Drug rechallenge following drug-induced liver injury.

Unlabelled: 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.

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-CYCLEN (norgestimate/ethinyl estradiol), COUMADIN (warfarin sodium), and PARNATE (tranylcypromine sulfate), were evaluated.

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.

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.

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.

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.

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.