REVIEW

Iron Sucrose: A Wealth of Experience in Treating IronDeficiency

Iain C. Macdougall . Josep Comin-Colet . Christian Breymann .

Donat R. Spahn . Ioannis E. Koutroubakis

Received: February 18, 2020 / Published online: April 15, 2020� The Author(s) 2020

ABSTRACT

Iron deficiency and iron-deficiency anemia areassociated with increased morbidity and mor-tality in a wide range of conditions. In manypatient populations, this can be treated effec-tively with oral iron supplementation; but inpatients who are unable to take or who do notrespond to oral iron therapy, intravenous ironadministration is recommended. Furthermore,

in certain conditions, such as end-stage kidneydisease, chronic heart failure, and inflammatorybowel disease, intravenous iron administrationhas become first-line treatment. One of the firstavailable intravenous iron preparations is ironsucrose (Venofer�), a nanomedicine that hasbeen used clinically since 1949. Treatment withiron sucrose is particularly beneficial owing toits ability to rapidly increase hemoglobin, fer-ritin, and transferrin saturation levels, with anacceptable safety profile. Recently, importantnew data relating to the use of iron sucrose,including the findings from the landmarkPIVOTAL trial in patients with end-stage kidneydisease, have been reported. Several years ago, anumber of iron sucrose similars became avail-able, although there have been concerns aboutthe clinical appropriateness of substituting theoriginal iron sucrose with an iron sucrose simi-lar because of differences in efficacy and safety.This is a result of the complex and uniquephysicochemical properties of nanomedicinessuch as iron sucrose, which make copying themolecule difficult and problematic. In thisreview, we summarize the evidence accumu-lated during 70 years of clinical experience withiron sucrose in terms of efficacy, safety, andcost-effectiveness.

Keywords: Anemia; Iron deficiency; Ironsucrose; Nanomedicine; Venofer

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12030552.

I. C. Macdougall (&)Department of Renal Medicine, King’s CollegeHospital, London, UKe-mail: iain.macdougall11@gmail.com

J. Comin-ColetDepartment of Cardiology, Bellvitge UniversityHospital and IDIBELL, University of Barcelona,Barcelona, Spain

C. BreymannPerinatal and Gynecology Center Seefeld Zürich,Zurich, Switzerland

D. R. SpahnInstitute of Anaesthesiology, University of Zurichand University Hospital Zürich, Zurich, Switzerland

I. E. KoutroubakisDepartment of Gastroenterology, UniversityHospital Heraklion, Crete, Greece

Adv Ther (2020) 37:1960–2002

https://doi.org/10.1007/s12325-020-01323-z

https://doi.org/10.6084/m9.figshare.12030552http://crossmark.crossref.org/dialog/?doi=10.1007/s12325-020-01323-z&domain=pdfhttps://doi.org/10.1007/s12325-020-01323-z

Key Summary Points

Intravenously administered (IV) iron isimportant for individuals who are unableto tolerate oral iron therapy, who are non-compliant with oral treatment, or inwhom oral preparations are not effective.

One of the first IV iron preparations to bemanufactured is iron sucrose (Venofer�;Vifor Pharma), which became available forclinical use over 70 years ago in 1949. It isthe most commonly used IV iron therapyworldwide, with clinical experienceencompassing 25 million patient-years.

Many studies across a broad range oftherapy areas consistently demonstratethat iron sucrose is able to correct irondeficiency, in addition to promotingerythropoiesis and subsequently reducingthe required doses of erythropoiesis-stimulating agents (ESAs). Not only is ironsucrose effective, but it is also welltolerated and rapidly increasesbioavailable iron supplies.

Since the last review focused on ironsucrose was published in 2014, reassuringclinical data have continued to becomeavailable on iron sucrose from a numberof studies. Most notably, the recentlypublished PIVOTAL trial in patients withend-stage kidney disease compared theefficacy and safety of high- versus low-dose iron sucrose.

Generic substitution of iron sucrosesimilar for iron sucrose should not beassumed to provide therapeuticequivalence, as the complexphysicochemical properties of the originalagent are extremely difficult to duplicateand studies have not been able toconclusively demonstrate that ironsucrose similars have safety and efficacyequivalent to that of iron sucrose.

INTRODUCTION

Iron plays an important role in key cellularmetabolic pathways in addition to its role inheme synthesis and subsequent oxygen trans-port [1]. Iron deficiency and iron-deficiencyanemia typically occur as a consequence of asevere underlying condition, such as inflam-matory bowel disease (IBD), gastrointestinal(GI) bleeding, chronic heart failure (CHF),chronic kidney disease (CKD), or cancer [2–9].Heavy menstrual bleeding and pregnancy mayalso result in iron deficiency [10, 11]. Effectivetreatment of iron deficiency/iron-deficiencyanemia is important to relieve symptoms,including extreme fatigue and tiredness, as wellas to alleviate the adverse impact on quality oflife [11–16]. Furthermore, anemia is a riskamplifier for mortality and morbidity inpatients with heart disease [17] and those withCKD [18–20]. Iron deficiency, even in theabsence of anemia, can be debilitating and canexacerbate any underlying chronic disease,leading to increased morbidity and mortality[21, 22]; for example, iron deficiency can bepredictive of negative disease outcomes and hasbeen associated with a worse prognosis in CHF[23, 24]. Additionally, in patients with irondeficiency undergoing cardiac surgery, mortal-ity is elevated threefold, irrespective of thepresence or absence of anemia [25]. Preopera-tive anemia, which is most commonly causedby iron deficiency, is also associated with anincreased risk of poor outcomes after surgery[26, 27]. Iron deficiency and iron-deficiencyanemia generate considerable financial burdensdue to additional medical costs and loss ofproductivity [28].

Iron administration is recommended for themanagement of iron deficiency/iron-deficiencyanemia associated with a variety of conditions[2–4, 7–10, 29, 30]. The Network for Advance-ment of Transfusion Alternatives recommendsthat iron deficiency is treated before using ery-thropoiesis-stimulating agents (ESAs) inpatients with anemia [31, 32]. This is alsoadvocated in guidelines for the treatment ofanemia in CKD [33, 34]. Corrective strategies tonormalize iron levels and hemoglobin (Hb) are

Adv Ther (2020) 37:1960–2002 1961

recommended as part of perioperative care tooptimize outcomes in patients undergoing sur-gery [35]. In patients lacking a response to, orunable to tolerate, oral iron therapy, treatmentwith intravenously administered (IV) ironshould be considered [9]. There are also cir-cumstances in which IV iron is recommendedfor use as first-line treatment, including cases ofsevere iron-deficiency anemia [2–4] and whenrapid correction of Hb levels is warranted (e.g.,when less than 6 weeks prior to surgery [35]), orin certain patient groups with iron deficiency/iron-deficiency anemia such as those with CHF[3, 4, 30], hemodialysis-dependent CKD[3, 4, 8], severe IBD, or cancer [7, 29]. Advan-tages of parenteral iron therapy include (1)similar or superior effectiveness, often with amore rapid response [36, 37]; (2) avoidance ofpoor or unreliable intestinal absorption, whichis particularly problematic in patients withincreased hepcidin levels associated withinflammatory conditions [37]; and (3) improvedtolerability, as the GI side effects of oral irontherapy are avoided [38]. Several IV iron carbo-hydrate preparations are available (Table 1).

One of the first IV iron preparations to bemanufactured is iron sucrose (Venofer�; ViforPharma), which became available for clinicaluse over 70 years ago, in 1949. Indeed, likeaspirin, it is one of the oldest therapeutic agentsstill being used widely today. The active ingre-dient of Venofer is an iron(III) hydroxide–su-crose complex, and the product is nowregistered in 91 countries worldwide. Indeed, itis the most commonly used IV iron formulationworldwide, with clinical experience encom-passing 25 million patient-years [39].

The aim of this article is to provide a com-prehensive overview of Venofer, focusingmainly on the characteristics, pharmacokinet-ics, efficacy, safety, and limitations associatedwith this iron preparation. While IV Venoferhas a long history, there are a number of reasonswhy a review of its therapeutic use is timely.Firstly, important new data on the use of thisiron sucrose preparation have recently becomeavailable. A large open-label, blinded-endpointstudy in 2141 patients undergoing hemodialysis(PIVOTAL study) has recently demonstrated theclinical benefits of a proactive high-dose iron

regimen of iron sucrose (Venofer) comparedwith a reactive low-dose iron regimen, includ-ing a lower incidence of death, heart attack,stroke, and hospitalization for heart failure, aswell as reduced ESA dose requirements and useof blood transfusions [40]. Secondly, variousiron sucrose similars have been developed andintroduced as generic alternatives to Venofer.However, several recent studies have suggestedthat the therapeutic equivalence of Venofer andfollow-on products cannot be assumed, giventhat these are complex nanomedicine entitiesthat may have clinically relevant differences intheir physicochemical properties.

In order to identify peer review publicationsof interest, we searched PubMed using the terms‘‘iron sucrose’’ and filtered results by publicationdate (limited to the last 25 years), article type(clinical trials and reviews), human species, andEnglish language. This review article is based onpreviously conducted studies and does notcontain unpublished data from any studies withhuman participants or animals performed byany of the authors.

PHARMACOKINETICSAND PHARMACODYNAMICS

Venofer is rapidly cleared from the serum ofhealthy subjects, with a terminal half-life of5.3 ± 1.6 h and total body clearance of1.23 ± 0.22 L/h (20.5 ± 3.7 mL/min) [41]. Fol-lowing IV administration of iron sucrose intopatients with anemia, iron is rapidly taken upby the liver, spleen, and bone marrow [42]. Themajority (97%) of injected iron is utilized for redblood cell (RBC) synthesis in these patients, andserum ferritin and transferrin saturation (TSAT)increase within 24 h and 1 week, respectively[42]. Furthermore, less than 5% of the overallelimination of Venofer in healthy individualscan be attributed to undesirable renal elimina-tion, due to a relatively large molecular mass(greater than 18 kDa) [21].

1962 Adv Ther (2020) 37:1960–2002

Table1

Overview

ofcharacteristicsof

approved

IViron

form

ulations.Adapted

from

Muñ

ozandMartı́n-Montañez.Reprinted

byperm

ission

ofthepublisher

(Taylor&

FrancisLtd,h

ttps://w

ww.tand

fonline.com)[175]

Iron

glucon

ate

Iron

sucrose

LMWID

Ferric

carboxym

altose

Iron

isom

altoside

1000

Ferumoxytol

Brand

name

Ferrlecit�

Venofer�

Cosmofer�

Ferinject�,

Injectafer�

Monofer�

FeraHem

e�

Manufacturer

Sanofi-Aventis

Vifo

rPh

arma

Pharmacosmos

Vifo

rPh

arma,

American

Regent

Pharmacosmos

AMAG

Pharmaceuticals

Carbohydrateshell

Gluconate

(monosaccharide)

Sucrose

(disaccharide)

Dextran

(branched

polysaccharide)

Carboxymaltose

(branched

polysaccharide)

Isom

altoside

(linear

oligosaccharide)

Polyglucosesorbitol

(branched

polysaccharide)

Molecular

weightmeasuredby

manufacturer,kD

a

289–

440

34–6

0165

150

150

750

Initialdistribution

volume,L

63.4

3.5

3.5

3.4

3.16

Terminalhalf-life(dosein

mgFe)

[176]

1.42

h(125)

5.3h(100)

27–3

0h

(500–2

000)

7.4/9.4h(100/

1000)

20.8/22.5h(100/

200)

14.7h(316)

Labile

iron,%

ofdose

3.3

3.4

1.9

0.6

10.9

Directiron

donation

to

transferrin,

%of

dose

5–6

4–5

1–2

1–2

\1

\1

Iron

content,mg/mL

12.5

2050

50100

30

Maxim

alsingledose,m

g

(minim

umadministration

time)a[176,1

77]

125(10–

60min)

200 (10–

30min)

20mg/kg

BW

(4–6

h)

1000

(15min)

20mg/kg

BW

(1h)

510(15min)

BW

body

weight,IV

intravenously

administered,

LMWID

lowmolecular

weightiron

dextran

aMostcommon

maxim

aldose

andcorrespond

ingminim

aladministrationtime;theexactposology

may

vary

betweenmarkets.Please

referto

localprescribing

inform

ation

Adv Ther (2020) 37:1960–2002 1963

https://www.tandfonline.com

Efficacy of Iron Sucrose in VariousConditions

The efficacy of iron sucrose has been demon-strated in a wide range of conditions that causeor are associated with iron deficiency and iron-deficiency anemia, as summarized below. Acrossthese various conditions, iron sucrose treatmentis associated with improved iron status (ferritin,TSAT); increased Hb levels, with or without ESAtherapy; and improved health-related quality oflife and clinical outcomes. When used in com-bination with ESA therapy, iron sucrose sub-stantially reduces ESA dose requirements.

Chronic Kidney DiseaseAs summarized in Table 2, studies have consis-tently reported that iron sucrose is an effectivetreatment for iron deficiency/iron-deficiencyanemia in patients with CKD, leading toincreased Hb, serum ferritin, and TSAT inpatients regardless of whether they are under-going hemodialysis or receiving ESAs[40, 43–54].

In adults undergoing maintenancehemodialysis, differing regimens, includingcontinuous and intermittent administration ofiron sucrose, have been examined[40, 43, 46–48, 50, 55]. While each of thesestudies has demonstrated benefits of ironsucrose in maintenance hemodialysis, the mostconclusive results are reported in the recentPIVOTAL study, a landmark trial that is alreadychanging clinical practice and will almost cer-tainly impact on future clinical guidelines.PIVOTAL was a multicenter, open-label trialwith blinded-endpoint evaluation in 2141hemodialysis patients; it is the largest prospec-tive, controlled clinical trial of IV iron inpatients with CKD [40]. In the PIVOTAL trial,patients were randomized into two groups: onereceiving high-dose iron sucrose proactively(400 mg monthly; with temporary discontinu-ation of treatment if safety cutoffs of ferritin700 lg/L or TSAT of 40% were exceeded) andthe other group receiving low-dose iron sucroseadministered reactively (0–400 mg monthly,adjusted to achieve minimum targets for ferritinand TSAT of 200 lg/L and 20%, respectively)

[40]. Importantly, within the context of a rig-orous study design, this study showed that therisk of cardiovascular adverse events (AEs),infections, hospitalization, and death was loweror similar with high-dose iron sucrose comparedwith low-dose iron sucrose.

High-dose iron sucrose was superior to low-dose iron sucrose with respect to the primarycomposite endpoint of non-fatal myocardialinfarction, non-fatal stroke, hospitalization forheart failure, or death (p\0.001 for non-infe-riority; p = 0.04 for superiority) [40]. The effectof high-dose iron sucrose on the primary end-point was consistent across all of the prespeci-fied subgroups (duration of dialysis treatment,diabetes status, and vascular access). In addi-tion, proactive administration of high-dose ironappeared to protect against recurrent cardio-vascular events. An additional benefit of high-dose iron sucrose was the subsequent reductionin ESA dose required by patients in this groupand the reduced likelihood of requiring bloodtransfusions [40].

Relative to the low-dose strategy, the high-dose approach to iron sucrose administrationwas not associated with any safety signals.There was no difference in vascular accessthrombosis, or in hospitalizations between thedosing groups [40]. Additionally, infection rateswere virtually identical between the high-doseand low-dose iron sucrose groups, suggesting noassociation between iron dose, ferritin/TSAT,and the risk of infection [40, 56]. This is reas-suring because it has been previously suggestedthat IV iron administration may increase therisk of infection [57].

Studies comparing iron sucrose with oraliron administration consistently show ironsucrose to be more effective in patients withCKD, with significantly better outcomes in Hb,hematocrit, serum ferritin, and TSAT, as well asreduced recombinant human erythropoietin(rhEPO) dose requirements [48, 51].

Randomized trials have indicated that ironsucrose has comparable efficacy to other IV ironformulations in CKD; for example, ferumoxytoland iron sucrose have similar efficacy inpatients with CKD, including in patientsundergoing hemodialysis [55, 58]. An addi-tional trial suggested superior efficacy of iron

1964 Adv Ther (2020) 37:1960–2002

Table2

Publishedclinicalstudiesusingiron

sucrosein

chronickidn

eydisease

Stud

yInclusioncriteria

Patients,n

Patient

dialysisstatus

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Studiesofiron

sucrose

Macdougall

etal.

(2019)

[40]

ESR

D

TSA

T\

30%

SF\

400ng/m

L

High-dose

IS?

ESA

:1093

Low

-dose

IS?

ESA

:1048

Hem

odialysisB

12months

priorto

screening

400mg,monthly

0–400mg,monthly

2.1years(m

edian

follow-up)

Significantlyfewer

events(non-fatalMI,non-fatal

stroke,h

ospitalizationforheartfailure,ordeath)

withhigh-doseIS

versus

low-doseIS

(29.3%

vs.

32.3%;p\

0.001[non-in

feriority];p=0.04

[superiority])

Nodifferencesbetweengroups

inSA

Es,

hospitalization,

infectionrate,o

rvascular

access

thrombosis

Haddad

etal.

(2009)

[43]

Intoleranceto

iron

dextran

IS?

ESA

:15

Hem

odialysis

100mgq.w.

Significant

hematocritincrease

Nohypersensitivity

reactionsor

effectson

intradialyticbloodpressure

Mircescu

etal.

(2006)

[44]

Hb\

11g/dL

SF\

200ng/m

L

IS:60

Nodialysis

200mg,monthly,

1year

Significant,continu

ous,andprogressiveHb

increase

Noworsening

ofrenalfunction,b

lood

pressure

changes,or

SAEs

Tagboto

etal.

(2008)

[45]

Hb\

11.5g/dL

IS:82

Nodialysis

49

200mg,q.w.

Hbincrease

in74%

ofpatients

Nospecificsafety

results

reported

Denget

al.

(2017)

[46]

RLS

TSA

T\

20%

SF\

200ng/m

L

IS:16

Placebo:

16

Hem

odialysis

100mg,t.i.w.(1000

mg

total)

2weeks

afterlastinjection,

decrease

inIRLSscore

wassignificantlygreaterforIS

versus

placebo,and

increasesin

SF,T

SAT,and

Hbweresignificantly

greaterforIS

versus

placebo

NoAEswereobserved

Adv Ther (2020) 37:1960–2002 1965

Table2

continued

Stud

yInclusioncriteria

Patients,n

Patient

dialysisstatus

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Wan

and

Zhang

(2018)

[47]

Hb10.0–1

3.0g/

dL

SF100–

500ng/

mL

iPTH\

800pg/

mL

Continu

ous

IS?

ESA

:17

Interm

ittent

IS?

ESA

:17

Hem

odialysis

100mgeverysession

(1000mgtotal;

completed

in1month)

100mgq.w.(1000

mg

total;completed

in3months)

SFlevelsincreasedsignificantlyin

both

groups

Hblevelsweresimilarbetweengroups,b

utinterm

ittent

ISsignificantlyreducedHb

variability

versus

continuous

IS

NoAEswereobserved

Mitsopoulos

etal.

(2020)

[54]

Hb9–

11.5g/dL

TSA

T\

45%

SF\

500ng/m

L

IS?

ESA

:18

Stableperitonealdialysis

200mgloadingdose,

followed

by100mg

monthlyfor

5months

HbandSF

increasedsignificantlyfrom

baselin

e

ESA

dose

was

reducedin

fivepatientsand

discontinu

edin

one

Nopatientsexperiencedanyside

effectsrelatedto

IS

Com

parativestu

diesofiron

sucroseversus

oral

iron

form

ulations

Liand

Wang

(2008)

[48]

Hb6.0–

9.0g/dL

TSA

T\

30%

SF\

500ng/m

L

IS?

ESA

:70

FeS?

ESA

:66

Hem

odialysis

100mgb.i.w

.thenq.w.

200mgFeSt.i.d.,

12weeks

Significant

Hbincrease

versus

baselin

ein

both

groups

andwithIS

versus

FeS

NoAEswithIS,3

3.3%

GIsymptom

swithFeS

Van

Wyck

etal.

(2005)

[49]

HbB

11g/dL

TSA

TB

25%

SFB

300ng/m

L

IS?

ESA

:91

FeS?

ESA

:91

Nodialysis

29

500or

59

200mg,14

days

65mgt.i.d.,56

days

Significantlybetter

Hbresponse

(DHbC

1.0g/

dL)andincrease

withIS

versus

FeS

Dysgeusiamostprom

inentIS-related

GIcomplaint

(6.6%)

Fewer

GIside

effectswithIS

200mg(11.5%

)and

IS500mg(3.3%)versus

FeS(17.6%

)

Liand

Wang

(2008)

[51]

Hb6.0–

9.0g/dL

TSA

T\

30%

SF\

500ng/m

L

IS?

ESA

:26

FeS?

ESA

:20

Peritonealdialysis

200mgq.w.o

ver

4weeks

then

q.2.w.

200mgFeSt.i.d.,

8weeks

Significant

Hbincrease

versus

baselin

ein

both

groups

andwithIS

versus

FeS

NoAEswithIS,4

0%GIsymptom

swithFeS

1966 Adv Ther (2020) 37:1960–2002

Table2

continued

Stud

yInclusioncriteria

Patients,n

Patient

dialysisstatus

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Agarwal

etal.

(2015)

[52]

Hb\

12g/dL

TSA

T\

25%

SF\

100ng/m

L

IS±

ESA

:69

FeS±

ESA

:67

GFR

[20

andB

60mL/

min/1.73m

2(no

hemodialysis)

IS200mg,weeks

0,2,

4,6,

8

FeS325mgt.i.d.,

8weeks

24months

Increasesin

Hbsimilarbetweengroups

SFwas

significantlyhigher

withIS

versus

FeSonly

from

baselin

eto

6months

ISwasassociated

withgreaterrisk

ofinfections

and

cardiovascular

complications

versus

FeS

GIAEsweremorecommon

withFeS,whereasgout

was

morefrequent

intheIS

group

Com

parativestu

diesofiron

sucroseversus

otherIV

iron

form

ulations

Bhand

ari

etal.

(2015)

[50]

Hb9.5–

12.5g/dL

TSA

T\

35%

SF\

800ng/m

L

IS?

ESA

:117

IIso

?ESA

:234

Hem

odialysis

ISaccordingto

local

packageinsert/

guidelines

IIso

500mg,single

bolus

IIso

(splitdose)100mg

(baseline)

?200mg

(weeks

2and4)

6weeks

(follow-up)

Nosignificant

difference

inHbcontrolbetween

groups

Increasesin

SFfrom

baselin

eto

weeks

1,2,

and4

weresignificantlygreaterforIIso

versus

IS

Frequency,type,and

severity

ofAEsweresimilar

betweengroups

Macdougall

etal.

(2014)

[58]

Hb\

11.0

and

C7.0g/L

TSA

T\

30%

IS:82

FeruM:80

Ondialysisandnoton

dialysis

200mg9

5within

14days(non-dialysis)

100mgfor10

consecutivesessions

(dialysis29

510mg

within5days)

5weeks

(follow-up)

Increasesin

Hbsimilarbetweengroups

AEprofilessimilarbetweengroups

Adv Ther (2020) 37:1960–2002 1967

Table2

continued

Stud

yInclusioncriteria

Patients,n

Patient

dialysisstatus

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Macdougall

etal.

(2019)

[55]

Hb\

11.5g/dL

TSA

T\

30%

SFB

800ng/m

L

IS:97

FeruM:196

Hem

odialysis

100mgfor10

consecutivesessions

29

510mgwithin

5days

5weeks

(follow-up)

Increasesin

Hbsimilarbetweengroups

AEprofilessimilarbetweengroups

Onken

etal.

(2014)

[53]

Hb\

11.5g/dL

TSA

TB

30%

SFB

100ng/m

L(orB

300ng/

mLifTSA

Tcriterionmet)

IS±

ESA

:1294

FCM

±ESA

:1290

GFR

\60

mL/m

in/

1.73

m2 ,non-dialysis-

depend

ent

IS200mgdays

0,7,

and14

?two

additionaldoses

(max.1

000mg)

FCM

15mg/kg

days

0and7(m

ax.

1500

mg),d

ay56

(end

oftreatm

ent)

Increase

inHbwas

statistically

higher

withFC

Mversus

IS

Increasesin

SF,T

SAT,and

serum

iron

were

significantlygreaterin

theFC

Mgroupversus

IS

Protocol-definedhypertensive

eventswere

significantlymorecommon

withFC

Mversus

IS,

whereas

protocol-definedhypotensiveeventswere

morecommon

withIS

than

FCM

Nosignificant

difference

intheprim

arycomposite

safety

endpoint

(all-causedeath,

non-fatalMI,

non-fatalstroke,u

nstableangina

requiring

hospitalization,

congestive

heartfailure

requiring

hospitalizationor

medicalintervention,cardiac

arrhythm

ia,and

hypertensive

orhypotensive

events)betweentreatm

entgroups

AEadverseevent,b.i.w

.twiceweekly,ESA

erythropoiesis-stimulatingagent,ESR

Dend-stagerenaldisease,FC

Mferriccarboxym

altose,FeruM

ferumoxytol,FeS

ferroussuccinate,

GFR

glom

erular

filtrationrate,GIgastrointestinal,Hbhemoglobin,

IIso

iron

isom

altoside

1000,iPTH

intact

parathyroidhorm

one,

IRLS

InternationalR

estlessLegsSynd

romeStudyGroup

rating

scale,IS

iron

sucrose,IV

intravenously

administered,MImyocardialinfarction,

q.2.w.every

2weeks,q.w.

weekly,RLSrestlesslegs

synd

rome,SA

Eseriousadverseevent,SF

serum

ferritin,t.i.d.

threetimes

daily,t.i.w.three

times

weekly,TSA

Ttransferrinsaturation

1968 Adv Ther (2020) 37:1960–2002

isomaltose versus iron sucrose in patients withnon-dialysis CKD, although different dosingregimens make a direct comparison of theseproducts problematic [59].

Limited data are available on the use of IViron in peritoneal dialysis patients. A recentstudy has assessed the safety and efficacy of ironsucrose in this patient population and hasshown that monthly maintenance with ironsucrose may improve iron parameters and ery-thropoietin response [54].

Chronic Heart FailureIron deficiency and anemia are commonlyobserved in patients with CHF. Anemia waspreviously thought to be a major contributor tothe progression of CHF [60, 61]. In patients withCHF, iron deficiency is associated withincreased mortality [24], increased risk of hos-pitalization [62], and reduced quality of life[14, 63]. A number of studies have evaluated thetreatment effects of iron sucrose in patientswith anemia and patients without anemia, bothalone [64–68] and in combination with rhEPO[60, 69, 70]. A summary of the studies on ironsucrose use in CHF is provided in Table 3.

Intravenous administration of iron sucrosealone to patients with anemia and CHFimproves the hematological parameters of Hb,ferritin, and TSAT [64–68]. Reductions ininflammatory markers such as natriuretic pep-tides and C-reactive protein (CRP) have alsobeen observed after iron sucrose treatment[64, 66, 70].

These biochemical changes appear to beassociated with symptom improvement inpatients with CHF, while in one study,echocardiographic evaluation demonstratedsignificant improvements in left ventricularsystolic diameter and left ventricular diastolicdiameter [66]. In line with these findings, animprovement in cardiac remodeling was alsoobserved in another study in patients with CHF[68].

Inflammatory Bowel Disease and OtherGastrointestinal DisordersA summary of the studies of iron sucrose use inadults with GI disorders is provided in Table 4.

IBD (including Crohn’s disease and ulcera-tive colitis) is often treated with anti-inflam-matory drugs, including tumor necrosis factor-alpha (TNFa) inhibitors. However, the persis-tence of anemia as a complication despite anti-TNFa treatment highlights the need for irontherapy even when biologics are used [71]. Oraliron therapy, however, is problematic forpatients with IBD as a result of chronic inflam-mation leading to poor absorption and toler-ance. In this respect, and consistent withfindings in patients with CKD, several studies inpatients with iron deficiency and iron-defi-ciency anemia associated with IBD indicate thatiron sucrose is more efficacious than oral irontherapy [72, 73].

A study in patients with iron-deficiencyanemia and IBD demonstrated significantlybetter outcomes in the iron sucrose arm for twoout of three primary endpoints compared withoral iron sulfate therapy: fewer iron sucrose-treated patients remained anemic and morepatients achieved Hb reference levels [72].

In a pooled analysis of four trials evaluating atotal of 191 patients with iron-deficiency ane-mia resulting from GI disorders, greater increa-ses in Hb levels were apparent in patientstreated with iron sucrose compared with thosereceiving oral iron therapy [74]. However, theinterpretation of these findings is somewhatproblematic because patients with Hb levelsbelow 10 g/dL were given iron sucrose treat-ment and patients with higher Hb levels (atleast 10 g/dL) were treated with oral ferroussulfate therapy. Iron sucrose treatment inpatients with lower Hb levels (below 10 g/dL)led to 77% of subjects achieving normal Hblevels after 3 months. Oral administration offerrous sulfate in patients with higher baselineHb levels (at least 10 g/dL) resulted in 89%achieving normalized Hb [75]. Although theauthors of this study reported that all patientswere in remission, more details on the overalldisease severity of the two groups would be ofinterest. Patients with IBD and severe anemia(Hb below 10 g/dL) usually have more severeand relapsing disease associated with a higherneed for iron supplementation compared withpatients with mild anemia and inactive disease.Moreover, the recurrence of anemia after iron

Adv Ther (2020) 37:1960–2002 1969

Table3

Publishedclinicalstudiesusingiron

sucrosein

patientswithchronicheartfailure

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,

treatm

entdu

ration

Outcomes

andsafety

inform

ation

Bolger

etal.

(2006)

[65]

Stablesystolicheartfailure

and

HbB

12g/dL

IS:16

200mg(10mL)IV

bolusover10

min

ondays

1,3,

and5of

study

ISim

proved

hematologicalparameters

(Hb,

serum

iron,S

F,TSA

T),

symptom

s,andexercise

capacity

(NYHA

functionalclass,MLHFQ

score,6M

WT).ISC

was

welltolerated

withno

localor

system

icAEs

Silverberg

etal.

(2003)

[60]

Octogenarians

withanem

iaandsevere,

resistantCHF

IS:40

Com

bination

ofSC

EPO

(4–5

KIU

/week,

increasing

to10

KIU

/weekto

atarget

Hbof

12.5g/dL

)andIS

200mg

in150mLsalin

eIV

infusion

over

60min

every1–

2weeks

untilSF

reached500lg/L

oriron

saturation

reached40%

orHbreached12.5g/dL

Mean±

SDduration

offollow-upwas

17.4

±10

months.IS

incombination

withEPO

significantlyincreasedHb,

serum

iron,S

F,and%

iron

saturation

andalso

improved

NYHA,L

VEF,

and

VASindex.Significantlyfewer

hospitalizations

werereported

comparedwithacomparableperiod

priorto

thestudy

Silverberg

etal.

(2003)

[69]

Individualswithandwithout

diabetes

withmoderateto

severe

resistantCHF

(and

CRF);NYHA

functionalclasses

I–IV

andHbrangeof

9.5–

11.5g/dL

IS:179(84

individuals

withtype

2diabetes;95

without

diabetes)

Com

bination

ofSC

EPO

(4–5

KIU

/week,

increasing

to10

KIU

/weekto

atarget

Hbof

12.5g/dL

)andIS

200mg

in150mLsalin

eIV

infusion

over

60min

every1–

2weeks

untilSF

reached500lg/L

oriron

saturation

reached40%

orHbreached12.5g/dL

Inindividualswith/without

diabetes

with

severe

CHFandmild

tomoderate

CRF,

correction

ofanem

iaby

the

combineduseof

EPO

andISC

was

associated

withim

provem

entsin

LVEF

andcardiacfunctionalstatus

(NYHA

andVAS)

andslo

wingof

therate

ofdeteriorationof

renalfunction

Com

in-

Colet

etal.

(2009)

[70]

Stableadvanced

CHF(N

YHA

class

III–IV)andanem

ia(m

en,

Hb\

13.0g/dL

;wom

en,

Hb\

12.0g/dL

)andmild

tomoderate

renaldysfun

ction

IS:27

EPO

(4KIU

/week,

adjusted

asnecessary

toachieveandmaintainatarget

Hb

between12.5

and14.5g/dL

).IS

200mgin

100–

200mLsalin

eIV

infusion

over

60–9

0min

q.w.for

5–6weeks

untilSF

reached400lg/L

orTSA

Tof

40%

orHb[

14.5g/dL

.IS

then

givenevery4–

6weeks

tomaintaintheselevels

Mean±

SDfollow-upwas

15.3

±8.6months.Long-term

combinedtherapywithEPO

andISC

increasedHb,

reducedNT-proBNP,

andim

proved

functionalcapacity

and

cardiovascular

hospitalizationrates

1970 Adv Ther (2020) 37:1960–2002

Table3

continued

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,

treatm

entdu

ration

Outcomes

andsafety

inform

ation

Toblli

etal.

(2007,

2015)

[64,

66]

LVEFB

35%;NYHA

functionalclass

II–IV;anem

iawithHb\

12.5g/dL

formen

and\

11.5g/dL

forwom

en;

SF\

100ng/m

Land/or

TSA

TB

20%.R

enalinsufficiency

(creatinineclearanceB

90mL/m

in)

IS:30

200mg/200mLISC

60min

IVinfusion

q.w.for

5weeks

At6monthspost-treatment,patients

receivingISC

infusion

experienced

significant

increasesin

Hblevel,SF,and

TSA

T.H

eartrateandbody

massindex

weresignificantlyreducedin

theIS

group,

whileLVEFwas

significantly

increased,

aswereNYHA

scores.

InflammatorymarkersCRPandNT-

proB

NPwerealso

significantlyreduced.

Echocardiographicevaluation

show

edsignificant

improvem

entsin

LVSd

and

LVDd,

suggesting

apositive

effect

oncardiacmuscle.A

significant

improvem

entin

renalfun

ctionwasalso

observed.S

ideeffectswereminim

alacrossboth

groups

andno

severe

drug-

relatedAEswerereported

Okonko

etal.

(2008)

[67]

AgedC

21yearswithsymptom

aticCHF

(NYHAfunctionalclassII–IV;exercise

limitationpV

O2B

18mL/kg/min;

Hb\

12.5g/dL

(group

withanem

ia)

or12.5–1

4.5g/dL

(group

without

anem

ia)

IS:24

ISadministeredat

200mgin

50mL

salin

eviaIV

infusion

over

30min

q.w.

for16

weeks.T

henat

weeks

4,8,

12,

and16

thereafter

ISresultedin

asignificant

treatm

enteffect

forSF,T

SAT,and

Hblevelsin

the

patientswithanem

ia.A

nim

provem

ent

inexercise

tolerance(pVO

2),N

YHA

functionalclass,PG

A,and

fatiguescore

wasalso

observed

withIS

inthepatients

withanem

ia.A

Eprofilesweresimilar

betweengroups:42%

and64%in

theIS

andcontrolgroups,respectively.All

eventswereun

related(76%

)or

unlikely

tobe

related(24%

)to

thestudydrug

Adv Ther (2020) 37:1960–2002 1971

Table3

continued

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,

treatm

entdu

ration

Outcomes

andsafety

inform

ation

Beck-da-

Silva

etal.

(2013)

[178]

AgedC

18years;NYHAfunctionalclass

II–IVandableto

perform

ergospirom

etry;L

VEF\

40%;H

bC

9andB

12g/dL

;TSA

T\

20%;

SF\

500lg/L

IS:10

FeS:

7

Placebo:

6

IS200mgIV

infusion

over

30min

q.w.

for5weeks

then

oralplacebot.i.d.for

8weeks

FeS200mgorallyt.i.d.for

8weeks

then

IVplaceboq.w.for

5weeks

Oralplacebot.i.d.for

8weeks,thenIV

placeboq.w.for

5weeks

3-month

follow-up

Correctionof

anem

ia,d

efinedas

Hb[

12g/dL

forwom

enand[

13g/

dLformen,w

asachieved

bytwo

patientswithIS,three

withFeS,

and

twowithplacebo.Hbincrease[

1.5g/

dLoccurred

inthreepatientseach

intheIS

andFeSgroups.S

Flevels

increasedfrom

baselin

ewithboth

ISandFeS(but

notplacebo),but

thiswas

onlystatistically

significant

forFeS.

TSA

T[

20%

was

achieved

byfive

patientsin

each

oftheIS

andFeS

groups

pVO

2increasedby

3.5mL/kg/min

with

ISwhereastherewasno

change

inpV

O2

withoraliron

(nostatistically

significant

difference

betweengroups)

Usm

anov

etal.

(2008)

[68]

Hb\

11g/dL

ontwooccasionswithin

1week;

serum

creatinine

\4mg/dL

andNYHA

classificationIII/IV

IS:19NYHAIII

and13

NYHA

IV;22

healthy

controls

IS100mgIV

q3wfor3weeks,thenq.w.

for23

weeks

(totaldose

3200

mgof

elem

entaliron

over

26weeks)

Hb,

serum

iron,S

F,andTSA

Twere

significantlylower

inpatientswith

NYHA

classificationIII/IV

versus

healthycontrolsat

baselin

e.The

mean

values

oftheseparameterswere

significantlyincreasedafter6monthsof

treatm

entwithIV

ISversus

baselin

e.Therewereno

AEsnotedin

anypatient

6MWT6-min

walktest,A

Eadverseevent,CHFchronicheartfailure,C

RFchronicrenalfailure,C

RPC-reactiveprotein,

EPO

erythropoietin,F

eSferroussulfate,

Hbhemoglobin,

ISiron

sucrose,ISCiron

sucrosecomplex,IVintravenous,LVDdleftventriculardiastolic

diam

eter,L

VEFleftventricularejection

fraction,L

VSd

leftventricularsystolicdiam

eter,MLHFQ

Minnesota

LivingwithHeart

Failure

Questionn

aire,NT-proBNPN-terminalpro-B-typenatriureticpeptide,NYHA

New

YorkHeartAssociation,P

GAPatientGlobalA

ssessm

ent,pV

O2peak

oxygen

uptake,q3w

every3weeks,q.w.w

eekly,SC

subcutaneous,SDstandard

deviation,

SFserum

ferritin,t.i.d.

threetimes

daily,T

SATtransferrinsaturation,V

ASVisualAnalogScale

1972 Adv Ther (2020) 37:1960–2002

Table4

Publishedclinicalstudiesusingiron

sucrosein

gastrointestinaldisorders

Stud

yInclusioncriteria

Patients,

nIron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Com

parativestu

diesofiron

sucroseversus

oral

iron

form

ulations

Lindgrenet

al.

(2009)

[72]

Hb\

11.5g/dL

SF\

300ng/m

L

IS:45

FeS:

46

200mgq.w.o

rq.2.w.u

pto

cumulativedose

of1000

mg

100mgb.i.d.,20

weeks

66%

versus

47%

Hbresponse

toIS

versus

FeS(p

=0.07)

One

possiblyrelatedSA

E(throm

bocytopenia)

withIS,A

EswithFeS

dominated

byGIevents

Lee

etal.(2017)

[73]

TSA

T\

16%

±SF

\30

ng/m

L(if

norm

alCRP)

or\

100ng/m

L(if

elevated

CRP)

IS:36

FeS:

36

39

300mg(irondeficiency

only);49

300mg(with

anem

ia)

300mgb.i.d

12weeks

(follow-up)

HbandTSA

Tlevelssimilarbetweengroups

SFsignificantlyhigher

withIS

versus

FeS

Gut

microbiotaandmetabolom

ealtereddifferently

byFeSandIS

Gisbertet

al.

(2009)

[75]

Hb\

12or

13g/dL

a

TSA

T\

12%

SF\

30ng/m

L

IS:22

FeS:

78

200mgb.i.w

.ifHb\

10g/

dLun

tilcalculated

dose

106mgq.d.

ifHb[

10g/

dL

77%

and89%

response

rate

inIS

andFeSgroup,

respectively

NoAEswithIS,5

.1%

withoraliron

therapyintolerance(nausea,

abdominalpain,and

constipation),which

ledto

discontinu

ationof

treatm

ent

Com

parativestu

diesofiron

sucroseversus

otherIV

iron

form

ulations

Lichtensteinand

Onken

(2018)

[74]

[Pooledanalysis

offour

studies]

HbB

12g/dL

(one

study);B

11g/dL

(three

studies)

SFB

100ng/m

Lor

B300ng/m

Lif

TSA

TB

30%

(allfour

studies)

IS:32

FCM:

101

Oraliron:

25

Other

IViron:61

15mg/kg

or750mg

(variabledosing

schedules)

Hb,

SF,and

TSA

Tvalues

increasedsignificantlyfrom

baselin

eforall

groups,w

iththeexceptionof

SFvalues

intheoraliron

group

FCM

andIS

resultedin

greaterincreasesin

Hbthan

orallyadministered

andotherIV

iron

products,w

hich

may

bedueto

lowerbaselin

eHblevels

Safety

profileof

FCM

was

comparablewiththeotheragents

Incidenceof

treatm

ent-relatedSA

Eswas

0%withFC

Mversus

6.3%

with

IS

Evstatiev

etal.

(2011)

[76]

Hb7–

12g/dL

formen

and7–

12g/dL

forwom

en

SF\

100lg/m

L

IS:235

FCM:

240

200mg(upto

11doses)

Maxim

umof

threeinfusions

of1000

or500mg

MorepatientswithFC

Mthan

ISachieved

Hbresponse(p

=0.04)or

Hb

norm

alization(p

=0.015).B

othtreatm

entsim

proved

qualityof

life

scores

byweek12

Studydrugswerewelltoleratedanddrug-related

AEswerein

linewith

drug-specific

clinicalexperience

AEadverseevent,b.i.d.twicedaily,b.i.w.twiceweekly,CRPC-reactiveprotein,FC

Mferriccarboxym

altose,FeS

ferroussulfate,G

Igastrointestinal,H

bhemoglobin,IS

iron

sucrose,IV

intravenous,q.2.w.every

2weeks,q.d.d

aily,q.w.w

eekly,SA

Eseriousadverseevent,SF

serum

ferritin,T

SATtransferrinsaturation

aFemaleHb\

12g/dL

,male\

13g/dL

Adv Ther (2020) 37:1960–2002 1973

treatment may be higher in patients with severeanemia.

When comparing iron sucrose with ferriccarboxymaltose (FCM), Hb response rates weresimilar to those seen in the studies describedabove and in Table 4; however, outcomes withFCM were significantly better [76]. The pooledanalysis in patients with GI disorders describedabove found that FCM was associated withgreater increases in ferritin and TSAT comparedwith iron sucrose, although increases in Hblevels were similar [74].

Pediatric studies in children with GI disordersare summarized in the relevant section below.

Women’s Health, Including Obstetricsand Gynecology

A summary of the studies investigating ironsucrose use in women’s health (including in thepregnancy and postpartum settings) is providedin Table 5.

Pregnancy and PostpartumMaintenance of normal iron stores is importantnot only for the health of the prospectivemother,but also for that of her child. A recent summary ofmeta-analyses of the effects of iron status and irontherapy concluded that maternal anemia wasassociated with adverse birth and neonatal out-comes and that iron treatment reduced the risk ofthis [77]. A recent Swedish cohort study ofover 500,000 children born between 1987 and2010 and followedupuntil the end of 2016 foundthat the risks of developing autism, attention-deficit hyperactivity disorder, and intellectualdisabilitywereall increased inchildrenofmotherswho had prenatal anemia during the first30 weeks of pregnancy [78].

Reflecting results in CKD and IBD, studies inpregnant women with iron deficiency indicatethat iron sucrose is more effective than oral ironadministration and is at least as effective inpregnant women with iron-deficiency anemia.For women with severe iron deficiency duringpregnancy, iron sucrose treatment has beenshown to increase Hb levels more effectivelythan an oral iron polymaltose complex [79],whereas in pregnant women with less severe

iron-deficiency anemia and in those using ironprophylactically, Hb levels were comparablefollowing either iron sucrose or oral ferroussulfate treatment [80, 81].

Administering iron sucrose from the thirdtrimester to pre-delivery can significantlyincrease Hb levels and reduce blood transfusionrates in pregnant women with third trimesterHb levels below 9.5 g/dL, compared withpatients who did not receive iron sucrose [83].Treatment with a minimum of three ironsucrose doses at least 2 weeks prior to deliveryappears optimal for increasing Hb levels andtreating antepartum anemia [84].

Addition of rhEPO to iron sucrose therapycan enhance the effectiveness of treatment ofiron-deficiency anemia in pregnancy. In a studyof pregnant women with iron-deficiency ane-mia resistant to treatment with oral iron ther-apy alone, iron sucrose administered either withor without rhEPO effectively treated anemia.However, increases in reticulocytes and hemat-ocrit were greater, and more patients achievedtarget Hb levels at 4 weeks with the combina-tion of rhEPO and iron sucrose compared withiron sucrose alone. Safety was similar in the twotreatment groups [85]. Selective addition ofrhEPO to iron sucrose for women with severeanemia or an inadequate response to ironsucrose alone has also been shown to be aneffective approach to treatment of iron-defi-ciency anemia in pregnancy [86].

Furthermore, iron sucrose has demonstratedequal if not superior efficacy compared withoral iron administration in women with iron-deficiency anemia in the postpartum setting.For these women, a study has shown that ironsucrose treatment can achieve higher Hb levelsthan oral ferrous sulfate treatment [88]. Ironsucrose followed by standard oral iron treat-ment after 4 weeks also replenished iron storesmore rapidly and resulted in a greaterimprovement in fatigue score compared withoral iron treatment alone in a randomized studyof women with postpartum iron-deficiencyanemia [90].

The effectiveness of iron sucrose either withor without rhEPO was assessed in a randomizedstudy in women with severe postpartum ane-mia. Hb returned to near-normal levels within

1974 Adv Ther (2020) 37:1960–2002

Table5

Publishedclinicalstudiesusingiron

sucrosein

obstetrics,gynecology,andwom

en’shealth

disorders

Stud

yInclusion

criteria

Patients,n

Iron

dose

(mg)/dose,

interval,

treatm

entdu

ration

Outcomes

andsafety

inform

ation

Useofiron

sucroseduring

pregnancyandpostpartum

Al-M

omen

etal.(1996)

[150]

Gest.

age\

32weeks

Hb\

9.0g/dL

SF\

20ng/m

L

IS:52

FeS:59

IS:200mgq.d.

ort.i.w.

FeS:

60mgt.i.d.

Significantlyhigher

HblevelswithIS

versus

FeS

Self-lim

itingfeverandtightnessin

skin

(one

each)withIS,3

0%GI

eventsand32%

non-compliancewithFeS,

6%couldnottolerate

FeS

Alet

al.

(2005)

[79]

Gest.age

26–3

4weeks

Hb8.0–

10.5g/

dL

SF\

13ng/m

L

IS:45

IPC:45

IS:200mgun

tilcalculated

dose,

5days

IPC:100mgt.i.d.,whole

pregnancy

Significantlybetter

Hbincrease

withIS

versus

IPC

PossiblyrelatedAEsto

IS:m

etallic

taste(n

=11),hotflush

(n=12),

dizziness(n

=8),n

ausea(n

=5),arthralgia(n

=1),vom

iting

(n=1);significantly

fewerGIsymptom

swithIS

versus

FeS(13.3%

vs.2

8.9%

upperGIevents)

Bayoumeu

etal.(2002)

[80]

Hb8.0–

10.0g/

dL

SF\

50ng/m

L

IS:24

FeS:

23

IS:69

200mgun

tilcalculated

dose,2

1days

FeS:

80mgt.i.d.,4weeks

Hbincrease

inboth

groups

without

significant

difference

‘‘Not-unp

leasanttaste’’onlyAEwithIS,duringinjection(dysgeusia).

One

treatm

entinterruption

dueto

AE(diarrhea)

withFeS

Bencaiova

etal.(2009)

[81]

Gest.age

15–2

0weeks

Hb\

10.5g/dL

SF\

100ng/m

L

IS:130

FeS:

130

IS:200or

300mg

FeS:

80mgq.d.

Significant

Hbincrease

versus

baselin

ein

both

groups

Mild

anem

ia(16.2%

),infections

(6.9%),musclepains(2.3%),pruritus

(2.3%),cough(1.5%),breastdisorders(1.5%)withIS;GIevents

onlywithFeS(17.7%

),14

SAEsin

ISgroup(preterm

contractions

n=3,

prem

atureruptureof

themem

branes

n=3,

moderate

anem

iaafterdeliveryn=2,threatened

preterm

deliverybecauseof

cervicalinsufficiency

n=2,

intrauterine

grow

threstrictionn=2,

infectionn=1,

injury

n=1),seven

SAEsin

FeSgroup(preterm

contractions

n=2,

vaginalbleeding

n=1,

prem

atureruptureof

themem

branen=1,

infectionn=1,

gestationaldiabetes

mellitus

n=1,

postpartum

pulmonaryem

bolism

n=1)

Adv Ther (2020) 37:1960–2002 1975

Table5

continued

Stud

yInclusion

criteria

Patients,n

Iron

dose

(mg)/dose,

interval,

treatm

entdu

ration

Outcomes

andsafety

inform

ation

Tariq

etal.

(2015)

[82]

Gest.

age[

12weeks

Hb\

10.5g/dL

SF\

12lg/L

IS:93

Iron

dextran:

105

C1antepartum

300mgIS

dose

ISandiron

dextranwereequally

effectivein

treatm

entof

IDAduring

pregnancy

Nomajor

side

effectswereobserved

ineither

group

Ham

met

al.

(2018)

[83]

Third

trim

ester

Hb\

9.5g/dL

IS:25

NoIS:364

C1antepartum

300mgIS

dose

The

earlierIS

wasreceived

beforedelivery,thegreaterthemedianHb

increase.O

nlythosereceivingIS[

2weeks

before

deliveryhada

significant

increase

inHblevelfrom

thirdtrim

esterto

delivery.

Increasing

administrations

increm

entally

impacted

Hbdifference

from

thirdtrim

esterto

delivery,withonlythosereceivingC

3dosesdemonstrating

statistically

significant

Hbchange

compared

withtheno

ISgroup

Ham

met

al.

(2019)

[84]

Third

trim

ester

Hb\

9.5g/dL

IS:65

NoIS:458

Exact

dosesnotstated

Third

trim

esterHbwaslower

intheIS

groupcomparedwiththeno

ISgroup

Despite

lower

starting

Hbin

theIS

group,

antepartum

ISreduced

transfusions

inpatientswithathirdtrim

esterHb\

9.5g/dL

Breym

ann

etal.(2001)

[85]

Hb\

10.0g/dL

SFB

15ng/m

L

IS:20

IS?

ESA

:20

200mg,b.i.w

.Bothregimenswereeffective;increasesin

hematocritweregreater

from

day11

(p\

0.01)andthemedianduration

oftherapywas

shorter(18vs.2

5days)withadjuvant

ESA

Welltolerated;m

etallic

tastewasreported

in8%

andwarm

feelingin

5%

Krafftet

al.

(2009)

[86]

Hb\

10.0g/dL

SFB

15ng/m

L

IS:27

IS?

ESA

:57

200mg,b.i.w

.IS

orIS

?ESA

was

effective:theoverallHblevelaftertherapywas

11.0g/dL

(note:32

patientsrespondedpoorlyinitially

toIS

alone,

thus

receivingadditionalESA

)

Welltolerated;

mostpatientsreported

metallic

taste

1976 Adv Ther (2020) 37:1960–2002

Table5

continued

Stud

yInclusion

criteria

Patients,n

Iron

dose

(mg)/dose,

interval,

treatm

entdu

ration

Outcomes

andsafety

inform

ation

Bencaiova

etal.(2006)

[87]

SFB

15ng/m

LIS

?ESA

:19

100mg,b.i.w

.Attheendof

therapy,Hb,

HCT,and

serum

EPO

werestatistically

significantlyim

proved

cf.atthestart(p

=0.01,p

=0.004,

and

p=0.006,

respectively)

Welltolerated

andno

detectablenegative

effectson

newborn

orfetus

Bhand

alet

al.

(2006)

[88]

Hb\

9.0g/dL

SF\

15ng/m

L

IS:22

FeS:

21

IS:200mge.o.d.,3

days

FeS:

200mgb.i.d.,6weeks

Significantlybetter

Hbincrease

withIS

versus

FeS

23%

metallic

taste,18%

facialflushingwithIS,3

3%GIeventswith

FeS

NoSA

Es,no

hemodynam

icdisturbances

during

orafterinfusion

Giann

oulis

etal.(2009)

[89]

Hb\

8.0g/dL

SF\

10ng/m

L

IS:78

FeProtSu:26

IS:100mgq.d.,3

days

FeProtSu:800mgq.d.,2

8days

Significantlybetter

Hbincrease

withIS

versus

FeProtSu

TwoAEswithIS

(headache,nausea),11

AEswithFeProtSu

(constipationn=5,

hiccup

n=4,

heartburnn=2)

Westadet

al.

(2008)

[90]

Hb6.5–

8.5g/dL

IS:58

FeS:

70

IS:200mgq.d.,3

days

FeS:

100mgb.i.d.,12

weeks

Hbincrease

inboth

groups

FewandtransientAEswithIS

(phlebitis,p

ainat

injectionsite),

22.9%

withdrewbecauseof

drug-related

AEswithFeS(G

Ievents

mostcommon

reason)

Perello

etal.

(2014)

[130]

Hb6–

8g/dL

IS?

FeS:

36

Placebo?

FeS:

36

IS:200mgq.d.,2

days

FeS:

525mgb.i.d.,30

days

Hbvalues

werecomparablein

wom

enreceivingIS

orplaceboin

addition

tooraliron

therapyat

anyof

thetimepoints.N

odifferenceswerefoun

dbetweenclinicalsymptom

sof

anem

ia,

psychologicalstatus,and

AEsbetweengroups

Krafftand

Breym

ann

(2011)

[91]

Hb\

8.5g/dL

24–4

8hafter

delivery

IS:20

IS?

ESA

:20

200mgq.d.,4

days

Hbvalues

werecloseto

norm

alin

both

groups

within2weeks

Bothtreatm

entswerewelltolerated;

minor

side

effectsincluded

metallic

tastein

30%

ofpatientsandwarm

flush

in8%

ofpatients

Adv Ther (2020) 37:1960–2002 1977

Table5

continued

Stud

yInclusion

criteria

Patients,n

Iron

dose

(mg)/dose,

interval,

treatm

entdu

ration

Outcomes

andsafety

inform

ation

Wågström

etal.(2007)

[92]

HbB

80g/dL

within72

hafterdelivery

IS:15

IS?

rhEPO

1:19

IS?

rhEPO

2:15

IS:200mgq.d.,d

ay0,

day3

IS?

rhEPO

1:IS

200mgq.d.,day

0,day3?

rhEPO

10,000

Uon

day0,

day3

IS?

rhEPO

2:IS

200mgq.d.,day

0,day3?

rhEPO

20,000

Uon

day0,

day3

Hbincreasedsignificantlyin

allthreegroups

over

time(p\

0.001),

andtherewereno

differencesbetweenthetreatm

entgroups

onany

dayof

evaluation

(p=0.59).The

totalmeanincrem

entin

Hbin

allsubjectswas

18g/dL

after1weekand28

g/dL

after2weeks

Breym

ann

etal.(2000)

[93]

Hb\

10.0g/dL

IS:20

IS?

ESA

:20

Oraliron:20

200mgq.d.,4

days

Allthreeregimenswereeffective;day7hematocritincreaseswere

higher

withadjuvant

ESA

than

forIS

ororaliron

alone:8%

versus

5%and4%

,respectively(bothcomparisons

p\

0.01)

Welltolerated

Useofiron

sucroseforgeneralwom

en’shealth

Krayenbuehl

etal.(2011)

[94]

HbC

12.0g/dL

SFB

50ng/m

L

IS:43

Placebo:

47

200mgq.d.,4

days

Trend

forbetter

improvem

entof

fatiguescorewithIS

versus

placebo

21%

drug-related

AEswithIS

(nausea,chills,headache,d

izziness,

chestpain,d

ysesthesia,d

ysgeusia),7%

AEswithplacebo(nausea,

headache,d

izziness,d

iarrhea)

Lee

etal.

(2019)

[96]

Menorrhagia

Hb\

10g/dL

SF\

30ng/m

L

IS:49

FCM:52

IS:200mgq.d.

(B600mg/week)

FCM:\

50kg,5

00mg/

week;

C50

kg,1

000mg/week

FCM

was

aseffectiveas

ISin

achievingHbC

10g/dL

within

2weeks

afterfirstadministration(78.8%

vs.7

2.3%

).The

timeto

reachHbC

10g/dL

was

significantlyshorterin

theFC

Mgroup

versus

theIS

group(7.7days

vs.1

0.5days).MeanHblevelswere

higher

intheFC

M-treated

patientsthan

intheIS-treated

patients

(borderlinesignificance,p=0.013).Q

oLscores

didnotdiffer

betweengroups.N

odeaths,anaphylacticreactions,or

transfusion

requirem

entswerereported

ineither

group.

AllAEsweremild

AEadverseevent,b.i.d.twicedaily,b.i.w

.twiceweekly,e.o.d.everyotherday;

EPO

erythropoietin,E

SAerythropoiesis-stimulatingagent,FC

Mferrouscarboxy-

maltose,FeProtSu

ferrousproteinsuccinylate,FeSferroussulfate,Gest.gestational,GIgastrointestinal,HCT

hematocrit,Hbhemoglobin,

IDA

iron-deficiency

anem

ia,IPC

iron

polymaltose

complex,ISiron

sucrose,q.d.

daily,Q

oLqualityof

life,SA

Eseriousadverseevent,rhEPO

recombinant

human

erythropoietin,SF

serum

ferritin,t.i.d.

threetimes

daily,t.i.w.three

times

weekly

1978 Adv Ther (2020) 37:1960–2002

2 weeks in both treatment groups. The findingssuggest that iron sucrose alone is sufficient forthe treatment of postpartum anemia for mostwomen, although additional rhEPO treatmentmay benefit a subgroup of patients with pro-nounced inflammatory responses [91]. A secondstudy in women with postpartum anemia foundthat the addition of rhEPO did not furtherincrease Hb concentrations above thoseachieved with IV iron sucrose treatment alone[92], while another study reported greatesthematocrit increases with rhEPO and ironsucrose compared with either iron sucrose ororal iron treatment alone (both p\0.01) [93].

General Women’s HealthBesides its use in pregnant women with iron-deficiency anemia, iron treatment can alsobenefit women with low ferritin levels andwithout anemia. In fatigued, premenopausalwomen with low ferritin levels and withoutanemia, iron sucrose treatment (four infusionsof 200 mg iron during the first two study weeks)showed a trend toward a greater improvementin fatigue compared with placebo. The differ-ence between the groups was significant inthose with initial serum ferritin levels of 15 ng/mL or below [94].

A large number of women are iron deficientand suffer from fatigue. It has therefore beensuggested that parenteral iron administrationcould benefit many women and could becomemore accepted. However, those who will benefitmost, and the doses of iron required for aneffect, need to be further defined [95].

Two randomized clinical studies havedemonstrated that iron sucrose is effective forthe correction of iron-deficiency anemia due toheavy menstrual bleeding (menorrhagia)[96, 97]; in one study, 72% of women whoreceived treatment with iron sucrose achievedHb levels of at least 10 g/dL within 2 weeks afterthe first administration [96].

Patient Blood Management

A summary of the studies assessing iron sucroseuse in patient blood management is provided inTable 6.

Preoperative Iron TreatmentPreoperative anemia is present in 30–40% ofpatients scheduled for elective surgery and cancomplicate surgery, increasing the likelihood ofblood transfusion or intensive care admission,increasing the risk of infections or throm-boembolic events, and prolonging the length ofhospital stay [35, 98–100]. In addition, and asmentioned previously, in patients undergoingelective cardiac surgery, iron deficiency withand without concomitant anemia is associatedwith a threefold increase in mortality, morepostoperative serious adverse outcomes, moreblood transfusions, and longer intensive careand hospital stay than patients without irondeficiency [25].

Iron sucrose is an effective pre-surgicaltreatment for iron-deficiency anemia and hasbeen shown to increase Hb, ferritin, and solubletransferrin receptor levels when administeredprior to orthopedic surgery [101]. Increases inHb were greatest 2 weeks after initiating ironsucrose treatment, suggesting that the optimaltime to initiate iron sucrose may be 2–3 weeksprior to elective surgery [101].

In patients without anemia receivingrhEPO who were due for elective surgery, ironsucrose was associated with significantlyhigher ferritin and reticulocyte counts thanwith oral ferrous sulfate therapy, and pre-vented iatrogenic iron depletion [102]. In aseparate study, there was no differencebetween oral iron therapy and IV iron insupporting preoperative erythropoietin-drivenstimulation of erythropoiesis (transfusionswere not reported) [103].

A benefit of iron sucrose and an ESA was alsodemonstrated in patients undergoing surgeryfor hip fractures. Combined treatment resultedin increased Hb levels and a lower transfusionrate compared with the use of either ironsucrose or ESA alone [104].

In surgical patients with iron-deficiencyanemia resulting from heavy menstrual bleed-ing, iron sucrose achieved significantly betterpreoperative Hb and ferritin levels than oraliron protein succinylate treatment [105]. How-ever, the study is limited by the premature ces-sation of the oral iron arm in the study.

Adv Ther (2020) 37:1960–2002 1979

Table6

Publishedclinicalstudiesusingiron

sucrosein

patientbloodmanagem

ent

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Useofiron

sucrosein

thepreoperativesetting

Theusinger

etal.

(2011)

[101]

Preoperative

orthopedic

surgery

IS:20

900mgover

10days

HbandSF

levelsincreasedsignificantly.T

SAT

didnot

change

significantly.E

ndogenousEPO

decreasedfrom

261to

190pg/m

L2weeks

afterIV

iron

treatm

ent

(p=0.050,

notsignificant

afterBonferronicorrection)

NoAEsrelatedto

ISwereobserved

Rohlin

get

al.

(2000)

[102]

Preoperative

elective

surgery

Hb\

14.0g/dL

IS?

ESA

:6

FeS?

ESA

:6

IS:200mgb.i.w

.,3weeks

FeS:

160mg/day,3weeks

Hblevelsincreasedin

both

groups;Hblevelincreased

significantlyover

3weeks

withIS

?ESA

butnotwith

FeS?

ESA

Preoperative

reticulocyte

coun

tandSF

weresignificantly

higher

withIS

?ESA

than

FeS?

ESA

Nodose-limitingAEsor

allergicreactionswereobserved

TwopatientsreceivingFeSreported

mild

GIeffects

(constipation,

epigastricpain)

Olijhoek

etal.

(2001)

[103]

Preoperative

elective

orthopedicsurgery

HbC

10.0

toB

13.0g/dL

SFC

50ng/m

L

IS?

ESA

:29

Oraliron

?ESA

:29

IS?

placebo:

25

Oraliron

?placebo:

27

IS:200mgday1andday8

Oraliron:200mg/day,

2weeks

IS?

ESA

andoraliron

?ESA

significantlyincreasedtotal

RBC

production,H

b,HCT,and

reticulocytesversus

respective

placebogroups;no

significant

differencesfor

IS?

ESA

versus

oraliron

?ESA

IS?

placebo,

andoraliron

?placebowas

notassociated

withincreasesin

hematologicalvalues

Incidenceof

AEssimilarbetweengroups;no

thrombotic

and/or

vascular

eventswerereported

1980 Adv Ther (2020) 37:1960–2002

Table6

continued

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Braga

etal.

(1995)

[179]

Preoperative

stom

ach

orcolorectalcancer

HCT\

34%

SF\

700ng/m

L

IS:11

IS?

ESA

:11

Noiron:11

(neither

anem

icnoriron

deficient)

IS:200mgq.d.,1

2days

IS?

ESA

:200

mgq.d.,days

1,4,

8,12

IntheIS

group,no

patientscoulddonateautologous

blood

comparedwithallpatientsin

theIS

?ESA

group

36%

ofpatientsin

theIS

groupreceived

perioperative

transfusionof

homologousbloodcomparedwithnone

intheIS

?ESA

group

Nomajor

AEswitheither

regimen

Xuet

al.

(2019)

[104]

Preoperative

hip

fracture

repair

IS:32

ESA

:32

IS?

ESA

:32

3days

before

surgery

Dosenotstated

Com

binedIS

?ESA

was

moreeffectivethan

either

EPO

orIS

alone

HbincreasedsignificantlymoreafterIS

?ESA

than

after

either

EPO

orIS

alone

Nosignificant

difference

intheincidenceof

adversedrug

reactionsam

ongthethreegroups

Kim

etal.

(2009)

[105]

Menorrhagia

Hb\

9.0g/dL

IS:39

FeProtSu:37

200mg,e.o.d.

t.i.w.

80mgq.d.,3

weeks

Significantlybetter

Hbincrease

andresponse

rate

withIS

versus

FeProtSu

Twomyalgiaeventsandoneinjectionpain

eventwithIS;

oneeventeach

ofnausea

anddyspepsiawithFeProtSu;n

osevere

AEsreported

Useofiron

sucrosein

theperioperativesetting

Karkouti

etal.

(2006)

[106]

Postoperativeanem

ia

Hb7–

9g/dL

IS:13

IS?

ESA

:12

Noiron:13

200mgdays

1,2,

3postoperatively

Withno

between-groupdifferences,earlypostoperative

treatm

entwithIS

aloneor

incombination

withESA

did

notappear

toaccelerateearlyrecovery

from

postoperative

anem

ia

Adv Ther (2020) 37:1960–2002 1981

Table6

continued

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Madi-Jebara

etal.

(2004)

[107]

Postoperativecardiac

surgery

Hb7–

10g/dL

IS:40

IS?

ESA

:40

Noiron:40

200mgq.d.

toreachtotal

iron

deficit

Nosignificant

difference

intransfusionrates

Nosignificant

difference

inHbincrease

PostoperativeIS,w

ithor

without

ESA

,isnoteffectiveat

correcting

postoperativeanem

ia

NoAEswithIS

Serrano-

Trenas

etal.

(2011)

[108]

Perioperativehip

fracture

surgery

IS:99

Noiron:97

200mg,39

e.o.d.

Nosignificant

difference

inRBC

transfusions

between

groups

3.0%

AE-related

treatm

entsuspension

withIS

(one

skin

rash,twogeneraldiscom

fort);overall,14.8%

infections

(mainlysuperficialsurgicalwound

infections

5.6%

)

Garrido-

Martı́n

etal.

(2012)

[109]

Perioperativecardiac

surgery

Hb\

8g/dL

coronary

patients;\

7g/dL

valvesurgerypatients

IS:54

Oraliron:53

Placebo:

52

IS:100mg9

3during

perioperativeperiod

Oraliron:105mgq.d.

pre-

andpostoperatively,and

1month

afterdischarge

Nobetween-groupdifferencesin

Hb,HCT,ortransfusions

NeitherIS

nororaliron

therapywereeffectivein

correcting

anem

iaaftercardiacsurgery

NoAEswithIS

Shin

etal.

(2019)

[110]

Perioperative

orthopedicsurgery

Meta-analysis

1869

patientsfrom

12clinicaltrials

Various

IViron

PerioperativeIV

iron

during

orthopedicsurgery,especially

postoperatively,appearsto

reduce

theproportion

ofpatientstransfused

andun

itstransfused,w

ithshorter

length

ofhospitalstay

anddecreasedinfectionrate

Xuet

al.

(2019)

[111]

Postoperativecardiac

valvular

surgery

Hb\

12.0g/dL

(wom

en)

or\

13.0g/dL

(men)

SF30–1

00ng/m

Lor

TSA

T\

20%

IS:75

Placebo:

75

200mge.o.d.,u

ntiltotal

iron

deficiencywas

achieved

Hbconcentrationandproportion

ofpatientswithanem

iacorrectedor

achievingHbincrem

ents[

2.0g/dL

were

significantlygreaterforIS

than

placebo14

days

postoperatively,butnot7days

postoperatively

SFweresignificantlyhigherforIS

versus

placebo7daysand

14days

postoperatively

ISwas

welltolerated:

noAEsor

infusion

reactionswere

observed

1982 Adv Ther (2020) 37:1960–2002

Table6

continued

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Muñ

ozet

al.

(2014)

[112]

Perioperative

orthopedicsurgery

HbC

10.0g/dL

IS:1142

IS?

EPO

:351

FCM:45

Noiron:1009

100–

200mgup

to39

(2–5

days

preoperatively

or2–

3days

postoperatively)

Veryshort-term

perioperativeIV

iron

inmajor

lower

limb

orthopedicprocedures

isassociated

withreduced

allogeneicbloodtransfusionratesandlength

ofhospital

stay

Inpatientswithhipfracture,IViron

isalso

associated

with

areductionin

postoperativenosocomialinfection

Nosignificant

AEswithIV

iron

ParejaSierra

etal.

(2019)

[113]

Perioperativehip

fracture

Descriptive

study

IS?

ESA

:40

Transfusion:12

Transfusion

?IS

?ESA

:51

Notreatm

ent:27

Hb\

8.5g/dL

:transfusion

Hb8.5–

10g/dL

:29

200mg(48hapart)

Hb10–1

1g/dL

:29

400mg(48hapart)

ISdidnotreduce

theproportion

oftransfused

patients

(56%

transfused

vs.44%

nottransfused

receivingIS),but

itdidreduce

thenu

mberof

bloodun

itsrequired

Patientswho

received

IShadbetterfunctionalrecoverythan

thosewho

didnot

NoAEswithIS

Montano-

Pedroso

etal.

(2018)

[114]

Postoperativebariatric

abdominoplasty

Hb\

11.5g/dL

SF\

11ng/m

L

IS:28

Oraliron:28

IS:200mgim

mediatelyand

1daypostoperatively

Oraliron:100mgb.i.d.

8days

Superiorityof

ISwas

notshow

n;theminim

umclinically

relevant

difference

inHbconcentrations

wasnotreached

NoAEsin

theIS

group

Constipation(18%

),diarrhea

(11%

),andnausea

(4%)were

reported

withoraliron

AEadverseevent;b.i.d.twicedaily,b.i.w.twiceweekly,e.o.d.everyotherday,EPO

erythropoietin,E

SAerythropoiesis-stimulatingagent,FC

Mferriccarboxym

altose,

FeProtSu

ferricproteinsuccinylate,FeSferroussulfate,G

Igastrointestinal,H

bhemoglobin,

HCThematocrit,IV

intravenously

administered,

ISiron

sucrose,q.d.

everyday,RBCredbloodcell,

SFserum

ferritin,t.i.w.three

times

weekly,TSA

Ttransferrinsaturation

Adv Ther (2020) 37:1960–2002 1983

Perioperative Iron TreatmentResults from four randomized controlled trialsdid not find convincing benefits of periopera-tive iron in orthopedic or cardiac surgery[106–109]. In contrast, however, a recent meta-analysis of IV iron therapies, including ironsucrose, showed that perioperative IV irontherapy during orthopedic surgery was associ-ated with several benefits, including reducedtransfusion rates and shorter hospital stays, butwithout impacting the mortality rate [110].Additionally, a separate randomized studyshowed that the use of iron sucrose can signif-icantly increase Hb levels versus placebo controlin patients undergoing cardiac surgery [111].This is important as patients undergoing cardiacsurgery are at risk of postoperative functionaliron deficiency.

For patients undergoing surgery for fractures,several studies have suggested a benefit of uti-lizing iron sucrose, particularly for hip fractures.A number of improved outcomes have beenassociated with perioperative IV iron (includingiron sucrose) in patients undergoing surgery forhip fracture and arthroplasty, as highlighted ina pooled analysis of observational data, withbenefits including reduced transfusion rates,shorter hospital stays, reduced infection rates(hip fracture only), and lower 30-day mortality(hip fracture only) [112].

Blood Donors

Birgegård et al. investigated the frequency andseverity of iron depletion in regular blooddonors and the effects of iron sucrose and oraliron sulfate therapy on iron status [115]. Ironsucrose was found to substitute iron loss inblood donors more efficiently compared withoral iron sulfate treatment, especially inwomen, and also reduced the severity of restlessleg syndrome, which can occur as a complica-tion of iron deficiency.

Oncology

A summary of the studies on iron sucrose use inoncology is provided in Table 7.

Anemia is a common side effect of cancertreatments and ESAs may be used to aid in RBCproduction. In patients with anemia and lym-phoproliferative malignancies who were notreceiving chemotherapy, the addition of ironsucrose to an ESA resulted in a significantlyfaster and greater Hb increase compared withESA therapy alone [116]. Furthermore, usingdata from this study [116], when iron sucrosewas given as an additional therapy, ESA doserequirements were reduced from week 5onward, allowing cost savings over the studyperiod [117].

In patients with multiple myeloma or lym-phoma who had undergone autologoushematopoietic cell transplantation, supple-mentation of an ESA with iron sucrose increasedthe proportion of patients with Hb responsesfrom 79% to 100%, reduced the medianresponse time, and lowered ESA dose require-ments compared with those receiving no irontreatment [118]. There was no impact of ironsucrose treatment on long-term clinical out-comes or survival [119].

Utilization of iron sucrose in the absence ofESAs can also benefit some oncology patients byimproving Hb levels and reducing the need forRBC transfusions [120–122].

Pediatric Populations

Data on the use of iron sucrose within pediatricpatients are limited. The data that are available,however, suggest that iron sucrose is an effec-tive option (Table 8).

In children with, or at risk of, iron defi-ciency/iron-deficiency anemia, iron sucroseappears effective in those who cannot tolerateor do not respond to oral iron therapy (recom-mended maximum single dose of 7 mg iron perkg to minimize the risk of AEs) [123]. Whereiron sucrose has been used in children with irondeficiency and iron-deficiency anemia, signifi-cant improvements in Hb levels have beenshown [124, 125].

Where children also suffer from IBD, the useof oral iron therapy is difficult. In this setting,iron sucrose is effective for the routine man-agement of iron-deficiency anemia. Children

1984 Adv Ther (2020) 37:1960–2002

Table7

Publishedclinicalstudiesusingiron

sucrosein

oncology

Stud

yInclusioncriteria

Patients,n

Iron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Hedenus

etal.(2007)

[116]

Clin

ically

stablelymphoproliferaltive

malignancy

Hb9.0–

11.0g/dL

IS?

ESA

:33

ESA

:34

100mgq.w.(weeks

0–6);100mgq.2.w.

(weeks

8–14)

16weeks

(follow-up)

SignificantlygreaterHbincreasefrom

week8onwardwithIS

versus

noIS

Proportion

ofpatientswithHbincrease

C2g/dL

wassignificantly

higher

withIS

(93%

)than

noIS

(53%

;p=0.001)

ESA

dose

lower

withIS

than

noIS

from

week5onward

AEsweredistributedevenlybetweengroups

Beguinet

al.(2013)

[118]

AutologousSC

T

SF[

100ng/m

L

IS?

ESA

:23

ESA

:25

NoESA

:24

200mgon

days28,42,

and56

afterSC

TCom

pleteHbresponse

within18

weeks

achieved

by100%

with

IS?

ESA

,79%

withESA

,21%

withno

ESA

Erythropoieticresponse

significantlyhigher

withIS

?ESA

than

ESA

,resulting

inlower

ESA

use,reduceddrug

costs,and

improved

qualityof

lifescores;effect

ontransfusions

was

not

significant

Safety

findingsweresimilarbetweengroups

Jasperset

al.(2015)

[119]

[Long-term

follow-up

ofBeguinet

al.

(2013)

[118]]

AutologousSC

T

SF[

100ng/m

L

IS?

ESA

:50

ESA

:52

NoESA

:25

1.4years(m

edian

follow-up)

Overallsurvival(1-yearand5-year)andprogression-free

survival(1-

year

and5-year)notsignificantlydifferentbetweengroups

Incidenceof

infections

remainedcomparablebetweengroups

Other

seriouscomplications

wereun

common

andhardly

attributableto

ESA

orIS

Dangsuw

anand

Manchana(2010)

[120]

Hb\

10.0g/dL

IS:22

FeS:

22

IS:200mg

FeS:

200mgt.i.d.

Significantlyhigher

Hbandsignificantlyfewer

RBC

transfusions

withIS

than

FeS

Mostcommon

AEsweremild

nausea

andvomiting;no

significant

difference

inAEsbetweengroups;no

SAEsor

hypersensitivity

reactions

Kim

etal.(2007)

[121]

Hb\

12.0g/dL

IS:30

Noiron:45

19

200mgperCT

cycle

Significant

reductionin

RBC

transfusions

withIS

versus

noiron

Notreatm

ent-relatedAEswithIS;transfusion-relatedallergic

reactionswithsimilarfrequencyin

both

groups

AEadverseevent,CTchem

otherapy,E

SAerythropoiesis-stimulatingagent,FeSferroussulfate,Hbhemoglobin,

ISiron

sucrose,q.2.w.every2weeks,q.w.every

week,

RBCredbloodcell,

SAEseriousadverseevent,SC

Tstem

celltransplantation,

SFserum

ferritin,t.i.d.

threetimes

daily

Adv Ther (2020) 37:1960–2002 1985

Table8

Publishedclinicalstudiesusingiron

sucrosein

pediatricpatients

Stud

yInclusioncriteria

Patients,

nIron

dose

(mg)/dose,

interval,treatm

ent

duration

Outcomes

andsafety

inform

ation

Crary

etal.

(2011)

[123]

AgedB

18years

C1dose

ofIS

Patientscouldnothave

CKD

IS:38

Mediandose:100mg

Mediannu

mberof

infusions:3

Patientshadagood

response

toIS,w

ithamedianHbrise

of1.9–

3.1g/dL

depend

ingon

theindication

ISwaswelltolerated

withonlyoneseriousreaction

(tem

poraryandreversible

hypotension)

inapatientwho

hadreceived

IS500mg,which

was

greater

than

therecommendeddose

of300mg

Akarsuet

al.

(2006)

[124]

SF\

12ng/m

L

Low

Hb(adjustedfor

age)

IS:62

Variabledepen