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Published on 29 April 2009

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Intravenous ferric carboxymaltose in treatment of postpartum iron-deficiency anaemia

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Postpartum iron-deficiency anaemia is common around the world, and current treatment modalities have their drawbacks. Ferric carboxymaltose is designed to be administered by rapid IV injection

RAK Jaiyesimi
FRCOG FWACS MBA LLM

Consultant in Obstetrics & Gynaecology

PV Bagade
MB BS

Specialist Registrar in Obstetrics & Gynaecology

Northumbria Healthcare
NHS Foundation Trust
North Tyneside
Hospital
North Shields
UK

Iron-deficiency anaemia is recognised as the most prevalent and disabling nutritional problem in the world, especially in the postpartum period.[1],[2] It represents a significant health issue in women, with more than half of the four million women who give birth each year in the USA developing iron deficiency, and approximately one million of these women progressing to iron-deficiency anaemia. Current treatment modalities – oral and intravenous iron and blood transfusions – have their drawbacks.

The global burden
In developing countries, the prevalence of iron deficiency anaemia ranges from 35% to 75%.[2] In Peru, 35% of women of childbearing age and 50% of pregnant women have anaemia.[3],[4]

There is evidence that postpartum anaemia is common among low-income women, even in resource-rich countries. Up to 40% of Hispanic and 48% of non-Hispanic African-American women are affected by this condition.[5]

In Europe, the prevalence of iron-deficiency anaemia in pregnant women varies from 6% to 30%. The highest levels are observed in countries where routine iron supplementation is not usually given during pregnancy.[6]

In spite of the lack of local data about postpartum iron-deficiency anaemia (PIDA), one can assume that the rate would be similar to the one for prevalence during pregnancy.

The personal impact
Postpartum iron-deficiency anaemia is an important cause of maternal morbidity and imposes a substantial disease burden during the critical period of mother–baby bonding. It has been associated with reduced mental and physical performance,  ncreased cardiovascular strain and exposure to blood transfusions. It not only adversely affects maternal mood, cognition and behaviour but may also give rise to developmental
deficits in infants of affected mothers.[7],[8]

Treatment of postpartum iron-deficiency anaemia
The currently available agents in the treatment of PIDA include oral and intravenous iron therapy. However, these therapies pose difficult challenges to effective iron replacement.

Oral iron preparations are associated with gastrointestinal side-effects such as nausea, vomiting, diarrhoea and constipation, which are primarily dosedependent. [8],[9] Hence, its efficacy is limited by patient noncompliance and inadequate duodenal absorption. However, it still remains the mainstay of treatment of iron-deficiency anaemia due to its cost-effectiveness and ease of administration.

Parenteral iron treatment is particularly advantageous in cases where oral iron therapy is not possible due to gastrointestinal side-effects and in patients with poor compliance or severe anaemia.[10],[11] Currently, there are four classes of intravenous iron that are used in practice – iron sucrose, iron dextran, ferric gluconate and ferric carboxymaltose.

Iron dextran is associated with risk of anaphylaxis in up to 0.6–2.3% of the patients and its use is limited.[12] Treatment with iron sucrose requires multiple doses, though it is much safer and more effective than iron dextran.[13]

Ferric carboxymaltose is a new non-dextran, type I polynuclear iron (III)-hydroxide carbohydrate complex, designed to be administered in large doses by rapid IV injection due to its nearly neutral pH and physiological osmolarity.[14] It does not require a test dose and can be administered in large (up to 1,000 mg) weekly doses. No upper dose limit is defined, although in trials the maximum allowed was usually set at 2,500–3,000 mg.

There have been three randomised controlled trials evaluating the efficacy and safety of this drug in the treatment of postpartum anaemia. Van Wyck et al published the results of a large, well-designed randomised controlled trial in August 2007, which found that IV ferric carboxymaltose (n = 174) was better tolerated, with a more rapid and reliable haemoglobin response, compared with oral ferrous sulphate (n = 178) when used for the treatment of postpartum anaemia.[15] The primary efficacy endpoint was defined as the proportion of patients with a haemoglobin increase of 2 g/ dl or more after treatment. It was also associated with a prompt rise in serum ferritin levels, higher transferrin saturation and serum iron levels and a fall in TIBC (total iron-binding capacity).

Statistically significant changes were observed in some non-haematological parameters such as fall in the serum phosphate levels. Reduction in the phos-phate levels after starting treatment for anaemia indicates cellular uptake of phosphate during accelerated erythropoeisis. A highly significant relationship between baseline-level phosphate and maximal decrease from baseline was observed in both arms of the study.

Seid et al, in a study comparing intravenous ferric carboxymaltose with oral ferrous sulphate in women with postpartum anaemia, found the hypophosphataemia to be transient and asymptomatic.16 The greater degree of phosphate fall in the IV iron-treated group likely reflects greater efficacy of IV iron in stimulating erythropoeisis, replenishing iron stores, or both.

However, there was no significant difference in the health-related quality-of-life assessments between the two groups. No serious drug-related adverse event occurred in either treatment group. One patient assigned to intravenous ferric carboxymaltose died seven days after the intravenous injection and autopsy confirmed peripartum cardiomyopathy. The event was not considered to be drug-related by the investigator. However, those assigned to intravenous ferric carboxymaltose were more likely to experience mild and transient skin disorders, mainly mild pruritus and rash shortly after the infusion, which resolved in 5–15 minutes.

Withdrawals from treatment due to drug-related adverse events occurred with one patient in the IV iron group and five patients in the oral iron group. The trial by Seid et al16 showed that ferric carboxymaltose-treated patients were significantly more likely to achieve a haemoglobin greater than 12 g/dl in a shorter time period with a sustained haemoglobin greater than 12 g/dl at day 42 and to achieve a haemoglobin rise of 3 g/dl or greater more quickly. In addition, higher serum transferrin saturation and ferritin levels were attained with ferric carboxymaltose. The trial showed that ferric carboxymaltose was superior to oral ferrous sulphate in the treatment of PIDA. The trial was limited by the fact that the study was considered only for up to 42 days, and longer trials will be needed to confirm whether the higher iron stores achieved signify a persistent treatment benefit in women with ongoing menses or subsequent pregnancy.

Breymann et al reported the results of a multicentre, open-label, randomised controlled trial comparing intravenous ferric carboxymaltose (n = 227) and ferrous sulphate (n = 117) to treat iron-deficiency anaemia in the postpartum period.14 Based on the primary efficacy variable (haemoglobin rise at week 12), iron carboxymaltose was considered to be at least as effective as ferrous sulphate. Again, increase in serum ferritin and transferrin saturation demonstrated replenishment of iron stores, which may indicate a particular advantage in those receiving recombinant human erythropoietin treatments where rapid and steady availability is important.

Ferric carboxymaltose was well tolerated, and treatment was not associated with any clinically relevant safety concerns. Statistically significant differences were seen with regard to administration site conditions such as burning (2.2%) and infusion site pain (1.3%) in the ferric carboxymaltose group, and arthralgia (1.7%) in the oral iron group. Two patients experienced severe adverse reactions with elevated hepatic enzymes and evidence of hypersensitivity. There was no significant differences in the overall adverse event profile (p = 0.510), and there were no safety concerns identified in breast-fed infants (n = 11).

This study demonstrated that compliance with oral iron and its inability to replenish iron stores is of particular concern in patients with more severe anaemia and that they are at high risk of recurrence once menstruation restarts. Ferric carboxymaltose, on the other hand, is a safe and effective treatment option for postpartum anaemia with a shorter treatment period, ensured compliance, no gastrointestinal side-effects and rapid replacement of iron stores. There have not been studies comparing the efficacy of this drug with other forms of parenteral iron in the treatment of postpartum iron-deficiency anaemia.

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Cost–benefit analysis
Oral iron preparations remain the mainstay of treatment of postpartum iron-deficiency anaemia due to their cost-effectiveness and ease of administration. However, in patients who require parenteral iron therapy, ferric carboxymaltose is quicker and easier to administer than the other parenteral iron preparations. The doses shown in Table 1 are for general comparison and do not imply therapeutic equivalence.[18] Although the basic cost of ferric carboxymaltose is higher than that of ferric gluconate and iron dextran, a cost-minimisation analysis adding in consumables, nursing time to administer the latter drugs and the cost of patient transport services can be argued to offset its higher cost.

Safety profile
In February 2008, a drug safety and risk management advisory committee of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research evaluated several studies and identified 10 deaths after intravenous ferric carboxymaltose exposure and no deaths after oral iron exposure.[19] Five of the deaths were from cardiac causes. The FDA was of the opinion that intravenous ferric carboxymaltose was associated with a mortality disadvantage compared with oral iron and that the available efficacy and safety data do not
support a favourable benefit–risk assessment for intravenous ferric carboxymaltose in the treatment of irondeficiency anaemia in postpartum women.

In March 2008, the FDA issued a non-approvable letter for intravenous ferric carboxymaltose requesting safety data from additional clinical studies, especially the mortality statistics. Hence, readers should be aware of the mortality signal associated with the above drug. The first study,13 which states that the maternal death was not considered to be drug-related and that no serious drug-related adverse events occurred in either treatment group, awaits clarification in the light of the FDA report.[18]

After reaching registration in 18 EU countries and in Switzerland, intravenous ferric carboxymaltose (Ferinject®) was launched in Germany in November 2007 and in Switzerland in February 2008. In May 2008 it was launched in the United Kingdom with a licence for the treatment of iron deficiency when oral iron preparations are ineffective or cannot be used.

The Scottish Medicines Consortium has completed its assessment of intravenous ferric carboxymaltose and advised that it is not recommended for use within NHS Scotland for the treatment of iron deficiency when oral preparations are ineffective or cannot be used. The licence holder has indicated an intention to resubmit.[18]

Conclusion
Intravenous ferric carboxymaltose has proven to be a drug with superior efficacy and reliability when used to treat postpartum iron-deficiency anaemia. It still has to be evaluated by organisations such as the National Institute for Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN).

Ferinject obtained a broad label for the indication of iron-deficiency anaemia based on several studies on patients with the condition due to heavy uterine bleeding, inflammatory bowel disease, chronic kidney disease or postpartum anaemia. More safety data are needed to ascertain its use in the treatment of postpartum iron-deficiency anaemia.

References
1. Yip R. J Nutr 1994;124(8 Suppl): 1479S-1490S.
2. World Health Organization. The prevalence of anaemia in women: a tabulation of available information. 2nd ed. Geneva: WHO; 1992.
3. Instituto Nacional de Estadística e Informática. Encuesta demográfica y de salud familiar 1996. República del Perú. Calverton, MD, Macro International Inc; 1997 (in Spanish).
4. Zavaleta N, et al. Prevalencia y determinantes de la anemia por deficiencia de hierro en una muestra representativa de gestantes en Lima Perú. Reporte final presentado a la Organización Panamericana de la Salud (OPS). Pan American Health Organization; 1993 (in Spanish).
5. Bodnar LM, et al. Am J Obstet Gynecol 2001;185:438-43.
6. Hercberg S, et al. Public Health Nutr 2001;4(2B):537-45.
7. Beard JL, et al. J Nutr 2005;135:267-72.
8. Perez EM, et al. J Nutr 2005:135:850-5.
9. Bodnar LM, et al. Am J Obstet Gynecol 2005;193:36-44.
10. Bhandal N, et al. BJOG 2006;113:1248-52.
11. Dede A, et al. Int J Gynecol Obstet 2004;90:238-9.
12. Walters BA, et al. Nephrol Dial Transplant 2005;20:1438-42.
13. Breymann C, et al. Eur J Clin Invest 2000;30:154-61.
14. Breymann C, et al. N. Int J Gynecol Obstet 2008;101:67-73.
15. Van Wyck DB, et al. Obstet Gynecol 2007;110:267-78.
16. Seid M, et al. Am J Obstet Gynecol 2008;199(4): 435.e1-7.
17. Scottish Medicines Consortium. Drug advice on ferric carboxymaltose. April 4, 2008. Available at www.scottishmedicines.org/smc/5768.html
18. Food and Drug Administration Center for Drug Evaluation and Research. Summary minutes of the Drug Safety and Risk
Management Advisory Committee. Available at: http://www.fda.gov/ohrms/dockets/AC/08/minutes/2008-4337m1-
Final.pdf
19. Urato AC. Obstet Gynecol 2008;112(3):703.

 



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