Daniel M. Keller, PhD

July 02, 2010

July 2, 2010 (Munich, Germany) — The reported rates of adverse events (AE) from all intravenous (IV) iron products have increased in North America and Europe since 2002. The use of the products has also increased, according to a study presented here at the XLVII European Renal Association-European Dialysis and Transplant Association Congress.

George Bailie, PharmD, PhD, professor of nephrology pharmacy at Albany College of Pharmacy and Health Sciences in New York, and colleagues analyzed sales and AE data from Europe and North America for the first quarter of 2003 to the second quarter of 2009. Iron-related AE data were obtained from reports to the World Health Organization (WHO) for 16 major European countries and for the United States and Canada. Iron could have been used in patients with and without chronic kidney disease; no distinction was made.

Sales data by product and country were standardized to 100 mg dose-equivalents (DEq) of iron. AE rates were calculated as the rate of AE's divided by the number of doses. Data were censored if the sales data were unreliable, a product had been in use for less than 2 years, there was obvious underreporting from a country, or if the reports were duplicated or unclear.

Dr. Bailie reported that during the 6-year observation period, annual sales increased in Europe for ferric gluconate (1.4 to 1.6 million DEq), iron sucrose (0.65 to 1.9 million DEq), and iron dextran, which has only been in a low-molecular-weight formulation since 2005 (0.02 to 0.15 million DEq). Sales increased in North America for iron sucrose (1.1 to 2.8 million DEq), were unchanged for ferric gluconate (1.0 to 0.97 million DEq), and decreased for iron dextran (0.33 to 0.26 million DEq).

In Europe and North America, the rates of total AEs, anaphylaxis, and anaphylactoid reactions were several-fold higher with IV iron dextran than with other IV iron products. All AE rates increased over time, as evidenced by the increase in rates for the 2008 and 2009 period, compared with the rates for the entire 2003 to 2009 period.

Table 1. Rate of Total AEs for IV Iron Preparations (Per Million Iron DEq)

Iron Preparations by Location 2008 and 2009 2003 to 2009
Europe    
Ferric gluconate 10.3 3.5
LMW iron dextran* 93.1 64.4
Iron sucrose 22.5 12.8
North America    
Ferric gluconate 27.7 12.6
Iron dextran* 99.7 54.8
Iron sucrose 7.9 4.4
North America and Europe    
Ferric gluconate 16.7 7.0
Iron dextran* 97.4 57.1
Iron sucrose 14.0 7.8
*Only low-molecular-weight (LMW) iron dextran has been sold in Europe since 2005. For North America, the figure represents the total sales of all forms of iron dextran.


Dr. Bailie speculated on some of the reasons for the differences in reporting rates of AEs between Europe and North America. One explanation could be differences in prescribing habits. "For example, in North America, physicians are permitted to use ferric gluconate at doses of 125 mg at a time, whereas in Europe they're limited to half that, 62.5 mg. Clearly a higher dose might give rise to a bigger incidence of serious adverse events," he told Medscape Medical News.

Furthermore, in Europe, products called "iron sucrose similars" are becoming increasingly available. He explained that all parenteral iron preparations are complex drugs, so it is very difficult to manufacture ones that are identical.

"Nevertheless, in Europe, iron sucrose similars are currently dealt with as being identical to the originator," he said, even though evidence shows that the physical chemical characteristics of the similars are very different from the originator, with possible toxicologic effects. He said it is only speculation until reports can be obtained from the WHO, separating out the similars and the originators. "Right now, they're all reported as just iron sucrose," Dr. Bailie said. A dozen or more similars are now on the market.

In addition, the difference in AE rates for iron dextran might reflect the higher use of high-molecular-weight iron dextran in North America. Finally, the differences in rates might be the result of the use of IV iron by nonnephrologists for other disease states, the use of unapproved dosing methods or high doses, or changes in reporting requirements.

Session moderator Francesco Locatelli, MD, head of the Department of Nephrology, Dialysis, and Transplantation at Manzoni Hospital in Lecco in Italy, who was not involved in the study, noted that physicians tend to use drugs that they are familiar with if there are no important differences between them for a particular indication. But if there are important differences between drugs, practices should change. "The data are very well presented and strong," he said, referring to this study, and should raise awareness of differences in AEs with the different IV iron preparations.

Vifor Pharma provided funding for the study. Dr. Bailie reports receiving grants, honoraria, or speaking fees from American Regent, Vifor Pharma, Fresenius, and Genzyme. Dr. Locatelli has disclosed no relevant financial relationships.

XLVII European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress: Abstract OSu056. Presented June 27, 2010.

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