10 Years of Nephrogenic Systemic Fibrosis: A Comprehensive Analysis of Nephrogenic Systemic Fibrosis Reports Received by a Pharmaceutical Company from 2006 to 2016.

OBJECTIVES: The aim of this study was to critically assess the evaluation and categorization process for nephrogenic systemic fibrosis (NSF) based on reports received by Bayer from 2006 to 2016. MATERIALS AND METHODS: A total of 779 NSF reports received by Bayer globally from 2006 to 2016 were included in the analysis. Arlington Medical Resources provided gadolinium-based contrast agent (GBCA) market share. Reports were conservatively categorized based on the Cowper/Girardi criteria. A statistical model simulated the impact of market share and market introduction on the number of unconfounded reports. RESULTS: For all reports, reported onset of disease ranged from 1996 and 2012. Of 779 reports, 325 involved a Bayer product only, 208 involved only products from other companies (or unknown GBCA), and 246 involved both Bayer and non-Bayer products. Most of all reports (86%) originated from the United States.Through 2006, Magnevist and Omniscan dominated the US market (>80% combined market share). All other GBCAs with fewer NSF reports comprised the remaining combined market share of less than 20% or were introduced after May 2007, after safety recommendations came into effect.A total of 563 reports (220 single-agent and 343 multiagent reports) involved Magnevist. In at least 150 of the 343 reports, a different GBCA (Omniscan, 118; OptiMARK, 15; MultiHance, 6; and macrocyclic agent, 11) showed the closest temporal relationship to onset of NSF-like symptoms.The simulation model demonstrated that patients receiving a GBCA with lower market share and late market introduction are less likely to be observed in an unconfounded setting. CONCLUSIONS: Year of market introduction, as well as US market share in 2000 to 2007, greatly influenced the absolute number of NSF reports for each GBCA, their a priori probability to cause NSF, as well as their a priori probability to be associated with unconfounded cases of NSF. Variability in case interpretation and pharmacovigilance approaches also influence the absolute number of unconfounded cases and should therefore not be used for comparative risk assessments. This should be primarily based on objective product parameters such as structure, stability, pharmacokinetics, and dose.

Safety of Gadobutrol: Results From 42 Clinical Phase II to IV Studies and Postmarketing Surveillance After 29 Million Applications.

OBJECTIVE: The aim of this study was to provide a systematic safety analysis of gadobutrol after more than 29 million applications in clinical routine. MATERIALS AND METHODS: Forty-two clinical development phase II to IV studies on gadobutrol or comparator and the postmarketing safety surveillance database for gadobutrol (1998-2015) were analyzed. Adverse events (AEs) and drug-related AEs were evaluated in the clinical development database and spontaneous adverse drug reactions (ADRs) in the postmarketing database. Subgroup analyses were run on patients with special medical history and on patients of different age groups. RESULTS: In the clinical development studies, 6809 and 2184 patients received gadobutrol or comparators, respectively. The incidence of drug-related AEs was 3.5% for both groups. With the exception of nausea (0.7% related cases in both groups), all other drug-related AEs were 0.3% or less in both groups. Hypersensitivity reactions were sporadic (<0.1%). Patients with history of allergies to contrast agents experienced slightly more drug-related AEs. No differences were seen between age groups.The overall reporting rate of ADRs from postmarketing surveillance was 0.05%. The most frequent ADRs were anaphylactoid/hypersensitivity reactions, nausea, vomiting, and dyspnea.For 3 single-agent reports of nephrogenic systemic fibrosis, using a conservative approach, association with gadobutrol could not be excluded. CONCLUSIONS: Gadobutrol is well tolerated and has a favorable safety profile for patients of all age groups.

Safety of gadoxetate disodium: results from six clinical phase IV studies in 8194 patients.

Background Safety data on routine clinical use of gadoxetate disodium for liver magnetic resonance imaging (MRI) is not reported yet. Purpose To assess the safety profile of gadoxetate disodium for liver MRI in the routine clinical setting. Material and Methods Six multicenter studies were performed in Europe, USA, Australia, and Asia to evaluate the safety and efficacy of gadoxetate disodium (Primovist®/Eovist®) enhanced liver MRI. Patients received a single intravenous bolus injection of the standard approved dose of 0.025 mmol/kg body weight (0.1 mL/kg). The number of patients, the characteristics of adverse events, related adverse events, and serious adverse events were analyzed. Results A total of 8194 patients were included in the database. A total of 141 patients (1.7%) reported 230 AEs of which 129 were considered being related to the use of gadoxetate disodium by the investigators. None of the AEs in the pediatric population ( n = 52) were related. The most frequent AEs independent of relationship to the drug included dyspnea (25/0.31%), nausea (22/0.27%), liver disorders (13/0.16%), and renal disorders (9/0.11%). Nine related SAEs were recorded. No patient died during the studies. Conclusion Gadoxetate disodium for liver MRI is safe and well tolerated in the routine clinical setting.

Safety of gadoxetate disodium: Results from the clinical phase II-III development program and postmarketing surveillance.

PURPOSE: To summarize the safety data of gadoxetate disodium, reported in 12 Phase II and III clinical development studies and in the postmarketing surveillance database. MATERIALS AND METHODS: Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. RESULTS: A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. CONCLUSION: Gadoxetate disodium for liver MRI has an excellent safety profile.

Safety of gadopentetate dimeglumine after 120 million administrations over 25 years of clinical use.

PURPOSE: We evaluated the safety of gadopentetate dimeglumine (Gd-DTPA), the first contrast agent for magnetic resonance imaging, using pharmacovigilance data for spontaneously reported adverse events (AEs) after 120 million cumulative administrations worldwide. METHODS: We analyzed spontaneously reported AEs for Gd-DTPA for pre-specified time periods between 1988 and 2011. RESULTS: Since the market introduction of Gd-DTPA in 1988, its global utilization reached 120 million cumulative administrations in 2011, more than 80% of which was by the USA, countries in the European Union (EU), and Japan. The global AE reporting rate was 21.2 in 100,000 administrations in 1988 and 14.4 in 100,000 administrations by 2011. Regional differences included higher reporting rates in the USA and Japan, and reporting rates lower than global rates in the EU. The reported rate of global serious AEs changed from 1.4 in 100,000 administrations in 1988 to 4.0 in 100,000 administrations in 2011. The highest number of reports of nephrogenic systemic fibrosis (NSF) was received from 2006 to 2008. Since 2009, no report of a current onset of NSF has been received. The reduced report rate of NSF may be due to increased awareness about the use of gadolinium-based contrast agents (GBCAs). CONCLUSION: After more than 120 million cumulative administrations, Gd-DTPA is a widely used GBCA that shows a consistently low and stable incidence of AEs.