Intravenous ibuprofen: the first injectable product for the treatment of pain and fever

This paper reviews the current data on the use of the first approved intravenous ibuprofen product for the management of post-operative pain and fever in the United States. The management of acute and post-operative pain and fever with nonsteroidal anti-inflammatory agents (NSAIDs) is well documented. A search in Medline and International Pharmaceutical Abstracts of articles until the end of November 2009 and references of all citations were conducted. Available manufacturer data on file were also analyzed for this report. Several randomized controlled studies have demonstrated the opioid-sparing and analgesic effects of 400 and 800 mg doses of intravenous ibuprofen in a series of post-operative patient populations. Two recent studies have also noted the improvement in fever curves in critically ill and burn patients. These data, along with pharmacokinetic and pharmacologic properties, are explored in this review, which addresses the clinical utility of a parenteral NSAID in a hospitalized patient for post-operative pain management and fever reduction. Further data on intravenous ibuprofen are needed to define long-term utilization, management of acute pain, and use in special populations

Major hemorrhage in chronic lymphocytic leukemia patients in the US Veterans Health Administration system in the pre‐ibrutinib era: Incidence and risk factors

Abstract Chronic lymphocytic leukemia (CLL) patients are at increased risk for major hemorrhage (MH). We examined incidence of and risk factors for MH in CLL patients before introduction of newer CLL therapies such as ibrutinib, which includes bleeding risk. This study included 24 198 CLL patients treated in the VA system before FDA approval of ibrutinib as CLL therapy. Data came from VA databases from 1999 to 2013. MH incidence was 1.9/100 person‐years (95% CI: 1.8‐1.9), with cumulative incidences of 2.3%, 5.2%, and 7.3% by year 1, 3, and 5, respectively. Median time from CLL diagnosis to MH was 2.8 years (range: 0‐15.7 years). In multivariate analyses, concurrent anticoagulant and antiplatelet use (HR: 4.2; 95% CI: 3.2‐5.6), anticoagulant use only (HR: 2.6; 95% CI: 2.3‐3.1), and antiplatelet use only (HR: 1.5; 95% CI: 1.3‐1.7) increased MH risk vs not receiving those medications; being nonwhite, male, having MH history, renal impairment, anemia, thrombocytopenia, and alcohol abuse were associated with increased MH risk. These pre‐ibrutinib data are important for providing context for interpreting MH risk in ibrutinib‐treated patients. As ibrutinib clinical use is increasing, updated analyses of MH risk among ibrutinib‐treated VA patients with CLL may provide additional useful insight

Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease

BACKGROUND. In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark’s identification and subsequent rapid eradication of NSF. METHODS. NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002–11). RESULTS. In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide’s renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported. CONCLUSION. A confluence of factors led to the development and eradication of NSF in Denmark

A Tale of Two Citizens: A State Attorney General and a Hematologist Facilitate Translation of Research Into US Food and Drug Administration Actions - A SONAR Report

PURPOSE: Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues. METHODS: Case study. RESULTS: The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. CONCLUSION: New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon