Julie I. Papay

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.

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

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.

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.

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

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).

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

The aim of this study was to develop an automated causality assessment algorithm to identify drug‐induced liver injury.

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).

Assessment of a Simplified Format of Written Patient Prescription Drug Information

Patients in the United States receive multiple forms of written information about their prescription medications. This pilot study was conducted to evaluate alternative formats of patient-directed written prescription information for four medications: cefaclor suspension, simvastatin tablets, albuterol inhaler, and capecitabine tablets. Fifty-four consumers evaluated this information using a 5-point satisfaction scale, responding to 10–12 questions, and participating in group discussion. Overall, consumers valued short, simple text, a question-answer format, a table layout, large font, adequate text spacing, bold type for emphasis, and easy-to-understand, actionable information that included impact statements on activities and lifestyle. This pilot study reveals that simplified prescription information with improved readability and reduced ambiguity may enhance consumer information retrieval and reinforce appropriate use of prescription medicines.

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.

Pharmacogenetics : From Bench Science to the Bedside

Pharmacogenetics has received considerable attention in recent medical news. Extensive research has been conducted to better understand how an individual patient may respond to and benefit from a particular drug. The clinical application of pharmacogenetics, like other medical advances, requires scientific validation and established clinical utility for widespread use among patients, prescribers, and payers. This activity reviews factors that contribute to the successful integration of pharmacogenetics in clinical practice, from the drug development process all the way to the patient.

Evidence-Based Liver Chemistry Monitoring in Drug Development

AbstractBackground: Liver safety issues affect patients and may result in compound termination during drug development or drug withdrawal postmarketing. While liver chemistries are monitored to protect patient safety, the frequency and timing of monitoring is largely empirically determined. Objective: To determine the optimal timing of liver chemistry monitoring in phase I–III drug development. Setting: Liver chemistries and safety were analysed from six GlaxoSmithKline (GSK) clinical development programmes discontinued with liver safety issues, marketed products and five products withdrawn from the market because of liver safety issues. Methods of assessment: Retrospective analysis of the temporal appearance, incidence, form of liver injury and severity of liver chemistry elevations and adverse outcomes observed with medication use. Results: In the phase I–III clinical studies, all six GSK compounds exhibited hepatocellular injury and/or jaundice in the first treatment month. Alanine aminotransferase (ALT) ≥3 × the upper limit of normal occurred within the first 2 weeks to 4 months in 2–50% of treated subjects. By contrast, drugs withdrawn from the market exhibited a more severe pattern of injury with a lower incidence of liver chemistry elevations observed after 3 days to >24 months of treatment. Conclusions: Liver chemistry monitoring appears to be most productive in the first few months of drug initiation. Evaluating the incidence of liver chemistry elevations proactively identifies whether there is a compound liver safety signal that requires further assessment.