P&T News: September/October 2001

New Intravenous Iron Products: Increasing Patient Safety at UIHC

Linda M. Schrand, Pharm.D., Sarah J. Johnson, Pharm.D., Stefanie S. Berkoski, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Michael Flanigan, M.D.

The risk of arthralgias, myalgias, and hypotension is related to rate of administration. Administering IV iron dextran at a rate not exceeding 5 mg/min can lessen the incidence of these events. A test dose of 25 mg is also recommended to minimize the risk of complications. However, anaphylactoid reactions are not dose-related and may occur with the test dose. Patients who have previously had severe reactions to IV iron dextran have been successfully retreated, but such patients require premedication with prednisone, diphenhydramine, and a histamine type II receptor antagonist (e.g., cimetidine).³

The underlying cause of the immediate severe reactions is unclear. Either the iron or the dextran component may be the culprit. Because anaphylactic reactions have complicated the use of dextran volume expanders, the dextran component has been proposed to be the cause of the severe reactions to IV iron dextran. However, allergic reactions can occur on the first exposure, as there may be preformed antidextran antibodies. Additionally, the glucose polymers that make up the dextran chains are of varying sizes. The increased size and the variability of size have also been proposed to contribute to the anaphylactic response.⁴ Theoretically, IV iron products free of dextran may decrease or avoid these severe reactions and even deaths.

New IV Iron Products
In an effort to reduce or avoid adverse events related to IV iron, two new products that do not contain dextran have recently been marketed in the United States. The first product, sodium ferric gluconate complex in sucrose (Ferrlecit®), has been used in Europe for over 40 years and was introduced to the United States marketplace in 1999. The second product, iron sucrose (Venofer®), has also been used for decades in Europe, but was not licensed for use in the United States until late 2000.⁴ The properties of each of these products are compared to iron dextran in Table 1.

The reactions reported with sodium ferric gluconate are mild to moderate and occur at a lower rate as compared to iron dextran. The most common reactions are transient hypotension, flushing, rash, and gastrointestinal symptoms.⁵ A post-marketing study of the adverse drug reactions reported for sodium ferric gluconate in Germany and Italy from 1976 to 1996 found 74 reported allergies with no reported deaths. This compares to a total of 196 allergic events and 31 known deaths reportedly due to iron dextran use within the United States over the same time period. In comparing similar numbers of exposures between the two products, 3.3 allergic episodes occurred per million doses for sodium ferric gluconate and 8.7 allergic episodes occurred per million doses for iron dextran.6 Based on this large safety study, the product labeling for sodium ferric gluconate was revised to eliminate the need for a test dose.⁵

The product safety reports for iron sucrose also demonstrate a low incidence of adverse effects. In one study of 77 patients receiving a total of 757 doses, only 4 patients reported adverse events considered to be related to the administration of iron sucrose. The events reported were diarrhea, abdominal pain, nausea, constipation, and a transient minty taste. Of note, ten patients in this study had a documented history of sensitivity reactions to iron dextran that were consistent with anaphylaxis and did not experience a hypersensitivity reaction upon administration of iron sucrose.⁷ Another study evaluating iron sucrose specifically enrolled only patients with a documented history of mild or severe reactions to iron dextran. Twenty-three patients were enrolled --16 patients with reactions that were sufficiently severe as to preclude them from further iron dextran therapy and 7 patients who had previously shown evidence of anaphylaxis to iron dextran. These patients received a total of 223 iron sucrose doses with only three adverse events believed related to the therapy. One patient experienced two episodes of transient, self-limited metallic taste and one patient experienced infusion rate-related pruritus. No patient had to discontinue therapy due to adverse reactions to the iron sucrose.⁸

Table 1. Comparison of Available Formulations of IV Iron
	Iron Dextran (InFeD®)	Sodium Ferric Gluconate (Ferrlecit®)	Iron Sucrose (Venofer®)
Composition	A complex of ferric hydroxide with partially hydrolyzed dextrans of low molecular weight.9	Ferric saccharate centers chelated by gluconate, which has a high affinity for ferric ions and forms a bridge between ferric oxide centers. 10	The polynuclear inner sphere of ferric hydroxide is surrounded by sucrose molecules. 7
Molecular Weight	~5000 to 7500 daltons9	~350,000 daltons10	~43,000 daltons7
Comparative Rate of Iron Dissociation from the Complex	Slow11	Rapid10,11	Intermediate11
Clearance by Hemodialysis	Minimal12	Minimal5	Minimal12

Due to the evidence supporting the safety of these two new products as compared to IV iron dextran, the Pharmacy and Therapeutics Subcommittee has decided to remove iron dextran from the Formulary. Once iron dextran use is phased out, sodium ferric gluconate and iron sucrose will be the only IV iron products on Formulary and available for use. Because indications for use, adverse effects, and cost are similar, and because no studies are available comparing the two agents, both iron sucrose and sodium ferric gluconate will remain on Formulary.

Dosing and Administration of the New IV Iron Products

Repletion of Iron Stores

Multiple IV Dosing
Multiple IV doses are often used for repletion of iron stores when frequent administration of parenteral iron products is convenient for the patient (e.g., outpatient hemodialysis patients). In these patients, iron sucrose (Venofer®) and sodium ferric gluconate (Ferrlecit®) may be given as a slow undiluted injection (IV push) or a slow IV infusion.

When using multiple IV doses, iron sucrose (100 mg per visit) or sodium ferric gluconate (62.5 mg to 125 mg per visit) may be given one to three times per week for a total dose of 1000 mg. Iron sucrose may be administered by IV push at a rate no faster than 20 mg/minute or by slow intravenous infusion by diluting the product in 100 ml to 250 ml of 0.9% sodium chloride and administering over 1 to 4 hours. Sodium ferric gluconate may be given IV push at a rate not to exceed 12.5 mg/minute and as a slow infusion by dilution in 100 ml 0.9% sodium chloride and administered over 30 minutes (62.5 mg) to 1 hour (125 mg).^13,14 See Table 2.

Total Dose Replacement
One time total dose replacement of iron stores is a useful way to treat iron deficiency anemia when multiple infusions are not convenient. Iron sucrose has been given in doses up to 500 mg by slow IV infusion; doses up to 800 mg have been reported in a small number of patients.^7,8,15 Sodium ferric gluconate may also be given in doses up to 250 mg by slow IV infusion.^8,16,17 Because hypotension is related to the total dose administered and the rate of infusion, it may be best to administer large doses of iron sucrose as a 2 to 4 hour infusion; the manufacturer of sodium ferric gluconate recommends a 2-hour infusion if 250 mg is administered.¹⁶ See Table 2.

Test Dose
In contrast to iron dextran, a test dose is not required prior to administration of IV iron sucrose or IV sodium ferric gluconate.^13,14 Of three clinical trials performed in hemodialysis patients to obtain approval of iron sucrose, two did not include a test dose; however, some patients received a test dose at the physician's discretion.¹³ If a test dose is desired, 2.5 ml of iron sucrose may be diluted in 50 ml of 0.9% sodium chloride and administered over 3 to 10 minutes.¹³ For sodium ferric gluconate, 25 mg (2 ml) may be diluted in 50 ml of 0.9% sodium chloride and infused over 60 minutes.¹⁴

Intramuscular Use (IM)
IM administration of iron products is no longer considered a routine practice. Iron sucrose is strongly alkaline (pH 10.5 to 11.1) and should not be given subcutaneously or IM.13 Sodium ferric gluconate is not approved as an IM injection.¹⁴ Although iron dextran may be administered IM, the possibility of leakage into the subcutaneous tissue causing pain, discoloration of the skin, or bleeding and/or tissue necrosis, severely limits its IM use.¹⁷

Table 2. Dosing and Administration Guidelines13,14
	Sodium Ferric Gluconate (Ferrlecit®)	Iron Sucrose (Venofer®)
How Supplied	62.5 mg elemental iron diluted in 5 ml of sucrose (12.5mg/ml)	100 mg elemental iron diluted in 5 ml of water (20mg/ml)
Usual Dose for Repletion of Iron Stores	125 mg per dialysis for 8 sessions, for total dose of 1000 mg	100 mg one to three times per week for total dose of 1000mg
Total Dose Infusion	62.5 mg administered over 30 minutes or 125 mg in 100 ml NS administered over 1 hour or 250 mg in 250 ml NS given over 2 hours16	500 mg* in 250 ml NS administered over 2 to 4 hours
Test Dose Required	No	No
Approved for IM Use	No	No
IV Push Administration	May be given undiluted at a rate of 12.5 mg/minute (10 minutes)	A maximum of 100 mg may be given no faster than 20 mg/minute
Slow IV Administration	Dilute in 100 ml to 250 ml of NS and administer over 30 minutes to 2 hours	Dilute in 100 ml to 250 ml of NS and administer over 1 to 4 hours
Compatibility Information	Not compatible with other medications or parenteral nutrition solutions	Not compatible with other medications or parenteral nutrition solutions
Monitoring Serum Iron Levels	Use caution during the 5 days after infusion. False elevations in serum iron levels may be due to laboratory assay of iron still bound to the sodium ferric gluconate complex during the first 24 hours following administration. In addition, falsely decreased serum iron levels may occur due to a non-specific rise in serum iron levels that can persist for 5 days.	Reliable serum iron levels may be obtained 48 hours after IV dosing
*Doses up to 800 mg have been used in a small number of patients.7,8,15

Dosing Calculations
Parenteral iron, regardless of the product used, should be initiated at calculated doses based on the lowest dose required to restore hemoglobin levels and iron indices to appropriate levels. Total iron doses for iron deficiency anemia are calculated according to the patient's body-weight and total iron deficit as follows:¹⁸

Dose (in mg) for Adults and Children over 15 kg (33 lbs) Dose (in mg) for Children 5 to 15 kg (11 to 33 lbs) Dose (in mg) for Replacement after Blood Loss W= Weight (in lbs) Hgb = Hemoglobin Hct = Hematocrit *Assumes that 14.8 is the normal mean Hgb **Assumes that 12 is the normal mean Hgb

= 0.3 x W x [100- (Hgb x 100)/14.8]* = 0.3 x W x [100 &endash; (Hgb x 100)/12]** = Blood loss (in ml) x Hct

Use with Erythropoietin
Iron sucrose and sodium ferric gluconate have been used to decrease the use of erythropoietin (EPO) in chronic hemodialysis patients. This practice may result in substantial cost savings through decreased use of EPO. In one study, use of 62.5 mg sodium ferric gluconate given every 2 weeks allowed an average 33% decrease in the EPO dose, while the hemoglobin concentration increased 1.3 g/dl.¹⁹ Regular iron sucrose use has also resulted in decreases in EPO dose requirements (27 to 75% reductions), while maintaining stable or increased hemoglobin/hematocrit concentrations with maintenance use. ^20,21

Regular weekly doses of 100 mg IV iron sucrose for 1 year resulted in an average increase in hemoglobin from 9.6 to 10.7 g/dl in 116 dialysis patients. Over the same period of time, the average EPO doses decreased from 13,277 units/week to 8976 units/week. Monthly iron costs during the study totaled approximately $6400 for all 116 patients enrolled in the study. However, the reduced use of EPO resulted in an average cost savings of $240 per patient per month. The annual cost savings from decreased use of EPO was over $300,000, easily outweighing the increased cost of iron of $38,600. ²²

Summary
Based on the improved safety profile, the use of IV iron dextran will be phased out at UIHC. Sodium ferric gluconate and iron sucrose will become the only IV iron products available on the Formulary. Iron sucrose and sodium ferric gluconate are similar with regards to indication for use, adverse events, and cost. These products may be administered as multiple IV infusions or as a total dose infusion for the repletion of iron stores. Regular doses of IV iron in conjunction with EPO can be cost-effective in patients with chronic continuing blood loss.

References

1. Kidney Int 1999;55:S119-24.
2. Am J Kidney Dis 2000;35:1-12.
3. J Am Soc Nephrol 1999;10:2029-43.
4. Semin Dial 2000;13(6):381-4.
5. Am J Kidney Dis 2001;37:879-83.
6. Am J Kidney Dis 1999;33:464-70.
7. Am J Kidney Dis 2001;37:300-7.
8. Am J Kidney Dis 2000;36:88-97.
9. Martindale: 32nd Ed. 1999;1348-9.
10. Am J Kidney Dis 1999; 33:471-82.
11. Arzneim-Forsch/Drug Res 1992;42:1439-52.
12. Formulary 2000;35:498-513.
13. Venofer® injection package insert, 2000.
14. Ferrlecit® injection package insert, 2001.
15. Nephrol Dial Transplant 1997; 12:2801-2.
16. Correspondence with the Schein, 3/28/00.
17. InFeD® injection package insert, 1996.
18. InFeD® injection package insert, 1993.
19. Nephrol Dial Transplant 1996;11:1079-83.
20. Lancet 1994;344:1305-6.
21. Nephron 1996;72:413-17.
22. Am J Kidney Dis 1999;34(4 suppl 2):S40-6.

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