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Breaking New Ground in Intravenous Iron Therapy
to the dextran content of iron dextran preparations, not to the iron
Figure 1: Balance of Risks for Development of Oxidative
content, and therefore the non-dextran-containing preparations are
Stress Reactions versus Hypersensitivity Reactions for
largely spared the problems of hypersensitivity reactions.
2,3
Two
Parenteral Iron Preparations
retrospective studies examined serious adverse events reported to the
Toxic effects of labile iron
1
FDA in the late 1990s and early 2000s. Both concluded that the risk of
Correlates with molecular weight of iron complex
such a type 1 reaction is greatest for iron dextran preparations and is
High Low
substantially less for gluconate and sucrose complexes. One study looked
at the number of reported adverse events for a high-molecular-weight
Iron
Ferric
iron dextran (Dexferrum
®
), a low-molecular-weight dextran (Infed
®
), sucrose
carboxymaltose
(Venofer
®
)
sodium ferric gluconate (Ferrlecit
®
) and iron sucrose (Venofer
®
).
2
(Ferinject
®
)
Correlates with anaphylaxis risk
Immunogeni
The authors obtained data on all adverse events in the US reported to
the FDA between 2001 and 2003, and separated these into non-life-
Ferric
gluconate
c
threatening and life-threatening (death, cardiac arrest, coma and
(Ferrlecit
®
)
ity
2
anaphylactoid reaction). There were 1,141 adverse events reported per
30 million doses administered. The absolute rates of life-threatening
adverse events were 0.6 per million for iron sucrose, 0.9 per million for
sodium ferric gluconate, 3.3 per million for low-molecular-weight iron Iron
dextran
dextran and 11.3 per million for high-molecular-weight iron dextran. It
(Cosmofer
®
)
was concluded that while the risk of adverse events is relatively low, High
the risk was lowest with the iron sucrose preparation and highest with
1. Van Wyck DB, J Am Soc Nephrol, 2004;15:107–11.
iron dextrans.
2. Hörl W, et al., Nephrol Dial Transplant, 2007;22(Suppl. 3):iii2–iii6.
Another study looked specifically at reports of allergic reactions to IV
Table 1: Classification of Toxicities Associated with
Parenteral Iron
iron treatment with dextran (high- and low-molecular-weight
combined), sucrose and gluconate complexes between 1997 and
Short-term Long-term
2002.
3
A a result of the granularity of clinician reporting of these
Dose-related (oxidative stress-related), allergic Mortality infection
effects, the authors constructed four clinical categories describing
hypersensitivity adverse events (anaphylaxis, anaphylactoid reaction,
Table 2: Characteristics of Parenteral Iron Formulations
urticaria and angioedema), and converted their findings into 100mg
dose equivalents. All-event reporting rates were 29.2, 10.5 and 4.2
Iron Dextran Iron Sucrose Iron Gluconate
reports per million 100mg dose equivalents, while all-fatal-event
Ferric Carboxymaltose
Preparations InFeD
®
Dexferrum
®
Venofer
®
Fesin
®
Ferrlecit
®
reporting rates were 1.4, 0.6 and 0.0 reports per million 100mg dose
Ferinject
®
equivalents for dextran, sodium ferric gluconate and iron sucrose,
Characteristic Robust, strong Semi-robust, Labile, weak
respectively. Dextran had the highest reporting rates in all four clinical
moderately strong
categories. Sodium ferric gluconate had intermediate reporting rates
Molecular mass (kDa) >100 30–100 <50
for urticaria and anaphylactoid reaction, and a zero reporting rate for Degradation kinetics Slow Intermediate Rapid
the anaphylaxis clinical category. Iron sucrose had either the lowest or
Potential for oxidative stress Low Moderate High
a zero reporting rate in all clinical categories (see Figure 2).
3
Adapted from Crichton RR, Danielson BG, Geisser P (eds), In: Iron Therapy, with special
emphasis on intravenous administration, 4th edition, Uni-Med Verlag AG, 2008;71.
Ferric carboxymaltose, which is also non-dextran-containing, was not in categorised, with no iron received as the reference category. This rolling
use at the time of these studies. However, it is also likely to have a one-month risk of mortality associated with cumulative iron doses over
reduced risk of allergy. Therefore, the additional clinical benefits of non- the previous six months was determined over a 21-month period. Fitting
dextran agents include the avoidance of test doses and pre-medication. multivariable models that appropriately account for time-varying
measures of iron administration and many other fixed and
Mortality Associated with Parenteral Iron time-varying measures of morbidity, the authors found no statistically
For many years there has been ongoing controversy about the risk of significant association between any level of iron administration and
long-term adverse effects, especially mortality. Two recent observational mortality at doses up to 1,800mg over six months.
studies examined data from large US dialysis chains.
4,5
The sophisticated
analysis, which sought to account for many co-morbid, confounding A second study reviewed records of 58,000 haemodialysis patients in
and time-dependent variables, concluded that long-term use of the US, and included an examination of multiple markers of the
parenteral iron was not associated with increased risks of mortality. One malnutrition–inflammation–cachexia syndrome as well as those of
of these examined data reported from over 32,000 haemodialysis iron status.
5
This study included patients being treated with
patients within one dialysis chain in the US.
4
These patients had to have non-dextran-containing iron preparations. Compared with those who
completed at least one year of dialysis between 1996 and 1997, when did not receive IV iron, administered IV iron up to 400mg per month
only iron dextran was available. For each month beginning six months was associated with improved survival, whereas doses greater than
after the end of the enrolment period and continuing until death or 400mg per month tended to be associated with higher death rates.
censoring, parenteral iron exposure over the most recent six months was One additional interesting finding was that similar benefits accrued
EUROPEAN HAEMATOLOGY 59
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