Intravenous Iron Sucrose for Children with Iron Deficiency Failing to Respond to Oral Iron Therapy

Abstract

Background

For decades parenteral iron has been used in patients with iron deficiency unresponsive to oral iron therapy and in hemodialysis-dependent patients receiving erythropoietin. Newer intravenous (IV) iron formulations such as iron sucrose have replaced high molecular weight iron dextran in dialysis patients; however, the use of parenteral iron in children without renal disease has not been well defined.

Procedure

Pharmacy records were reviewed on children (≤ 18 yrs of age) who received IV iron sucrose at Children's Medical Center Dallas between January 1, 2004 and June 30, 2009. Patients who received iron sucrose for chronic renal disease were excluded from analysis.

Results

Thirty-eight children received iron sucrose for non-renal indications, 13 with iron deficiency refractory to oral iron therapy, 13 with iron malabsorption or dependence on parenteral nutrition, 7 for chronic gastrointestinal blood loss, and 5 for miscellaneous indications. Among these 38 children, who received a total of 510 doses of IV iron sucrose, there were only 6 adverse reactions. Patients in all categories had a good response to the iron sucrose, with a median hemoglobin rise of 1.9 – 3.1 g/dl depending on the indication.

Conclusions

Parenteral iron is a safe and effective means to treat iron deficiency in children who cannot receive or do not respond to oral iron due to intolerance, poor adherence or iron malabsorption.

Introduction

Iron deficiency affects approximately 700,000 toddlers and 7.8 million adolescent females and women of childbearing age in the United States, about one third of whom have frank anemia.[1] A common etiology of iron deficiency anemia (IDA) is poor dietary iron intake, especially in the toddler who consumes large quantities of cow's milk. Cow's milk has low iron content, inhibits iron absorption from other foods and may lead to occult gastrointestinal blood loss.[2] Other causes of IDA in children are chronic blood loss from the gastrointestinal tract or menorrhagia. Rarely patients may present with an iron absorption defect due to medications such as proton pump inhibitors, short bowel syndrome with or without dependence on total parenteral nutrition, or primary malabsorption of iron. In the latter situations, oral iron therapy is impractical so iron must be given by the parenteral route, whereas in toddlers or adolescents non-adherence to oral iron is common so these children may also benefit from parenteral iron therapy.

For decades parenteral iron has been used to treat iron deficiency unresponsive to oral iron therapy and hemodialysis-dependent patients receiving erythropoietin. High-molecular weight (HMW) iron dextran, employed extensively in the past, frequently causes anaphylactic reactions, so its use and the use of other parenteral iron preparations in children with hematologic disorders has been very limited. Other iron preparations, including low molecular weight (LMW) iron dextran (INFeD^®, Watson Pharmaceuticals, Inc), iron sucrose (Venofer^®, American Regent, Inc.), ferric gluconate (Ferrlecit^®, Sanofi-Aventis), and the newest formulation, ferumoxytol (Feraheme^®, AMAG Pharmaceuticals), have generally replaced HMW iron dextran for use in both adults and children with chronic kidney disease due to their more favorable safety profiles. [3,4] Intravenous (IV) iron sucrose was approved by the FDA in 2000 for patients with non-dialysis dependent patients receiving or not receiving erythropoietin therapy and for dialysis dependent chronic kidney disease receiving erythropoietin. Iron sucrose has been reported to be safe and effective in adults with iron deficiency due various non-renal causes, including pregnancy or inflammatory bowel disease. [5-12] Since use of IV iron in children without kidney disease has to our knowledge been extremely limited [13-16], we sought to retrospectively review our institution's experience with IV iron sucrose in children with or at risk of iron deficiency and not having kidney disease.

Methods

Pharmacy records were reviewed on all patients ≤ 18 yrs of age who received at least one dose of IV iron sucrose at Children's Medical Center Dallas between January 1, 2004 and June 30, 2009. Patients with chronic renal disease were excluded from subsequent analysis. Complete medical records were then reviewed for patients receiving iron sucrose for other indications. Data abstracted included primary indication for iron sucrose, underlying diagnoses, prior iron therapy, laboratory values before and after therapy, and adverse reactions. We also collected information on the dosing and administration of iron sucrose. This retrospective study was approved by the Institutional Review Board at The University of Texas Southwestern Medical Center at Dallas. The response to oral and IV iron was analyzed using a paired t-test with significance set at 0.05.

Results

Patient Characteristics

One hundred fifty-seven children received at least one dose of IV iron sucrose during the study period, of whom 116 patients were excluded because of chronic kidney disease and 3 patients with insufficient medical records. The remaining 38 patients who received iron sucrose for other indications were analyzed (Table I). These children ranged in age from 3 months to 18 yrs (median 5 yrs). Thirteen patients received IV iron sucrose due to iron deficiency anemia non-responsive to oral iron therapy, the majority of whom had displayed poor adherence to oral iron or side effects that made it difficult to complete their treatment course. Before IV iron therapy one of these children underwent an iron absorption test [17], which showed a 10 fold increase in serum iron (from 24 mcg/dl to 247 mcg/dl) 1 ½ hours after a 1 mg/kg oral elemental iron dose. IV iron sucrose was also given to 13 patients with a chronic gastrointestinal disorder complicated by iron malabsorption or because of dependence on parenteral nutrition and to 7 children for ongoing chronic gastrointestinal blood loss. This latter group suffered from a variety of conditions which limited the effectiveness of oral iron supplementation primarily because of the large amounts required for maintenance of iron stores and the desire to avoid regular blood transfusions. Two patients received IV iron sucrose for presumed iron refractory iron deficiency anemia (IRIDA) [18], although no genetic testing was performed to confirm this diagnosis. Three children had anemia secondary to inflammation as an indication for iron therapy although the decision to treat with iron was not entirely clear from review of the medical record; only 1 had iron deficiency documented prior to iron sucrose administration. The patients and their indications for iron sucrose are summarized in Table I.

Table I.

Characteristics of the 38 children receiving iron sucrose

Patient	Age (years)	Etiology of absolute or relative iron deficiency	Total dose of iron sucrose (mg)	Total # of individual doses
Non-adherent/intolerant to oral iron
1	17	Menorrhagia	700	2
2	16	Menorrhagia	900	3
3	17	Menorrhagia	300	1
4	17	Menorrhagia	800	3
5	17	Chron's disease	1900	8
6	18	Poorly controlled SLE and inflammation	300	3
7	4	Intermittent gastrointestinal blood loss, unclear etiology	300	3
8	17	Dietary iron insufficiency	800	4
9	3	Dietary iron insufficiency	72	2
10	2	Dietary iron insufficiency	250	2
11	3	Dietary iron insufficiency	200	2
12	5	Dietary iron insufficiency	42	1
13	3	Dietary iron insufficiency	525	7
Malabsorption
14	19	Short bowel syndrome and TPN dependency	250	5
15	11	Short bowel syndrome and TPN dependency	3700	37
16	9	Short bowel syndrome and TPN dependency	100	1
17	2	Short bowel syndrome and TPN dependency	120	3
18	1	Short bowel syndrome and TPN dependency	60	3
19	1	Short bowel syndrome and TPN dependency	50	1
20	4	Chronic gastritis	200	2
21	4	Chronic gastritis	300	12
22	5	TPN dependency	30	3
23	3	TPN dependency	200	2
24	6	TPN dependency	700	7
25	12	TPN dependency	66	1
26	2	TPN dependency	50	1
Chronic gastrointestinal blood loss
27	16	Intestinal venous malformations	25500	255
28	9	Intestinal venous malformations	2500	25
29	8	Intestinal venous malformations	200	1
30	15	Chronic proctitis	700	3
31	19	Blue rubber bleb nevus syndrome	19200	64
32	4	Liver transplant and chronic GI bleeding	400	3
33	7	Ulcerative colitis	350	14
Other
34	6	Anemia of inflammation	1100	22
35	18	Anemia of inflammation	75	1
36	4	Anemia of inflammation	200	1
37	2	Iron refractory iron deficiency anemia	120	2
38	3	Iron refractory iron deficiency anemia	400	4

Dosing and administration of IV iron sucrose

The number of IV iron sucrose infusions per patient ranged from 1 to 255 (mean 13, median 3), and the individual doses ranged from 25mg to 500mg (median 100mg). Three children received a single dose each of iron sucrose greater than the recommended maximum to prevent adverse reactions.[19] Iron sucrose was diluted in a maximum of 250mL of normal saline and administered over 15 minutes to 3.5 hours, depending on dose and patient weight. Only 7 of the total 510 doses given were preceded by a test dose. The wide variation of doses and schedules employed reflected physician choice and lack of clear guidelines in the package insert.

Efficacy

Table II shows the response in each group of patients to both oral iron and IV iron sucrose. The response to oral iron was determined by the difference in the hemoglobin concentration just prior to oral iron therapy and immediately prior to switching to iron sucrose. The response to IV iron sucrose was then measured by the difference between hemoglobin value just prior to starting iron sucrose and either the most recent value obtained after IV iron sucrose (if continuing treatment) or when the course of IV iron sucrose ended. IV iron sucrose was effective at raising the hemoglobin concentration in all 4 patient groups and was superior to oral iron in the children refractory to oral iron or with malabsorption (p<0.001 and p=0.04, respectively).

Table II.

Response to both oral iron and IV iron sucrose based on indication for IV iron therapy

Primary indication for IV iron sucrose	n	Median hemoglobin rise after oral iron, g/dl (range)*	Median hemoglobin rise after IV iron sucrose, g/dl (range)
Non-adherent/intolerant to oral iron	13	0.05 (−1.0, 1.0)	3.1 (0.8, 7.6)
Malabsorption	13	0.4 (−0.4, 3.3)	1.9 (−2.7, 5.8)
Chronic blood loss	7	0.65 (−1.4, 5.7)	1.9 (0.2, 6.6)
Other†	5	1.1 (0, 2.2)	2.1 (0.6, 2.7)

^*Oral iron therapy not previously administered to 8 patients

^†Iron refractory iron deficiency anemia (n=2), anemia of inflammation (n=3)

Adverse events

Among the 38 children who received a total of 510 doses of iron sucrose, 6 adverse reactions in 6 patients were attributed to the infusions. Five were mild and included headache (n=1), abdominal pain (n=2), transient mild hypotension (n=1) and vasovagal syncope (n=1). The doses of iron sucrose associated with these mild adverse reactions ranged between 100 mg to 300 mg (3.0 mg/kg to 5.1 mg/kg). The only serious reaction occurred in a 15 year old female weighing 57 kg who received 500 mg iron sucrose diluted in 250mL of normal saline over 35 minutes. Approximately 10 minutes following completion of the infusion the patient developed body aches, facial swelling, thready pulse, and hypotension but promptly recovered following epinephrine, diphenyhydramine and methylprednisolone. This dose was greater than the recommended maximum dose of 300 mg. [19]

Adverse reactions to the oral iron supplements, primarily ferrous sulfate, were also reported in 10 of the 28 evaluable patients who had previously been treated with oral iron. These reactions were abdominal pain, nausea or vomiting in 8 and constipation in 2 patients. One patient additionally reported intermittent leg cramping after starting ferrous sulfate.

Discussion

Intravenous iron sucrose is FDA approved only for patients with chronic renal disease. Reports of its safety and efficacy in this population have been very positive. Although there are also favorable reports of its use in adult cancer patients, [12,20] in pediatric practice parenteral iron preparations have been slow to be adopted outside of the chronic renal failure population. However, it is logical that circumstances exist in which IV administration might be the preferred route of iron replacement in children and adolescents.

To our knowledge only a few such reports of iron sucrose exist in the literature. The best described series includes 45 patients in Israel with iron deficiency due to nutritional iron deprivation and various other causes who had failed previous treatment with oral iron. [15] They received 5 mg/kg/day of elemental iron in the form of IV iron sucrose until the calculated iron deficit was replete. These children had an excellent response, with a significant increase in hemoglobin concentration at both 14 days and 6 months following treatment. Iron sucrose was well tolerated, with only one patient having transient hypotension and emesis and two patients experiencing drug extravasation. Our current study confirms these findings. Iron sucrose has also been safely used in combination with erythropoietin in infants with anemia of prematurity [14] and for rapid correction of iron deficiency anemia in children. [13] In this latter study, 62 children with iron deficiency received IV iron sucrose over 2-3 days to replenish their calculated iron deficit. The authors reported an improvement in hemoglobin and iron parameters during the first two months after therapy, but the iron stores began to decline by 3 months after therapy without ongoing supplementation. Approximately 13% of patients in this study reported mild adverse effects including rash, fever and irritability during or shortly after the infusion. Unfortunately further information about the patients and the indications for iron therapy is unavailable.

Intravenous iron preparations other than iron sucrose have recently been studied in adults and children. Sodium ferric gluconate complex has demonstrated a similar safety profile to iron sucrose in children receiving hemodialysis who were treated with erythropoietin.[21] Like iron sucrose, ferric gluconate must be given in divided doses, which is not convenient for most conditions encountered by hematologists including iron deficiency resulting from poor dietary intake. The benefit of the iron polysaccharide formulations (iron sucrose and ferric gluconate) is the low rate of serious adverse events and the lack of needing a test dose prior to administration.[22] Another IV iron product, ferumoxytol, has also been safely utilized in adults for the treatment of iron deficiency anemia in chronic kidney disease.[23] The side effect and efficacy profiles of this agent appear favorable. Although most pediatric hematologists have avoided iron dextran infusions in view of reports of serious adverse events, LMW iron dextran has a similar safety profile to iron sucrose in adults and therefore may be a reasonable alternative to the non-dextran iron preparations, but pediatric studies are lacking.[24-26] A major benefit of LMW iron dextran and ferumoxytol is the ability to replace the iron deficit in a single large infusion rather than divided doses.[23,27,28]

In patients with chronic kidney disease 100 mg of undiluted iron sucrose is typically administered as a slow IV push over 2 to 5 minutes, repeated one to three times weekly.[29,30] Unlike patients with renal failure receiving dialysis, most children with iron deficiency anemia, especially when secondary to dietary deficiency or acute blood loss, do not require ongoing iron replacement once their iron stores are replete. Therefore optimal therapy would correct the iron deficit using the fewest doses possible with the least side effects. Unfortunately doses of iron sucrose greater than 200 mg as a IV push or 300 mg as an infusion have been poorly tolerated, and doses of 400 mg or more may lead to hypotension, abdominal pain, and nausea/vomiting.[19] Our experience in one case confirms these findings. These dose dependent adverse effects are not thought to represent anaphylaxis, but rather vasoactive reactions due to circulating free iron since the non-dextran iron preparations do not bind iron as avidly as dextran. [19,31] Circulating transferrin may thus become temporarily oversaturated during the infusion, resulting in circulating free iron which can be toxic. Based on our and the limited published experience with iron sucrose we propose a dosing strategy [Table III] using IV iron sucrose for the initial repletion of the iron deficit in children with iron deficiency anemia who are refractory to oral iron. It should be noted that this approach has not yet been formally evaluated but is based on a similar dosing schedule used in all but 3 of the patients reported here.

Table III.

Recommended treatment regimen using IV iron sucrose for initial repletion in children with iron deficiency anemia

1. Calculation of total iron deficit for initial repletion:[29]
Total cumulative dose (mg) = [Target Hb − Actual Hb] × weight(kg) × 0.24 + [15 × weight(kg)]
*Hb in g/dl
2. Dosing:
a) Divide calculated total cumulate dose and give every 3-7 days until total dose is administered.
b) Recommended maximum single dose is 300 mg or 7mg iron/kg to prevent adverse effects.
3. Administration:
Children (>1month of age):	Dilute doses ≤ 100mg 1:1 with NS. Infuse over 30 min.
	Dilute 200mg in 200 mL NS. Infuse over 1 hour.
	Dilute 300 in 250mL NS. Infuse over at least 1 ½ hours.
Test dose: Not necessary.

We acknowledge several limitations of our analysis, given that it is retrospective. Therefore the decision to treat and the dosing of iron sucrose, dependent on the individual treating physician, was not standardized. Side effect data are accordingly limited to comments recorded in the medical record and were not systematically collected. In addition, not all children had iron studies performed prior to initiation of iron therapy, so we are therefore unable to comment on the effect of iron sucrose on various iron measurements compared to the effects of oral iron therapy. Despite these limitations we believe that this study strongly supports the limited published data describing the use of IV iron preparations in children with iron deficiency in various clinical settings.

In conclusion, parenteral iron is a safe and effective means to treat and/or or prevent iron deficiency in children who 1) do not respond to oral iron due to intolerance or poor adherence, 2) cannot absorb oral iron due to congenital or acquired gastrointestinal disorders, and 3) who have ongoing blood loss making preventive oral supplementation ineffective. Prospective studies of IV iron preparations in children using standardized dosage guidelines are indicated to confirm and extend these results.