PARENTERAL IRON DEXTRAN THERAPY

Vanessa J. Kumpf and Eileen G. Holland

ABSlRACf: Parenteral iron thernpy is indicated in patients with iron-deficiency anemia associated with conditions that interfere with theingestion or absorption of oral iron. Replacement doses of ironrequired to replenish iron stores are based on body _ight and theobserved hemoglobin value. Methods of administering iron dextrnnare reviewed, including intmmuscular and intravenous injections ofthe undiluted drug, intravenous infusion of a diluted preparation, andas an addition to parenteral nutrition solutions. The overall incidenceof adverse reactions associated with the parenteral administration ofiron is low, but the potential for an anaphylactic reaction requires thatan initial test dose be given followed by careful patient observation.

DICP Ann Pharmacother 1990;24:162-6.

parenteral iron.4 Another indication for parenteral ironmay be in the patient with significant blood loss whorefuses blood transfusions and in whom oral iron adminis-tration is not possible.'

Product Information

Iron dextran injection is commercially available as a ster-ile solution of iron dextran complex containing 5% iron and20% dextran. It contains 50 mgimL of elemental iron, mostof which is present in the ferric state. Iron dextran is astable, clear brown solution available in 2- and 5-mLampuls and a 10-mL multiple-dose vial. Because of itsphenol content, the multiple-dose vial should only be usedfor intramuscular administration.6 In the blood, iron dex-tran is a highly stable complex from which elemental iron isslowly released to the carrier protein, transferrin.

IN GENERAL, CHRONIC BLOOD LOSS is the most commoncause of iron deficiency and, more specifically, gastroin-testinal blood loss is the most common cause of iron-defi-ciency anemia. Therapy for iron-deficiency anemia in-cludes treatment of its underlying cause and restoration ofnonnal hemoglobin concentrations and iron stores. In theacute setting blood transfusion may be indicated topromptly supply oxygen to tissues; however, the mainstayof treatment is iron replacement accomplished by the oral,intravenous, or intramuscular routes. Although the oralroute is preferred, situations exist in which the parenteralroute is indicated. This article will review the use of paren-teral iron therapy, including guidelines for dose and admin-istration, adverse effects, and its use in parenteral nutritionsolutions.

Intravenous vs. Intramuscular Route

Once it is decided to replace the iron stores parenterally,it must be determined whether to give the iron via the.

- ~ ~ ~

dose that can be administered im is limited to 2 mL (100mg) per injection. Therefore, up to 20 injections may beneeded for a single course of therapy.7 Not uncommonly,patients experience considerable discomfort secondary tothe multiple injections. Multiple im injections may also bea problem in the malnourished patient with limited musclemass. Other risks include bleeding, staining of the skin,formation of sterile abscesses, tissue necrosis or atrophy,and sarcoma formation.7-9 The Z-track technique of iminjection, in which the subcutaneous tissue over the injec-tion site is firmly pushed aside before inserting the needle,may minimize skin staining.

In view of the numerous problems associated with imadministration, the iv route is generally preferred whenever

Indications

Indications for the administration of iron via the paren-teral route are limited (Table 1).1-4 Candidates for paren-teral iron therapy are those patients who have iron-defi-ciency anemia associated with the inability either toadequately absorb or tolerate the oral intake of iron. Non-compliance with oral iron dosage regimens may also be anindication for parenteral iron therapy.

In addition, there are less obvious conditions that war-rant parenteral iron therapy. Hemodialysis, which chron-ically results in significant blood loss, may necessitate theuse of parenteral iron therapy to restore the hemoglobinlevel. A high intake of antacids or other substances that bindto iron and inhibit its absorption may also warrant the use of dextran administration.

VANESSA J. KUMPF, Pharm.D., is a Clinical Phannacist, Nutritional Support,Department of Phannacy, OJrist Hospital and Medical Center, 4440 W. 95th St., OakLawn, IL 60453; and En-EEN G. HOLLAND, Phann.D., is a Clinical ~yResirenl-Fellow, Department of Family Medicine, Uni~ty of Ge.H"gja and MedicalCollege of GeAJrgia. Reprints: Vanessa 1 Kwnpf, Phann.D.

Total Dose Infusion

162 . D1CP, The Annals of Pharmacotherapy. 1990 February, Volume 24

Dosage and Administration

The amount of iron required to restore the hemoglobinconcentration to normal and to replenish iron stores is basedon body weight and the observed hemoglobin value. Thedose is calculated using the following equation:18

14.8where wt = weight in pounds and Hgb = observed hemo-globin level in gidL. This equation assumes a normal meanhemoglobin of 14.8 gidL. For children weighing less than13.6 kg a normal mean hemoglobin of 12.0 gidL is used inplace of 14.8 in the above equation.19

To determine the iron replacement dose in patientsactively bleeding, a different equation is used. Estimatediron requirements are based on the assumption that I mL ofnormocytic, normochromic erythrocytes contain I mg of

Table 2. Methods of Iron Dextran Administration

INrERMm'ENT1M

INI'ERMm'ENTIV mI

Dose !KIt to exceed 100 !KIt to exceed 100 IKIrninister calcu-mg (2 mL) per mg (2 mL) per laled replocementinjection injection dose over 2-6 h

!KIt to exceed !KIt to exceed 100100 mg/d mg/d(manufacturer rate: !KIt to exceedrecommendations) 50 mg/min

(manufacturerrecommendations)

L - - IKIrninister IKIrninister 250-1 (XX) mL ofundiluted undiluted NaCI 0.9%

injectionTest dose 25 mg (0.5 nIL) im 25 mg (0.5 mL) iv IKIrninister

observe patient observe patient approximately 25for at least I h for at least Ih mg of diluted

preparation by ivinfusion over5-10 minobserve patient forat least Ih beforeresuming dteinfusion

Diluent

- - - -tions were identified as those requiring resuscitative treat-ment. In all seven cases the reaction occurred withinminutes of starting the infusion, the women were in thethird trimester of pregnancy, and all recovered from theincident with no ill effects. Although no cause to explainthis unexpectedly high incidence of reactions was identi-fied, the authors felt this fonD of treatment could no longerbe justified.12 Numerous letters to the editor followed thepublication of the study questioning the results.\3-15 Rea-sons attempting to explain why the results of this studydiffered from the experiences of others included: (I) possi-ble differences in technique; (2) the group of patients stud-ied; (3) underlying folic acid deficiency which may havebeen present resulting in enhanced susceptibility to a reac-tion; and (4) the use of dextrose 5% injection as the diluentinstead of NaCI 0.9%.

Subsequent studies have been conducted to support thesafety and efficacy of the TDI technique of iron dextranadministration.3.7.16.17 Halpin et al. studied six childrenwith inflammatory bowel disease and iron deficiency ane-mia. The children received a single dose of iron dextran275-840 mg in 200 mL of NaCI 0.9% over two hours. Allpatients demonstrated a satisfactory hemoglobin response(average increase in hemoglobin was 3.5 g/dL) with noobserved adverse reactions.17

Benito and Guerrero compared the response of a singleiv infusion to multiple im injections of iron dextran in 27malnourished children with iron-deficiency anemia. Eigh-teen children received a single iv infusion of iron dextranand the remaining nine received multiple im injections on adaily or every-other-day basis until the entire calculateddose was administered. Periodic follow-up studies wereperfonned in nearly all of the children for three months. Arise in mean hemoglobin and hematocrit values was notedin each treatment group and one child in each groupdeveloped an urticarial rash. No other adverse reactionswere noted. 7

Auerbach et al. administered a TDI of iron dextran to 87patients with anemia to better define the type and frequencyof adverse reactions and to detennine if the rate of infusionor premedication influenced the frequency of adverseeffects. The results demonstrated that there was no dif-ference in the frequency of adverse effects associated withan infusion at a rate of 2 mg/min compared with 6 mg/min.Premedication with aspirin, diphenhydramine, or steroids

Table I. Indications for Parenteral Iron Therapy

FDA yes yes noapprovedComments inject deeply into iron dexbM die use of dextrose

die uJ'Ix:r outer injection contain- 5% injection in-quadrantofdle ing phenol should stead ofNaClbuttock not re used for iv 0.9% as die diluentto ~ skin injection is associated wim astaining: higher incidence of(I) use me Z-track local pain andtechnique phlebitis(2) use a separateneedle to withdrnwdrug fromcontainer

Conditions interfering with absorption of oral iron. e.g.:shorl-bo_1 syndromesubtotal gastrectomymalabsorption syndromechronic ~l obstructioninflammatory bo_l diseaseprotein calorie malnutritionhigh intake of antacids

Hemodialysis!\)or compliance with oral iron regimen

FDA = RxJd aIKi Drug Administration; ffil = tolai dose infusion.

DICP, The Annals of Pharmacotherapy. 1990 February, Volume 24 . 163

elemental iron. The dose of iron replacement secondary toblood loss is estimated using the following equation:6

Iron dextran injection (mL) =0.02 x blood loss (mL) x Hct

where Hct = observed hematocrit expressed as a decimalfraction.

may also exist for malnourished patients with low serumtransferrin concentrations. When these patients are given asubstantial amount of iron, an excessive level of circulatingfree iron may result. Therefore, a blood transfusion may bean option to consider in patients with severe protein mal-nutrition who require treatment for iron-deficiency ane-mia.22

Hepatosplenic siderosis, the accumulation of iron in theliver and spleen, has been observed in hemodialysispatients receiving long-term intravenous iron dextrantherapy. 23 These patients may exhibit a paradoxicaldepletion of iron in the bone marrow and only smallincreases in hematocrit values. A lack of equilibriumbetween iron taken up by the reticuloendothelial system(primarily liver and spleen) and marrow iron may exist inthese patients. The result is a lack of accessible iron forerythropoiesis. Also contributing to the risk of developinghepatosplenic siderosis with parenteral iron dextran is thatthis route bypasses the intestinal mechanism for the regula-tion of iron absorption coupled with a limited ability of thebody to excrete excessive amounts of iron. 24

Individuals with a history of allergies, asthma, or activeinflammatory disease appear to be highly susceptible to theadverse effects of iron dextran. Other high-risk patients arethose with active rheumatoid arthritis or active systemiclupus erythematosus. An 80-90 percent risk of developingan adverse reaction has been reported in these patient popu-lations.1 Therefore, extreme caution should be observedwhen administering iron dextran to these groups of patientsand they should all receive the standard test dose. Pre-medication with methylprednisolone 100 mg iv is also rec-ommended.3

-solution (0.5 mL) or as an iv infusion of a diluted TDIdelivered over five to ten minutes. After the test dose isgiven, the patient should be observed closely for at leastone hour. In the absence of untoward reactions, patientsreceiving a TDI may be given the remaining solution overthe next two to six hours.3

Adverse Reactions

The reported incidence of adverse reactions followingiron dextran administration is low. In one series of 481 irondextran recipients, 26 percent experienced a reaction, but inonly 5 percent of these (25 patients) did the reaction limit orinhibit ordinary activity.4 It is important to note that theincidence of adverse reactions associated with the im routeis similar to that with the iv route. 1.4 Complications associ-ated with the administration of iron dextran can be classi-fied as mild, transient reactions; more severe, systemiccomplications; and anaphylactic reactions.

Mild and transient reactions such as malaise, flushing,fever, myalgia, and arthralgia are the most common andgenerally appear within 24 hours of administration. Moresevere systemic reactions include headache, dizziness,hypotension, urticaria, diaphoresis, nausea, vomiting, diar-rhea, delayed arthralgia, generalized pain, and lymphad-

Addition to Total Parenteral Nutrition

Total parenteral nutrition (TPN) solutions have beenused as a vehicle for the administration of iron dextran inboth maintenance2ll.2S and therapeutic replacementdoses.2.5 Iron is not routinely added to TPN solutions andis not a component of current injectable multiple trace-ele-ment preparations. Although protein hydrolysate solutioncontained an amount of iron that appeared to meet dailyrequirements, its use has been replaced with syntheticamino acid solutions that contain only negligible amountsof iron.26,27 Iron supplementation is not required duringshort-term therapy in patients without existing iron defi-ciency. However, the use of low-dose daily or periodic ironsupplementation via TPN solutions in patients receivinglong-term therapy (e.g., two to three months or longer) hasbecome common practice to meet estimated requirements.

Norton et al. prospectively evaluated varying dosages ofiron dextran (0-25 mg/d) added to TPN solutions in 42patients requiring at least 20 days ofTPN. Based on serumiron concentration response a dose of 12.5 mg/d was deter-mined most appropriate. However, the addition of iron didnot affect hemoglobin levels, reticulocyte counts, transfu-sion requirements, or red blood cell indices. In addition, itis unknown whether the increase in measured serum ironwas transferrin-bound or iron-dextran-bound.2S Althoughthis study failed to document a clear benefit to the use oflow-dose iron supplementation in these patients, there wasno evidence of risk associated with its use. No adverse reac-tions were observed and the incidence of sepsis was notincreased with increasing doses of iron, based on study cri-

hydramine (50 mg), epinephrine (0.3-0.5 mL of 1:1000solution), methylprednisolone (100 mg), oxygen, and othersupportive equipment be available at the patient's bedsideduring the test dose. 1.4 Although the incidence of anaphy-lactic reactions does not appear to differ significantlybetween the im and iv routes of iron administration, ananaphylactic reaction following an im injection mayrequire prolonged treatment due to slow absorption fromthe injection site.

mentioned, the im administration of iron may bC associatedwith severe pain, formation of sterile or pyogenic intra-muscular abscesses, tissue staining due to residual iron andmelanin deposition, sarcoma formation of the buttock, andmuscle necrosis with ulceration.8.9

An increased susceptibility to bacterial infections hasbeen observed in neonates receiving prophylactic iron dex-tran.21 It has been suggested that excessive amounts ofcirculating iron may stimulate growth of bacteria in thesepatients. In a similar manner, an increased risk of infection

164 . DICP. The Annals of Pharmacotherapy. 1990 February, Volume 24

ltuenterallron

injections of the undiluted solution. However, in manypatients it may be more advantageous to provide the calcu-lated replacement dose either via a total dose infusion or asan addition to parenteral nutrition. Regardless of themethod of administration, patients should first receive a testdose of iron dextran to determine susceptibility to an ana-phylactic reaction.~

teria. In fact, no allergic or systemic reactions have beenreported to date in any patients receiving low-dose irondextran diluted in TPN solutions.

In opposition to the routine practice of parenteral ironadministration in the long-term TPN patient is a currentreport addressing trace-element metabolism in adults onTPN, including long-term home TPN. The report was pre-pared at the request of the Committee on Clinical Issues inHealth and Disease of the American Society of ClinicalNutrition. It recommends limiting the administration ofparenteral iron to those TPN patients with well-docu-mented iron deficiency and established intolerance orinability to absorb oral iron.28 The recommendation wasbased on the potential for the accumulation of iron in theliver and spleen and resulting organ damage, which hasbeen observed in hemodialysis patients given parenteraliron routinely. 23 It was also based on the theoretical risk of

infection associated with parenteral iron administration, aspreviously discussed. The report does recognize, however,the difficulty in diagnosing iron deficiency in malnourishedpatients on TPN therapy.

If the diagnosis of iron deficiency is determined, the useof TPN solutions as a vehicle for the administration of aniron replacement dose may be considered. The addition ofrepletion doses of iron to TPN solutions was clinically eval-uated in eight patients with moderate-to-severe anemia whorefused blood transfusions. Total doses of iron dextranranged from 1.6 to 7 g, with a maximum concentration of500 mg/L. In the six patients with acute blood loss, hemo-globin levels increased from a mean initial value of 5.0g/dL (range 2.6-8.4) to a mean value of 10.6 g/dL (range7.5-12.8). Final hemoglobin values were measured withina range of 7-21 days after completion of the iron dosageregimen. In the two patients with chronic anemia, hemo-globin levels increased from an initial mean value of 3.8g/dL to a mean of 10.6 g/dL over a mean treatment period of121 days. No adverse reactions were observed in anypatients. The authors concluded that replacement doses ofiron dextran via TPN solutions can stimulate hematopoiesisand allow rapid and safe repletion of the red blood cellmass.' From a compatibility and stability standpoint, thehigh concentration of iron dextran (500 mg/L ofTPN) usedin this study has not been evaluated.

No physiochemical evidence of instability or incom-patibility is apparent when iron dextran is added to TPNsolution (100 mg/L) and stored at room temperature for 18hours.Z9 Longer periods of storage or higher concentra-tions in conventional TPN solutions have not been evalu-ated. A single study evaluating the stability of iron dextranin a total nutrient admixture tested a concentration of 50mg/L stored at 4 °C for 14 days. By day 14, light microscopyrevealed that the lipid particles in the admixture were trans-formed from a normal spherical shape to an elongatedshape. The authors recommend a 24-hour room tempera-ture expiration date when iron dextran is added to a totalnutrient admixture.30

SummaryTherapy with parenteral iron dextran is limited to pa-

tients with documented iron deficiency anemia associatedwith conditions which preclude the use of oral iron therapy.Currently, the only FDA-approved method of administer-ing iron dextran is via multiple intramuscular or intravenous

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