Serious Liver Injury Associated with Macitentan: A Case Report.

Several endothelin receptor antagonists (ERAs) that were developed for the treatment of pulmonary arterial hypertension (PAH), including bosentan and sitaxentan, have been linked to clinically significant hepatocellular injury, as well as liver failure. We describe the first case of fulminant hepatitis to be reported in association with the ERA macitentan. This case was recently identified within the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and describes liver transplantation occurring 13 months after macitentan initiation in a young patient (23 years old) with idiopathic PAH New York Heart Association (NYHA) functional class III.

Profiling cumulative proportional reporting ratios of drug-induced liver injury in the FDA Adverse Event Reporting System (FAERS) database.

BACKGROUND: Early prediction and accurate characterization of risk for serious liver injury associated with newly marketed drugs remains an important challenge for clinicians, the pharmaceutical industry, and regulators. To date, a biomarker that specifically indicates exposure to a drug as the etiologic cause of liver injury has not been identified. OBJECTIVES: Using cumulative proportional reporting ratios (PRRs), we investigated 'real-time' profiles of a set of pharmaceuticals, over the first 3 years of US marketing, for the signaling of clinically serious drug-induced liver injury (DILI) in a large spontaneous-reporting database. METHODS: Using report counts of hepatic failure or clinically serious liver injury obtained from the FDA Adverse Events Reporting System (FAERS) database, PRRs of adverse drug event terms were calculated by division of counts of domestic reports of these events by counts of all serious adverse events for each of 13 selected drugs associated with a broad range of hepatotoxic risk (including three linked to only rare instances of clinically apparent liver injury) with reference to all other drugs in the database. Drug-specific cumulative PRRs were measured at successive intervals (calendar quarters) using cumulative tallies of FAERS reports to generate time-based profiles over the initial 3 years of US marketing. RESULTS: In the set of drugs analyzed, those with no known hepatotoxic risk demonstrated time-based cumulative PRR profiles that approximate the background rates of hepatic failure and serious liver injury reported in the entire FAERS database. In contrast, those that were removed from marketing or subjected to marketing restrictions due to their potential to cause liver injury were associated with profiles of rapidly rising cumulative PRRs that were greater than 5 within the first 10 million domestic prescriptions or the first four quarters of US marketing. The systematic tracking and identification of rising PRRs for DILI associated with newly marketed pharmaceutical and biological agents is a valuable tool for identification of safety signals within the FAERS database. LIMITATIONS: Disproportionality profiling of spontaneous reports in FAERS (e.g., cumulative PRR measurements), which signals an association between a recently marketed drug and liver injury, is not a method to quantitatively measure drug-related risk. Regulatory actions in response to emerging drug safety concerns often depend on an accurate assessment of risks using multiple sources of data and the consideration of overall benefits and risks of the agent. Causality must be determined through analysis of individual cases to exclude other etiologies of liver injury. CONCLUSION: The FAERS database can be used to advance empiric hepatotoxicity time-trending reporting levels for newly marketed agents in order to rapidly identify recently launched potential hepatotoxic agents and initiate further evaluation.

Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors.

PURPOSE: To assess spontaneous reports of rhabdomyolysis associated with simvastatin (SV) and pravastatin (PV) for evidence of CYP3A4 interaction. Clinical trial results advocate cholesterol lowering in high-risk patients including diabetics and the elderly. Given the association between advancing age, metabolic, and cardiovascular disease, many patients are treated with concomitant medications upon statin initiation. Although statins are generally safe, minor and severe adverse reactions arise, especially when given to patients taking concomitant medications that inhibit the statin clearance and lead to increased statin plasma concentration. METHODS: We conducted a comparative case series of rhabdomyolysis reports associated with SV and PV. Domestic spontaneous reports were obtained from the FDA's Adverse Event Reporting System (AERS). Drug utilization data were obtained from IMS HEALTH and the National Ambulatory Medical Care Survey (NAMCS). Adverse event reporting rates (AER) and ratios (AERR) of rhabdomyolysis associated with SV and PV-with and without stratification by CYP3A4 inhibitor concomitancy were determined. RESULTS: Stratification by CYP3A4 inhibitor concomitancy did not change the rhabdomyolysis AER for PV with or without a CYP3A4 inhibitor (2.4 cases and 3.1 cases per 10 million Rx, respectively). However, stratification of SV reports with or without a concomitant CYP3A4 inhibitor resulted in a rhabdomyolysis AER (38.4 and 6.0 cases per 10 million Rx, respectively). The corresponding AERR with or without a CYP3A4 inhibitor were 0.77 for PV and 6.43 for SV. CONCLUSIONS: Spontaneous adverse event reports provide evidence of increased risk for rhabdomyolysis based on interaction between SV and selected CYP3A4 inhibitors.

Telithromycin-associated hepatotoxicity: Clinical spectrum and causality assessment of 42 cases.

UNLABELLED: Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions. CONCLUSION: Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion.

Spontaneous reports of thrombocytopenia in association with quinine: clinical attributes and timing related to regulatory action.

Quinine has been marketed in the United States (U.S.) both over-the-counter (OTC) and by prescription for numerous purposes, including malaria and muscle spasms. In 1994 and 1995, the U.S. Food and Drug Administration (FDA) acted to limit the marketing of quinine based on the conclusion that no data supported its safe and efficacious use in these settings. This report includes clinical attributes from the largest case series to date of apparently isolated thrombocytopenia in association with quinine and trends in the receipt of spontaneous adverse event reports to FDA's Center for Drug Evaluation and Research (CDER) for this drug-event combination in relation to regulatory action. In this study, we reviewed reports of spontaneous adverse drug events received by CDER. From 1974 through December 2000, CDER received 397 adverse event reports for quinine. Based on crude, unreviewed counts, 141 (35.5%) of these reports described apparently isolated thrombocytopenia. Reporting for this event peaked in 1995, coincident with regulatory action, and has subsequently declined. After elimination of cases confounded by acute or chronic disease or concomitant drug therapy, 64 reports of quinine-associated thrombocytopenia were used to form a case series. This case series, including 11 cases since January 1996, supports the potential for rapid time-to-onset (median 7 days) and clinical severity (hospitalization reported in 55 of the 64 cases). Although the number of reports since regulatory action is limited, CDER continues to receive reports of thrombocytopenia in association with quinine in use for nocturnal leg cramps. Extrapolation of spontaneous adverse event reports for a product with substantial OTC use precludes estimates of rates/incidence. Therefore, the effect of regulatory actions in 1994/1995 is difficult to measure using this approach. Although reports have decreased since regulatory actions on quinine, quinine remains available in the U.S. by prescription and in food products/dietary supplements. This case series confirms previous smaller series that suggest quinine-associated thrombocytopenia may present rapidly with symptoms of profound thrombocytopenia. Clinicians evaluating patients with new-onset and apparently idiopathic thrombocytopenia should maintain clinical vigilance for ingestion of quinine and elicit a detailed food/dietary supplement history from the patient.