definitions were developed for the RUCAM criteria to operationalize an electronic RUCAM (eRUCAM). The eRUCAM was tested in a population of patients taking 14 drugs with a characteristic phenotype for liver injury. Quality assurance for programming specifications involved comparisons between scores generated by the eRUCAM, for probable and highly probable cases, and expert manual RUCAM (n = 20). Concordance between eRUCAM and manual RUCAM subscores and total score was tested using the Wilcoxon signed rank test. RESULTS: Causality scores were the same for 6 of 20 patients (30%) by manual and eRUCAM algorithms. Analysis of subscores revealed ≥80% concordance between manual and eRUCAM for five of the seven criteria. In general, the total scores tended to be higher for the eRUCAM compared with the manual RUCAM. Programming issues were identified for criterion 5 'non-drug causes of liver injury' where significant differences existed between manual and eRUCAM scoring (p = 0.001). For criterion 5, identical scores occurred in 9 of 20 patients (45%), and manual review identified additional codes, timing criteria, and laboratory results for improving subsequent eRUCAM revisions. CONCLUSION: The eRUCAM had generally good concordance with manual RUCAM scoring. These preliminary findings suggest that the eRUCAM algorithm is feasible and could have application in clinical practice and drug safety surveillance.

Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data.

PURPOSE: To evaluate the incidence, phenotypes, and outcomes of drug-associated liver injury identified in electronic medical record (EMR) data using standardized criteria for drug-induced liver injury (DILI). METHODS: This retrospective cohort study used EMR data from a large integrated healthcare system. Study inclusion required 18 years of age or older, ≥1 prescription fill for any of 14 medications associated with hepatotoxicity between 1 January 2003 and 30 June 2009, and ≥12 months of membership prior to the drug exposure. Patients with underlying non-drug causes of liver injury were excluded to minimize capture of liver injury events unrelated to drugs. Drug-associated liver injuries were identified by liver chemistry elevations temporally associated with drug use based on standardized criteria for DILI. Cases were classified by clinical pattern and severity. Outcomes of liver transplant and all-cause and liver-related death were examined. RESULTS: A total of 1 053 979 drug exposures were identified in 601 125 patients. We identified 265 drug-associated liver injuries (32.8 per 100 000 persons) occurring in 250 patients. Isoniazid exhibited the highest incidence rate of 606 per 100 000 persons. Of the 265 cases, 41% were mild; 12% exhibited moderate drug-associated liver injury (with concomitant ALT ≥ 5× ULN and bilirubin ≥2× ULN); and 17% exhibited coagulopathy, ascites, encephalopathy, or other organ failure. Last, seven cases (3%) were associated with death, and there were no liver transplants. CONCLUSIONS: Study results align with earlier prospective studies, supporting the value of standardized methodology to identify drug-associated liver injury in the EMR. These methods can potentially enhance safety and clinical outcomes.

Spontaneous adverse event reports of Stevens-Johnson syndrome/toxic epidermal necrolysis: detecting associations with medications.

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are medically serious skin reactions that are often drug induced. The mainstay of therapy and future prevention is to discontinue and avoid the use of the suspected inducing drug. However, many cases of SJS/TEN occur in patients who are taking multiple medications, and it is often difficult to determine which drug to stop. This analysis was conducted to identify drugs that were most associated with SJS/TEN in the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database and to identify medications that were likely innocent bystanders. METHODS: A Multi-item Gamma Poisson Shrinker value with an EB05 ≥ 2 was considered a disproportional increase in reporting frequency (at least two times higher than expected). The identified drugs with reporting frequency of SJS/TEN in the US FDA AERS database were then compared to the EuroSCAR (European case-control surveillance of severe cutaneous adverse reactions) study results as a reference to define signals. The EB05s were calculated as a cumulative relative reporting frequency from 1968 to 3Q2009. RESULTS: Fifty drugs were identified as being associated with SJS/TEN. This included 12 "highly suspect" drugs and 36 "suspect" drugs. Meloxicam was the only drug that appeared on the "highly suspect" list from EuroSCAR that did not show a disproportional increase in relative reporting frequency (EB05 = 0.734). In addition, several drugs did not have an association with SJS/TEN (EB05 < 2). CONCLUSIONS: There was good concordance between the reporting frequencies observed in the FDA AERS database and the published risk estimation of medications implicated in SJS/TEN.

A pre-marketing ALT signal predicts post-marketing liver safety.

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an "ALT signal". We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT ≥ 3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 ≥ 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT ≥ 3× ULN in treated versus placebo) was examined. An ALT signal of ≥ 1.2% was significantly associated with a post-marketing liver safety signal (p ≤ 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT ≥ 3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety.

The evaluation of drug rechallenge: the casopitant Phase III program.

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, is associated with 13% mortality in prospective series. Rechallenge generally results in much more rapid injury than the initial liver event. The neurokinin-1 antagonist casopitant or its placebo was administered cyclically with ondansetron and dexamethasone in two randomized chemotherapy-induced nausea and vomiting clinical trials in nearly 3000 subjects. Grade 3 ALT elevations were observed in up to 2% of subjects receiving casopitant or placebo treatment. Similar rates of positive rechallenge were observed in the casopitant 8/29 (28%) and placebo groups 2/8 (25%), with no Grade 4 ALT elevations, hypersensitivity or liver-related serious adverse events. Publishing available rechallenge data (positive and negative) will advance our clinical understanding. Rechallenge should only be considered when the potential drug benefit exceeds the risk.

Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury.

BACKGROUND & AIMS: Acetaminophen-induced liver injury is the most common cause of acute liver failure in the United States; it occurs inadvertently in approximately half of all cases. Concomitant use of other medications might impact susceptibility to acetaminophen hepatotoxicity. We investigated its association with administration of drugs that have been shown to modulate liver injury and/or repair in preclinical studies. METHODS: We analyzed data from 6386 cases of acetaminophen-associated liver injury that were defined in the FDA database of reported adverse events. Data reported in the severe adverse event categories of "died" or "life-threatening" (defined as "fatal" cases, n = 2512) were compared with those of "non-fatal" cases (n = 3874). Potential associations between fatality and concomitant use of 9 drug classes were assessed using multiple logistic regression analyses after adjusting for other variables. RESULTS: Among female subjects, concomitant use of statins, fibrates or nonsteroidal anti-inflammatory drugs was associated with decreased likelihood of fatality, whereas ethanol use was associated with increased likelihood. Among male subjects, concomitant use of statins was associated with decreased likelihood of fatality, whereas concomitant use of sympathetic stimulants or ethanol was associated with increased likelihood. Concomitant use of angiotensin converting enzyme inhibitors or angiotensin receptor II antagonists was associated with decreased likelihood of fatality among younger subjects. CONCLUSIONS: Concomitant use of medications that have been shown in preclinical studies to modulate liver injury and/or repair influenced acetaminophen hepatotoxicity. Drugs that reduce injury or increase repair are protective, whereas those that exacerbate injury or reduce repair are detrimental.

Drug-induced liver injury following positive drug rechallenge.

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury. A retrospective review of a large pharmaceutical safety database was conducted to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury. Positive rechallenge with suspect drug was reported in 770 of 36,795 hepatic adverse events. A total of 88 cases met inclusion criteria for analysis. Mean age was 44 years (range 0.5-83) and 56% were male. A broad spectrum of suspect drugs were identified. Many patients exhibited hepatitis symptoms or jaundice on the initial and rechallenge liver event. Twelve patients (14%) exhibited clinically worrisome severe hepatocellular injury and jaundice on either initial or rechallenge event and two died, reflecting a 2.3% fatality rate in those with positive rechallenge. The two fatalities developed severe hepatocellular injury with jaundice only upon rechallenge. Liver injury recurred in most rechallenges. Improved identification and communication of possible drug-induced liver injury is needed to avoid potentially serious and/or fatal drug rechallenges. Clinicians should generally avoid such rechallenges.

Consumers Better Understand and Prefer Simplified Written Drug Information: An Evaluation of 2 Novel Formats Versus the Current CMI.

Patients in the United States receive multiple forms of written drug information with their prescription medicines. This study solicited consumers' preferences about formatting of information, their motivation to read drug information, and their ability to navigate and understand the information. A 3 × 3 study design was used in which 3 prototypes for 3 prescription drugs, ORTHO TRI-CYCLENTM (norgestimate/ethinyl estradiol), COUMADINTM (warfarin sodium), and PARNATETM (tranylcypromine sulfate), were evaluated. The prototypes included 2 novel formats ("new" and "bubble") and the "current" format that patients now commonly receive with their prescriptions. A total of 105 consumers participated in the study. Consumers correctly answered more questions about the medicine when presented with a new (70%-95%) or a bubble prototype (83%-92%) than with the current format (53%-74%). All attributes scored higher with both prototypes compared with the current format. However, in terms of overall preference, consumers favored the new prototype and indicated that they would be more motivated to read it. Consumers also reported that simple icons assisted them in finding important information. The new and bubble prototypes were favored by participants more than the current format. Key attributes preferred by consumers must be considered as new formats for patient medication information are developed.

Monitoring liver safety in drug development: the GSK experience.

To promptly identify and evaluate liver safety events, an evidence-based liver safety system was created for global Phase I-III clinical trials. The goals of this system included improving clinical trial subject safety, expanding information on liver safety events, and improving data quality across studies by establishing and communicating: Two different algorithms for liver stopping criteria were developed. The most stringent criteria were selected for healthy volunteers in Phase I studies, where no treatment benefit is anticipated and clinical safety data are limited. With an interest in assessing potential liver "tolerance" or adaptation with accruing safety information, slightly higher liver chemistry thresholds were set for Phase II-III studies. This paper will describe the importance of liver safety in drug development, laboratory tests used to monitor liver safety, the rationale for selected liver chemistry subject stopping criteria, and implementation of this safety system.