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I.V. ferric carboxymaltose (FCM) permits rapid administration of up to 1000mg iron as a single dose. This paper provides answers to pertinent questions about FCM’s efficacy, safety and cost-effectiveness in clinical use
BSc MD FRCP
Department of Renal Medicine
Pharmacy Team Leader Haematology/Oncology
Pharmacy Team Leader Renal, King’s College Hospital, London
Iron, as an element, is essential for life, playing an important role in many key biological processes. The most important of these is in the synthesis of haem which forms the basis of haemoglobin, the oxygen-carrying protein in the blood. However, other processes associated with iron appear to have a significant effect on the overall health of patients, eg, in those with chronic heart failure. Lack of iron is one of the principal causes of anaemia in the general population. It is also a major factor in the development of anaemia associated with chronic kidney disease, which is associated with adverse cardiovascular outcomes and reduced quality of life.
Iron supplementation may be given orally, intramuscularly or intravenously, but in chronic kidney disease many patients require intravenous (i.v.) iron. This is because oral iron is poorly absorbed from the gastrointestinal tract due to upregulation of hepcidin, a peptide hormone that is central to iron homeostasis.[1,2] The i.v. iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell consisting of polymers such as dextran, sucrose or gluconate. This carbohydrate shell controls the iron release from the complex and also limits the total dose that can be given in any one administration.[3,4] Thus, iron from the iron sodium gluconate complex is released the most rapidly, and doses of 62.5–125mg are given as a single administration. For iron sucrose, doses of 200–300mg may be given fairly rapidly, whereas for iron dextran, doses up to 1g may be given as an i.v. infusion. Dextran polymers, however, have a potential risk of inducing anaphylaxis, although there is some evidence that this risk is lower with low molecular weight dextrans compared to high molecular weight compounds.
In recent times, two new i.v. iron preparations have been developed (ferumoxytol in the USA and ferric carboxymaltose [FCM] in Europe). Both of these preparations could potentially have a better safety profile than the more traditional i.v. compounds, since neither requires a test dose and both preparations may be given more rapidly than their predecessors.[6,7]
The purpose of this review is to discuss some pertinent issues in relation to FCM, which was licensed in Europe in June 2007. In order to ensure that this article is relevant to pharmacists, I asked two of the senior pharmacists in my hospital, Mee-Onn Chai from the Renal Department and Jackie Chappell from the Haematology Department, to put together a series of questions, which I have answered in turn.
Questions and answers on ferric carboxymaltose
1. What are the licensed indications for ferric carboxymaltose?
FCM is indicated for the treatment of iron deficiency when oral iron preparations are ineffective or cannot be used.
2. What is the therapeutic efficacy of ferric carboxymaltose?
The effectiveness of i.v. FCM has been demonstrated in randomised, multicentre, phase III trials in patients with a range of conditions associated with iron deficiency with or without anaemia, including chronic kidney disease,[9–12] chronic heart failure, heavy uterine bleeding, postpartum iron deficiency[15–17] and inflammatory bowel disease. Most of these trials have used oral iron as a comparator, and FCM was shown to produce the most rapid increases in levels of haemoglobin and serum ferritin levels. In addition, FCM maintained iron stores for longer than other i.v. or oral iron compounds, so that quality of life and fatigue scores were improved. FCM can also be used to treat functional iron deficiency (FID), which occurs when the demand for iron exceeds the amount of iron that can be obtained from the body stores. FID is common in chronic inflammatory conditions, such as chronic kidney disease, inflammatory bowel disease and chronic heart failure.
3. What is the licensed dose of ferric carboxymaltose?
Intravenous bolus injection
FCM may be administered by i.v. injection up to a maximum single dose of 200mg of iron per day but not more than three times a week.
Intravenous drip infusion
FCM may be also administered by i.v. infusion up to a maximum single dose of 1000mg of iron over at least 15 minutes, but not exceeding 15mg of iron per kg body weight or the calculated cumulative dose. The administration of 1000mg of iron as an infusion is not permitted more than once a week.
4. The calculation required to work out the dose is quite complex. Is it crucial to work out such a precise dose or is there a simpler way that the dose can be calculated?
This is a classical example of ‘science’ versus requirements for regulatory authorities. In developing a drug, the regulatory authorities are very strict with dosing and safety, and this requires very fine tuning in the development of a new agent. In practice, working out the dosage is, in my view, completely unnecessary, and we do not do this in routine clinical practice. Thus, if a patient requires a ‘lot’ of iron supplementation, then I would generally recommend 1g of FCM as a 15-minute infusion; if a lesser amount of iron supplementation is required, then 500mg of FCM can be given. Any additional ‘fine tuning’ is, in my view, not only unnecessary, but has no biological or scientific rationale.
There is, however, some dosage guidance that has been produced in a tabular form by Vifor Pharma for FCM, based on body weight and increase in haemoglobin that is required (Table 1). This tool is based on the Ganzoni formula, as specified in the Summary of Product Characteristics (SmPC).
5. How is ferric carboxymaltose administered?
FCM is administered only by the i.v. route, either by bolus injection undiluted, or by drip infusion diluted in sterile 0.9% sodium chloride solution.
6. Is further treatment with ferric carboxymaltose indicated if the cumulative iron deficit has been replenished but the patient’s laboratory results indicate that they are still iron deficient without any other obvious cause? If so, are there recommendations for a minimum time between courses or a maximum lifetime dose?
Any patient who fails to achieve the expected increase in serum ferritin following i.v. iron administration should be suspected of having significant occult or overt bleeding. In a pre-menopausal woman, menstrual loss is the most likely cause, whereas in men and post-menopausal women, occult gastrointestinal loss may be present. Thus, clinicians should have a low threshold for recommending further investigations in such patients. In the meantime, it is perfectly acceptable to give the patient a further top-up of i.v. iron. In patients with normal levels of haemoglobin but low serum ferritin levels, a further 500mg of FCM can be administered to replenish iron stores, although the treating physician should make the decision on the dose required.
7. Why is it specified in the SmPC that you can only administer doses by intravenous bolus injection a maximum of three times a week?
This specification is based on total serum iron levels and pharmacokinetic profiles from the early registration studies. In these studies, FCM was cleared from serum with a terminal half-life of approximately 7–12 hours. The pharmacokinetic profiles were satisfactorily characterised by an observation period of 24 hours with regards to the 100 mg dose level, and 72 hours regarding the 500–1000mg doses. These results provide the rationale for permitting three doses (up to 200mg of iron) per week by i.v. bolus injection, and only one i.v. infusion (1000mg of iron) per week.
8. Do you need to give premedication or a test dose when administering ferric carboxymaltose to prevent hypersensitivity reactions?
In contrast to iron sucrose, iron sucrose similar (ISS) preparations and iron dextran, FCM does not require a test dose before administration.[3,4]
9. Clinics in primary care settings may want to administer intravenous ferric carboxymaltose. The SmPC recommends that facilities for cardio-pulmonary resuscitation should be available. What are the minimum requirements that would be acceptable to make this safe?
Some parenterally administered iron preparations can cause hypersensitivity reactions. This is why the SmPC recommends that facilities for cardio-pulmonary resuscitation be available. However, in the clinical setting, we do not know what constitutes ‘minimum requirements’ for safe administration. These compounds are used extensively in the community setting with ambulatory patients (eg, home-dialysis patients) and the community health workers are only equipped with auto-injectable epinephrine devices in case of potential hypersensitivity reactions.
10. What are the main adverse events associated with ferric carboxymaltose?
Randomised, controlled clinical trials have demonstrated that FCM has a much lower rate of adverse events than oral iron, and most side effects are mild to moderate in intensity. The most common reported adverse event is headache, occurring in 3.3% of patients. Gastrointestinal disorders, injection site reactions and rash occur in less than 3% of patients. To date, more than 3,600 patients have been treated with FCM with no drug-related serious adverse events.[7,9,11,22,23]
11. What are the advantages and disadvantages of ferric carboxymaltose in comparison to other available intravenous iron preparations?
The greatest advantage of FCM is that, compared to earlier forms of i.v. iron, it is a more stable complex that allows a high dose of iron to be administered rapidly. For example, if a patient requires 1000mg of i.v. iron to correct his or her iron deficit, this can be administered 20 times more rapidly for FCM than for iron dextran (0.25 hours vs 5.86 hours) and 10 times more rapidly than for iron sucrose (0.25 hours vs. 2.7 hours). For iron sucrose, 1000mg of iron administration requires five hospital visits, rather than one visit for FCM. Moreover, as mentioned above, dextran-induced anaphylactic reactions are not associated with FCM and so test doses are not required. FCM is also pH neutral, thereby causing less pain at the injection site.
Clinical trials show that i.v. FCM also corrects iron levels faster than i.v. iron sucrose because it is more efficiently utilised.[11,12] In addition, haemoglobin and serum ferritin levels are maintained for longer after treatment.
12. What is the cost comparison against other intravenous iron preparations?
As discussed earlier, FCM is a novel i.v. iron product with a favourable safety profile which allows for administration of a high iron dose in a much shorter time-frame than other available i.v. iron preparations. As the studies cited in this section demonstrate, the acquisition costs of FCM are greater than for iron sucrose or iron gluconate, but these are offset by the lack of need for multiple injections and the more rapid administration times. In comparing costs, therefore, it is important to consider not only the drug acquisition costs but also the costs of travel and clinic visits.
A study by Szucs et al, which aimed at establishing the economic benefit of using i.v. iron in anaemia treatment, demonstrated that the cost of administration of 1000mg of iron was lowest for FCM compared with other i.v. iron preparations (Figure 1).
Pugh-Clarke et al. demonstrated that, although FCM (800mg) costs more than iron sucrose (200mg x four doses), there are several positive outcomes associated with single-dose FCM (Table 2). In this study, the costs associated with FCM were mitigated by reduced consumables and patient transport costs.
13. Are there any patient populations where it may be more cost effective to use ferric carboxymaltose?
As discussed previously, studies demonstrate that FCM is cost effective across all patient populations where health economic aspects have been studied. However, patients who may benefit in particular from the use of FCM are those with poor venous access and needle phobias, as well as those living large distances from the hospital. Furthermore, those patients with a very low ferritin level in whom multiple doses of other i.v. iron compounds may be required, might be better off receiving i.v. FCM.
Although FCM costs more than other i.v. iron preparations, because both administration times and the number of hospital visits may be reduced, it may work out more cost effective in the long run. FCM is particularly cost effective in patients who need iron 1000mg as a top-up.
Cost effectiveness is often discussed within the context of erythropoiesis-stimulating agent (ESA) usage; for example, in the treatment of chemotherapy-induced anaemia (CIA). Recent studies suggest that the efficiency of ESAs can be maximised by optimising iron stores and bioavailability. Szucs et al26 estimated the incremental cost effectiveness of adding i.v. FCM in patients with CIA in Switzerland. The authors concluded that adding i.v. FCM to ESA appears to be economically viable in patients with CIA because it engenders a marked increase in response rate.
FCM is a novel i.v. preparation that can be given more rapidly than previous i.v. iron products and does not require a test dose. It is used to replenish iron deficits when oral iron preparations are ineffective or cannot be used. When compared with oral iron, FCM increases haemoglobin and serum ferritin levels more rapidly in a wide range of conditions that cause iron deficiency. Although FCM may cost more than other i.v. iron preparations, cost-effectiveness studies demonstrate that total administration costs are lower with FCM. In addition, the costs associated with FCM are mitigated by reduced consumables and patient transport costs.
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