Shares of AMAG Pharmaceuticals, Inc. (NASDAQ:AMAG) traded as low as $37.70 today, down nearly 17% from the prior close of $45.25 due to purported safety concerns regarding Feraheme® [ferumoxytol], the company’s marketed product for the treatment of iron deficiency anemia [IDA] in adult patients with chronic kidney disease [CKD].
Despite the use of recombinant erythropoietin, anemia remains a significant problem for patients with CKD and end-stage renal disease [ESRD]. As such, parenteral iron formulations in conjunction with erythropoietin have become standard practice.
Iron replacement therapy background
All parenteral iron preparations consist of a central core containing elemental iron, shielded by a carbohydrate shell consisting of molecules such as dextran, sucrose, dextrin or gluconate. Once injected, the iron-carbohydrate complex is metabolized [by macrophage of the reticuloendothelial system] and the iron is released where it then binds to transferrin in plasma and the redundant carbohydrate moiety is then cleared by the liver. The degradation of the various iron complexes, however, is very different.
Iron complex degradation
In general, iron is most rapidly released from the smaller molecular weight compounds, and is released more slowly from the iron dextran preparations. These properties determine the maximum dose that can be administered at any one time. If too much intravenous iron is administered, there is a danger that the iron will be released from the complex too rapidly. This “free iron” overloads the buffering capacity of the transferrin molecule.
Parenteral iron reactions
“Free iron” reactions are anaphylactoid in nature. The symptoms are similar to the anaphylactic reactions seen in a small proportion of patients given dextran-based parenteral iron. This latter complication is thought to be associated with immunologic reactions to dextran, which resulted in black box warnings for iron dextran-based products and spurred the development of short-chain carbohydrate-based iron compounds [eg, gluconate or sucrose complexes] that were “believed” to be less immunogenic than dextran.
It has previously been noted that high molecular weight dextran formulations could induce allergic reactions more frequently than low molecular weight dextran formulations. This was validated by the publication of data from the FDA on reported adverse drug events [ADEs] related to the provision of three formulations of intravenous iron during 1998-2000 [Nephrol Dial Transplant (2004) 19: 1571-1575]:
- Low molecular weight dextran [INFeD®] by Watson Pharmaceuticals, Inc. (WPI)
- High molecular weight dextran [Dexferrum®]
- Non-dextran, sodium gluconate complex in sucrose [Ferrlecit®]
The publication covered more than 21 million doses of parenteral iron administered between 1998-2000. Overall ADE rates were low, with only 1,981 among the 21 million doses [or approximately 94 per million doses].
Interestingly, low molecular weight dextran [INFed®] produced the fewest number of serious ADE’s per million doses [11.6], yet the product caries a black box warning in its label. The serious ADE rate for Ferrlecit® [non-dextran] was nearly four times higher [49.6].
Introduced in 2000, Venofer® is another non-dextran parenteral iron agent. Based on use in an estimated 2 million patients that received Venofer® worldwide between 1992 and 2002, 83 hypersensitivity reactions have been reported, including serious or life threatening reactions. This translates into 41.5 serious ADEs per million, which is more than 3.5 times the rate reported for INFed®.
Regardless of the iron shield complex, parenteral iron-related ADE’s are rare. Despite the fact that life-threatening ADE rates are significantly higher among recipients of both high molecular weight dextran and non-dextran products than among recipients of low molecular weight dextran, such safety concerns have not translated into comparable black box warnings for either Venofer® or Ferrlecit® since their market introduction. As a non-dextran product, AMAG’s Feraheme should be viewed no differently, although investors are understandably nervous in view of a safety-conscious regulatory agency.
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