Ferric Carboxymaltose

Efficacy and safety of ferric carboxymaltose incorrecting iron-deficiency anemia: a review ofrandomized controlled trials across different indications

George R. Baffle

Albany Nephrology Pharmacy (ANephRx) Group, Albany, New York, USA

Correspondence to: George R. Bailie, PharmD, PhD, Albany College of Pharmacy and Health Sciences,106 New Scotland Aye, Albany, NY 12208, USA; e-mail: george.bailie@acphs.edu

AbstractKey words

• Anemia• Ferinject• Ferric carboxymaltose,

efficacy, safety• Intravenous iron• Iron deficiency

Arzneimlttelforschung201 0;60(6 a) :386—398

Ferric carboxymaitose (FCM, Ferinject')was effective and well tolerated in thetreatment of iron-deficiency anemia(IDA) in nine, Phase III, randomizedcontrolled, multlcenter trials in a diverserange of indications, including patientswith inflammatory bowel disease (IBD),post-partum anemia (PPA) or abnormaluterine bleeding (AUB), chronic heartfailure (CHF), non-dialysis-dependentchronic kidney disease (CICD) and thoseundergoing hemodialysis (HD).

In most trials, patients received eitherFCM doses of 1000 mg, administeredintravenously (Lv.) over <15 mm. or oralferrous sulfate (FeSuIf) 325mg (65 mgiron), three times daily (t.i.d.), or 304mg(100mg iron), twice daily (b.LdJ. in onetrial, patients on HI) received 200mg Lv.of either FCM or iron sucrose (ISC), two-to-three times weekly. In a pilot study inpatients with CHF and CKD, patientsreceIved 200 mg of FCM by push injectioncompared with 200mg of ISC slow Injec-tion. FCM was usually administered untilthe patient's calculated total ironreplacement dose was achieved.

Treatment with FCM Improved indicesof anemia (hemoglobin [Hbl, ferritin andtransferrin saturation ITSATI values). Inpatients on HD with IDA secondary toCKD, FCM demonstrated comparableefficacy to ISC in achieving an increase inHb. In patients with IBD or PPA, Im-provements in Hb levels were more rapidwith FCM than with FeSuIf. Patients withPPA receiving FCM compared with thosereceiving oral iron achieved an Hb rise�2.0 g/dl earlier (7 days compared with14 days; p <0.001), were more likely toachIeve an Hb rise �3.0 gldl at any timebeginning at day 14 (86.3% comparedwith 60.4%; p< 0.001), and achieve an

Hb >12.0 gldl at the end of the study(Day 42; 90.5% compared with 68.6%,p <0.01). Serum ferritln increased In theLv. FCM treatment group, but not in theoral iron group. Differences betweengroups were significant at each studyinterval. TSAT increased significantly atevery interval in both groups; however,FCM-treated patients showed higherTSAT at each interval after the first week.FCM improved patient quality of life to anequivalent extent to oral FeSuif in pa-tients with IBD or PPA, and to a greaterextent than oral FeSuif in women withAUB. FCM also improved quality of life aswell as functional symptoms and exercisecapacity in patients with CHF. Safety datafrom more than 3000 patients showedthat FCM was well tolerated. No safetyconcerns have been identified in breast-fed infants of mothers receiving FCM.FCM is, therefore, an effective and well-tolerated option in the treatment of IDA.

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Ferric Carboxymaltose

1. IntroductionIron(I1I)-hydroxide polymaltose complex (fenic carboxy-maltose, FCM; Ferinject, Vifor (International) Inc., St.Gallen, Switzerland) is a novel, next-generation complexfor intravenous (i. v.) iron treatment, developed to re-duce the limitations of previous i. v. iron preparationssuch as high pH, high osmolarity, long administrationtime, or dosage limitations [11. FCM does not react withdextran antibodies, has a pH between 5.0 and 7.0, andup to 1000 mg iron (as FCM) can be infused within15 mm 11]. FCM has a unique carboxymaltose shell,which leads to a highly stable, type I polynuclear iron(111)-hydroxide carbohydrate complex [11, with a mole-cular mass of approximately 150,000 Daltons. FCM re-leases minimal amounts of iron into the circulation.The iron is taken up in a controlled way by the macro-phages, and delivered to transfemn and ferritin via thephysiological iron metabolism pathways.

To date, the safety and efficacy of FCM in correctingiron deficiency have been investigated in a diverse rangeof indications in ten completed Phase I — HI studies. Thekey findings of the following nine published Phase IIIstudies will be discussed in this review:

adverse drug eventadverse eventabnormal uterine bleedingtwice dailyCrohns diseasechronic heart failurechronic kidney diseaseerythropoiesis-stimulating agentFerinject® Assessment in patients with IRondeficiency and chronic Heart Failureferric carboxymaltoseferrous sulphategastrointestinalhemoglobinhemoclialysishemodialysis-dependent chronic kidney diseaseintravenousinflammatory bowel diseaseiron-deficiency anemiairon sucroseintention-to-treatnon-dialysis-dependent chronic kidney diseaseNew York Heart Associationper-protocolpost-partum anemiaquality of life36-item short-form questionnairethree times dailytreatment-emergent adverse eventtotal iron-binding capacitytransferrin saturationulcerative colitis

• iron-deficiency anemia (IDA) secondary to inflamma-tory bowel disease (IBD) 121

• post-partum IDA [3—51• IDA from abnormal uterine bleeding (AUB) 161• IDA in patients with non-dialysis-dependent chronic

kidney disease (NDD-CKD) [71• IDA associated with maintenance hemodialysis (HD)

181

• IDA in patients with chronic heart failure (Cl-IF) 191• IDA in patients with a variety of chronic conditions

including NDD-CKD, HD-dependent CKD, pentonealdialysis-dependent CKD and IBD [101.

2. FCM in the management of IDAsecondary to IBD [2]Anemia is a frequent complication of IBD (Crohn's dis-ease ICDI and ulcerative colitis IUCI) 12, 111. The causeof iron deficiency has been attributed to chronic bloodloss from the ulcerated intestinal mucosa, and to im-pairment of iron intake and uptake, resulting in a nega-tive iron balance 12, 121. In active disease, inflammatorymediators may alter iron metabolism (by retaining ironin the reticular-endothelial system), erythropoiesis, anderythrocyte survival. This condition is termed anemia ofchronic disease. Iron supplementation should be in-itiated when IDA is present [131.

In recent years, the use of oral iron replacement ther-apy for IBD has been questioned. Iron absorption maybe compromised in patients with IBD, making oral irontherapy ineffective in patients with ongoing iron loss 121.Intolerance and discontinuation due to adverse events(AE5) with oral iron are frequent 111]. In contrast, i.v.iron replacement, particularly with iron sucrose (ISC;Venofer®, Vifor (International) Inc.) has been found tobe effective and well tolerated 1141, although a potentialdisadvantage is the need for repeated infusions and longinfusion times; single doses should not exceed 500 mgiron per infusion per week', infused over at least 3.5 h.This requires repeated hospital visits by the patient,therefore consuming both time and resources.

Consequently, a multicenter, open-label, randomized,controlled study was conducted by Kulnigg et a!. [2] toestablish the non-inferiority and safety of FCM in com-parison with oral ferrous sulfate (FeSuif) in reducingIDA (defined by hemoglobin [Hbl � 10.0 g/dl and trans-femn saturation ETSAT] <20% or serum femtin<100 ig/l) secondary to chronic IBD (CD or UC).

Two hundred adult patients (aged 18—80 years) wererandomized in a 2:1 ratio (FCM, n = 137; FeSulf, n =63) to receive FCM (maximum 1000 mg iron per infu-sion and no more than three infusions permitted pertreatment cycle) at 1-week intervals until the patients'calculated total iron deficit (Ganzoni equation) [15] was

'The single maximum dosage may vary from country to coun-try; refer to local Summary of Product Characteristics formore prescribing information.

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AbbreviationsADE

AE

AUB

b. i. d.

CDCHFCKD

ESA

FAIR-HF

FCM

FeSuIfGI

HbHDHD-CKDi. V.

IBDIDA

ISC

ITFNDD-CKDNYHA

PP

PPA

QoLSF-36t.i.d.TEkETIBCTSAT

Uc

Ferric Carboxymaltose

r

reached, or 304 mg FeSulf (100 mg iron) orally, twicedaily (b.i.d.) for 12 weeks. The primary endpoint waschange in Hb from baseline to week 12. Exclusion crite-ria were: untreated vitamin B12 or folate deficiency,other types of anemia, erythropoietin treatment within8 weeks prior to enrollment, and iron replacement ther-apy or blood transfusion within the previous 30 days.Concomitant medication use was recorded, but erythro-poietin treatment was not permitted during the study.Quality of life (Q0L) (assessed using the 36-item short-form questionnaire ISF-361) and disease activity weredetermined at baseline and every 4 weeks.

The median calculated iron deficit was 1405 mg(range 937—2102 mg) in the FCM group and 1392 mg(range 982—1927 mg) in the FeSuIf group. The medianHb improved from 8.7 to 12.3 g/dl in the FCM groupand from 9.1 to 12.1 g/dl in the FeSuIf group; non-infer-iority was demonstrated (intention-to-treat [ITF I analy-sis: p = 0.6967; per protocol LPP] analysis: p = 0.80 16).

Secondary efficacy endpoints included: change in Hb,serum ferritin and TSAT from baseline to weeks 2, 4, 8,and 12; number and proportion of patients whoachieved target levels of Hb, ferritin, and TSAT at weeks2, 4, 8, and 12; proportion of patients discontinuing dueto lack of response, QoL, and disease activity). AEs andconcomitant medications were recorded at each visit.

Response (defined as the proportion of patients withan Hb increase of >2.0 g/dl) was faster for patients inthe FCM group than those in the FeSulf group at week 2(p = 0.005 1) and week 4 (p = 0.0346). The statistical ana-lysis of the cumulative Hb responder rate over 12 weeksdemonstrated a statistically significant difference be-tween the treatment groups (log-rank test, p = 0.0009).Median ferritin increased from 5.0 to 323.5 ig/l atweek 2, and decreased to 43.5 ig/l at week 12). In theFeSuif group, a moderate increase from 6.5 to 28.5 tg/lat week 12 was observed. The final percentage of re-sponders (defined as the proportion of patients withserum ferritin within target levels of 100—800 tg/l) atweek 12 was 26.5% in the FCM group versus 3.3% inthe FeSulf group (Kaplan-Meier analysis: log-rank test,p < 0.001).

TSAT increased in both groups, from 4% to 23% inpatients treated with FCM, and from 6% to 17% in pa-tients treated with FeSulf. The percentage of responders(defined as the proportion of patients with 20—50%TSAT) was significantly higher in the FCM group atweek 2 (p = 0.0006) and week 4 (p = 0.0 130), but thepoint estimates at week 12 appeared similar. Analysesover the 12-week period, however, showed statisticallysignificant differences between the two groups (log-ranktest, p = 0.0086).

There was an improvement in Q0L in both groups,with a slightly higher median change from baseline inthe SF-36 total score in the FCM group than in theFeSuIf group at all time points (+ 14 versus +8.6 atweek 12) [21. Both the Crohn's Disease Activity Indexand the Colitis Activity Index showed decreases in mean

total scores during the study in both treatment groups,indicating that FCM may also improve Q0L.

FCM was well tolerated, and the dosing schedule wasnot associated with any clinically relevant safety con-cerns. Treatment-related AEs were experienced by28.5% and 22.2% of patients in the FCM and FeSulfgroups, respectively. A higher proportion of patients inthe FeSuIf group discontinued study medication due toan AE (2 11.5%] patients in the FCM group versus 5(7.9%] patients in the FeSulf group, Fisher's Exact test,p = 0.033). There were no cases of anaphylactic shock!reaction.

In summary, FCM was effective in the treatment ofIBD-associated IDA, providing a fast increase in Hb lev-els and the refill of iron stores, and allowing convenientadministration of up to 1000 mg iron within 15 mm.FCM may also improve patient Q0L.

This study had an open design, but the main outcomeparameter for the trial was an objective measure (Hbincrease) and is thus unlikely to be influenced by anon-blinded trial. However, subjective parameters, suchas Q0L or disease activity scores might have been influ-enced by patient perception and observer bias. Thenumber of patients who discontinued treatment due toAEs was unexpectedly low, as intolerance of FeSuIf isexpected to occur in approximately 25% of patientswith IBD [161. As patients with a history of iron intoler-ance were excluded, selection bias for iron-tolerant pa-tients may play a role in these findings.

FCM offers a convenient treatment option for IBD-as-sociated anemia. To simplify the therapeutic schemefurther, additional trials on the use of FCM for the sim-ple and pragmatic correction of anemia in IBD are cur-rently ongoing, and results are expected in 2010 (clini-caltrials.gov).

3. Post-partum IDA and FCM [3-5]Post-partum anemia (PPA) arises frequently, imposes asubstantial disease burden during critical periods of ma-ternal—infant interaction and may give rise to lastingdevelopmental deficits in infants of affected mothers15, 17). Iron deficiency is a common cause of anemia inthe post-partum period [18]. Oral treatment with FeSulfhas been considered the standard of care in PPA. How-ever, parenteral iron treatment is expected to be advan-tageous in cases in which treatment with oral iron is notpossible due to gastrointestinal (GI) AEs, in patientswith poor compliance, or in patients with severe anemia[31.

Three randomized, open-label, controlled studieshave been conducted to compare the efficacy of large-dose i. v. FCM (total iron dose was calculated using theGanzoni formula, modified to include adjustment forbaseline iron status) 1151 versus oral FeSuIf in womenwith IDA (defined as Hb � 10.5 g!dl) within the 10-daypost-partum period 13—5] (Table 1).

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Ferric Carboxymaltose

Table 1: Ferric carboxymaltose (FCM) and oral ferrous sulfate (FeSuIf) in women with post-partum anemIa: study designs(3—51.

Objectives To evaluate the efficacy and safety of FCM versus oral FeSuif (3—5]

Materials andmethods

Open label, multicenter, randomized, controlled trial 13—51

Study Breymann et aL [3] Seid et aL 141 Van Wyck et aL [5]

Dosage FCM (1000 mg iron) as a single dose,�3 weekly infusions(n = 227), or 304mg oral FeSuIf(100mg iron), b.i.d. for 12 weeks(n= 117)

FCM (1000 mg iron) as a single dose.�2500 mg cumulatively (n = 143) or325mg oral FeSuif (65mg iron), t. i.d.for 6 weeks(n= 148)

FCM (1000 mg iron) asa single dose, �2500 mg cumulatively(n = 174), or 325mg oral FeSuIf(65 mg iron).t.i.d. for6weeks(n = 178)

Inclusion criteria I-lb � 105 g/dl post-partuni Hb � 10.0 g/dl 10 days or fewer post-partum

Hb � 10.0 g/dl 10 days post-partum

Primary endpoint Change in Hb levels from baseline toweek 12

Proportion of patients achieving Hb>12.0 g/dl

Proportion of patients with Hbincrease �2.0 g/dl

b. i. d., twice daily; Hb, hemoglobin; t. i. d., three times daily.

d

In the first non-inferiority study undertaken by VanWyck et a!. 151, patients (aged 15—49 years) receivedeither i. v. FCM (� 1000 mg iron over 15 mm, repeatedweekly to achieve a total calculated iron replacementdose) or FeSuIf (325 mg [65 mg iron], orally, three timesdaily (t. i.d.) for 6 weeks) (Table 1). Patients with Hb<10.0 g/dl were enrolled; patients were excluded if theyhad demonstrated previous non-adherence to pre-scribed oral iron therapy, active severe infection, serumTSAT >50%, serum ferritin >500 tg/l, received erythro-poiesis-stimulating agents (ESAs) within 3 months ofscreening, a history of myelosuppressive therapy, or anhematological disorder other than iron deficiency. Pre-mature withdrawal was required if an alternative inter-vention for the management of anemia was given. Redblood cell transfusion, initiation of ESAs or iron admin-istration were not included in the study protocol.

One-hundred and seventy-four patients received350 doses of i.v. FCM (mean total dose 1403 mg) inthree, two, or one injections (19 [10.9 %l, 138 179.3 %Jor 17 (9.8%] of patients, respectively); 178 patients re-ceived FeSulf. To estimate sample size, 80% of patientsin each treatment group were assumed to be compliantwith dosing and achieve the primary endpoint. Based onthis assumption, a sample size of 160 patients per treat-ment group provided 85% power to achieve a 97.5%two-tailed lower confidence bound > 15% for the treat-ment difference (i. v. iron minus oral iron) in successrate. Health-related Q0L was assessed using normalizeddata from the SF-36 questionnaire 1191 and the FatigueLinear Analog Scale Assessment 1201.

The primary efficacy endpoint was the proportion ofpatients with an Hb increase �2.0 g/dl post-treatment.There was no between-group difference in the propor-tion of patients who achieved a rise in Hb �2.0 g/dl atday 42 (96.4% versus 94.1%; p = 0.443). FCM was non-inferior to oral FeSuIf (Fig. 1A). Adherence to prescribedtherapy was greater among patients in the i. v. FCM

group compared with those in the oral FeSuIf group(mean adherence 98.0% versus 83.9 %).

Secondary efficacy endpoints included the proportionof patients attaining an Hb increase �3.0 g/dI and an Hblevel � 12.0 g/dl (correction of anemia; normal valueused to assess response), time to achieve primary out-come, peak Hb increase from baseline, time to peak Hbincrease, maximal increase in serum ferritin, TSAT, reti-culocyte count, number of patients requiring interven-tion, time to intervention, proportion of patients withan Hb increase �2.0 g/dl and serum ferritin � 16.0 ig/l,and the proportion of patients with improved Q0L. Pa-tients receiving i. v. FCM were more likely to achieve anHb rise �3.0 gIdl at any time from day 14 onwards dur-ing the study than those receiving FeSuIf (p <0.001; theproportion of responders at day 42 were 86.3 % versus60.4%) (Fig. 1B). Patients receiving i.v. FCM were morelikely to achieve an Hb level � 12.0 g/dl at the end of thestudy (day 42) (han those receiving FeSuIf (90.5% versus68.6%, p <0.01) (Fig. IC). Patients assigned to i.v. FCMachieved an Hb rise �2.0 g/dl sooner than those as-signed to oral FeSulf (median time to achieve primaryendpoint: 7 days compared with 14 days, respectively,p < 0.001).

Among patients assigned to i. v. FCM, overall erythro-poeltic response (Hb, hematocrit. reticulocytes, meancorpuscular volume, mean corpuscular Hb and reticulo-cyte Hb content) was more robust at most treatment in-tervals than for patients treated with FeSuIf.

Serum ferritin increased rapidly in the i.v. FCM treat-ment group, but did not increase in the oral FeSuIfgroup (Fig. 1D). Importantly, the serum femtin levelwas in the normal range at the end of the study in theFCM group. Differences between groups were signifi-cant at each study interval. TSAT increased significantlyand at every interval in both groups, related to a rise inserum iron and a fall in total iron-binding capacity(TIBC). Patients treated with i. v. FCM showed higher

Armelmlttelforschung 201060(6a)386-398C ECV- Editlo Cantor Verlag Aulendorf (Germany) Bailie - Ferric carboxymaltose 389

Ferric Carbaxymaltose

Fig. 1: Percentage of patients with post-partum anemia (PPA) achieving anemia endpoints according to treatment assignment(i.v. ferric carboxymaltose IFCMI � 1000mg over 15 minI given on days 0,7 and 14, or oral FeSuif 1325 mg, equivalent to 65mgironi twice daily, on days 0—42). A) Primary study endpoint, Hb �2.0 gIdI; B) secondary endpoint, Hb increase g/dl; C) sec-ondary endpoint achieved, Hb � 12.0 g/dl; D) Change in markers of iron status (serum ferrltln) from baseline according to treat-ment assignment in patients with PPA 151.Between-group comparisons. *p <0.05; p <0.01; *a*p <0.001.Solid line with circle, i.v. FCM; solid ilne with triangle, oral FeSulf.Reproduced from Van Wyck etaL 2007 151. Reprinted with permission from Woiters Kiuwer Health. Van Wyck DB, Martens MG,Seld MH, Baker JB, Manglone A. Intravenous ferric carboxymaltose compared with oral iron in the treatment of postpartumanemia: a randomized controlled trial. Obstet GynecoL 2007;l 1th267-78.

9-

TSAT than patients treated with FeSuif at each intervalafter the first week, associated with a more pronouncedrise in serum iron and fall in TIBC. No patient in eithertreatment group received red blood cell transfusion.Patient Q0L increased in both treatment groups; be-tween-group differences were not significant. The with-in-group change from baseline to day 42 met or ex-ceeded criteria for the minimum important differencefor every health-related Q0L scale except SF-36 Role-Emotional.

Information on the efficacy of oral FeSuif in PPA inthe current trial was restricted to 42 days of administra-tion. Longer trials will be needed to confirm whether thehigher iron stores achieved in patients treated with i. v.

iron signify a persistent treatment benefit in womenwith ongoing menses or subsequent pregnancy.

In the second non-inferiority study, conducted byBreymann et al. 131, patients (aged 18—44 years) withPPA (Hb <10.5 gldl) were randomized (2: 1 ratio) to re-ceive i. v. FCM over 2 weeks (up to three weekly doses of1000 mg iron, maximum, per dose, given in 15 mm;maximum of three infusions; n = 227) or 304 mg FeSuif(100mg of iron), orally, b.i.d., for 12 weeks (n = 117).

Changes in Hb and iron stores up to week 12 were ana-lyzed (Table 1). Patients with anemia other than thatcaused by blood loss secondary to delivery and irondeficiency were excluded from the study. The plannedsample size of 348 patients was based on a 90 % power

'OArznelmlttelfor,diung 201060(6a)386-398

s)J Bailie - lerric carboxvmaltose 5 ECV. Editio Cantor Verlag. Aulendorf (Germany)

A

100

B

75

100

Q50I

75

25

D?i4F

ii

50

25

0 14 28 42

TIit. after initiating

0

0

C

14 28

Tim. after initiatingfrea (42

D

iiq

I

0 14 28

rm. after initialing

14 28 42

Tim. after initiatingfreatmerd (daya)

Ferric Carboxymaltose

Fig. 2: Mean (SD) hemoglobin levels (g/l) by visIt In patients with post-partum anemIa (per protocol population, n = 268) (3).Ferric carboxymaltose, at a maxImum dose of 1000 mg iron over 15 mm (15 mg lronlkg body weIght, if body weight <66 kgj onday 1, with subsequent doses at 1-week intervals until each patient's calculated total Iron requirement was reached (up to3 weekly infusions), or oral ferrous sulfate, 100 mg, twice daily, for 12 weeks.Reproduced from Breymann et aL 2008 131. Reprinted with permission from the International Federation of Gynecology andObstetrics (FIGO): Breymann C, GlIga F, Bejenarlu C, Strlzhova N. Comparative efficacy and safety of intravenous ferriccarboxymaltose in the treatment of postpartum Iron deficiency anemIa. Intl Gynaecol Obstet. 2008;101:67-73.

• to detect non-inferiority using a margin of 5.0 gIl andalpha of 0.025 (one-sided) and expected standard devia-tion of 12.0 gIl, with a 20% drop-out rate. The mean cal-culated iron deficit was 1365 mg (range 720—2024) and1393 mg (range 829—1918) in the FCM and oral FeSulfgroups, respectively (PP population).

Primary efficacy endpoint was the change from base-line to week 12 in Hb levels. Intravenous FCM was aseffective as FeSuIf in increasing Hb, despite the muchshorter treatment period. Mean Hb changes from base-line to week 12 were 33.7 g/l and 32.9 g/l in the FCMand FeSulf treatment groups, respectively (Fig. 2).

Secondary efficacy endpoints included change frombaseline in fenitin and TSAT; response rate of patientsachieving Hb levels of 12.0—16.0 g/dl; ferritin levels of50—800 tg/l; TSAT levels of 20—50%; and the numberand proportion of patients who needed transfusions.Ferritin levels were significantly higher in patients treat-ed with i.v. FCM than in patients treated with oralFeSuIf (p <0.0001). Mean ferritin levels increased from39.9 ig/l at baseline to 568.2 tg/l at week 1 for patientsin the FCM group. A decrease was seen in followingweeks, but ferritin levels remained above baseline at allvisits (mean: 161.2 ig/l at week 12). Patients in theFeSuIf group showed only a marginal ferritin increasefrom 32.4 ig/l at baseline to 43.3 tg/l at week 12(p < 0.0001). Changes from baseline in mean TSAT val-ues were significantly higher in the FCM group com-pared with the FeSuif group at all visits (p � 0.0004). Re-sponse rates for TSAT were significantly higher in theFCM group at all visits; at week 2, 125 (69.8%) patientsreceiving FCM responded compared with 32 (36.0%)patients receiving FeSuif (p < 0.0001). Correspondingrates at 12 weeks were 139 (77.7%) for FCM and 59(66.3%) for FeSulf (p <0.05). Only one patient (in theFCM group) had a transfusion to replace intra-operativeblood loss.

Compliance with oral therapy was encouraged andmonitored (unlike the "real-life" situation), and wasvery high (>90 %), but iron stores were nonetheless notreplenished. Therefore, patients with more severe PPAmight be at a higher risk of IDA once menstruationrestarts. The iron deficit could also be carried forwardto subsequent pregnancies.

A further superiority clinical trial, undertaken by Seidet al. 141, has also examined the efficacy, safety, and tol-erability of i.v. FCM, compared with oral FeSuif in291 women � 10 days post-partum (mean i-lbon two or more laboratory tests) (Table 1). Women(aged 16—43 years) were randomized (1: 1) to receiveFCM (n = 143) � 1000 mg iron over � 15 mm. repeatedweekly to a calculated replacement dose (maximum2500 mgi or FeSuIf (n = 148) 325 mg (65 mg iron), orally,t. i. d., for 6 weeks. The primary efficacy endpoint wasthe percentageof patients achieving Hb >12.0 g/dl be-tween baseline and end of study. Exclusion criteria in-cluded: myelosuppressive therapy or asthma therapyand recent blood transfusions or erythropoietin therapywithin the 3 months prior to screening. Study withdra-wal was required if the patient needed an intervention(i. e., ESA, blood transfusion, or i. v. or oral iron outsidethe study protocol). Patients were also stratified accord-ing to average baseline Hb levels (�8.Og/dl, 8.1—9.0 g/dl, or 9.1—10.Og/dl), requirement for caesarean, andscreening ferritin levels (� 25 or >25 ig/l).

It was assumed that success rates for the FeSuIf groupand the FCM group were 70% and 80%, respectively,and the alpha level for the two-sided Fisher's exact testwas 0.05. Accordingly, approximately 320 randomizedpatients would provide 300 patients for the modifiedITF population (the protocol-specified primary popula-tion for evaluating all efficacy endpoints, treatment ad-ministration/compliance and subject characteristics)and 270 patients for the evaluable population to achieve

Aizneimlttelfor.thung 201(k60(6a)386—398© ECv. Editlo Cantor verlag. Aulendorf (Germany) Bailie - Femc carboxymaltose

150

140

30120

110

19080

70

ScreenIng 1 Screening 2 Screening 3 Baseline Week I Week 2 Week 4 Week 12

—— Fernc carboxymaftose

—U— Fermus sulfate

Ferric Carboxymaltose

r

Fig. 3. Percentage of patients with post-partum anemiaachieving correction of anemia (Hb � 12.0 g/dl), by severityof anemia at baseline. The difference in efficacy between fer-nc carboxymaltose and ferrous sulfate was greatest in pa-tients with the most severe anemia.

= 0.0286; asp = 0.0008; tp = 0.0054; p = 0.1000 (not sig-nificant).nIN, number of patients who achieved an Hb � 12.0 g/dlInumber of patients in the treatment group 141.Reproduced from Seld et aL 2008 141. CopyrIght 2008 Else-vler reproduced with permission: Seid MH, Derman RJ, Ba-ker JB, Banach W, Goldberg C, Rogers R. Ferric carboxymal-tose Injection In the treatment of postpartum iron deficiencyanemia: a randomized controlled clinical trial. Am I ObstetGynecoL 2008; 199:435-7.

95% or greater power for the study. Further details re-garding methodology can be obtained from Seid et aL

(4].

Mean iron exposure during the study was 1503 mgand 7906 mg in the FCM and FeSulf groups, respec-tively. Patients receiving FCM were significantly morelikely than those receiving FeSuIf to: a) achieve Hb>12.Og/dl (91.4% versus 66.7%; p<0.0001)inashortertime period (median 14 versus 27 days; p = 0.0002) witha sustained Hb � 12.0 g/dl at day 42 (85.4% versus58.0%; p<O.0001); b) achieve Hb �3.0 g/dl morequickly (median 15 versus 28 days; p <0.0001); and c).at-tam higher TSAT and serum ferritin levels.

Among patients who achieved an Hb level � 12.0 g/dlat any time during the study, the largest difference be-tween FCM and FeSulf groups was observed in patientswhose baseline Hb was <8.0 g/dl (78.9% versus 43.5%;p = 0.0286) (Fig. 3). The overall incidence of drug-re-lated AEs, was lower in patients treated with FCM (15/142 I10.6%1) than with FeSuif (32/147 l21.8%1).

The findings of these three studies illustrate that high-dose i. v. FCM is an effective treatment option for PPA,offering advantages over oral FeSuif in terms of rapidnormalization of iron stores and reliable correction ofanemia over a shorter treatment period.

392 Bailie - Femc carboxymaltose

4. FCM and IDA due to AUB [6]Women with AUB are often untreated or inadequatelytreated for anemia (21]. AUB impacts women's health-related Q0L and puts a heavy economic burden on so-ciety [221.

A multicenter, open-label, randomized, Phase IIIstudy was undertaken to determine the efficacy andsafety of rapid, large-dose i. v. FCM versus oral FeSuIf inwomen with IDA secondary to AUB [61. Two-hundredand thirty women (aged 18 years or older) with IDA(defined as Hb �11.Og/dl, TSAT serum ferritin<100 ig/l) and AUB received FCM at a dose calculatedto correct anemia and replenish iron stores (� 1000 mgiron over 15 mm, repeated weekly to achieve a total cal-culated replacement dose); 226 women received FeSulf,325mg (65 mg elemental iron), t.i.d., for 6 weeks. Ex-clusion criteria included: red blood cell transfusion orparenteral iron administration within the prior 8 weeks,or an anticipated need for blood transfusion during thestudy; use of ESAs within the prior 12 weeks; initiationof hormonal therapy potentially affecting uterine bleed-ing in the 8 weeks before study entry; endometrial hy-perplasia, and chronic viral infection. Randomizationwas stratified by Hb level (�8.0, 8.1—9.5, or 9.6—11.0 g/dl) and by degree of uterine bleeding during the pre-vious 28 days (mild/moderate, severe, or very severe)and the presence or absence of a poor response to priororal iron therapy. According to statistical power andsample size calculations and using a two-sided Fisher'sexact test and 5% significance level, it was estimatedthat the study would have at least an 85% power to de-tect a 25% i. v. FCM treatment effect in comparison withoral FeSulf if at least 390 patients were enrolled (61.

Patients assigned to either group showed a similarseverity of IDA at baseline (Hb, 9.4 g/dl in both groups;TSAT, 5.8% versus 5.6%; serum ferritin, 6.9 tg/l versus6.8 g/l, in the i. v. FCM and FeSuIf groups, respec-tively). The primary efficacy endpoint was an increasein Hb �2.0 g/dl after initial treatment. Patients assignedto i. v. FCM were more likely to achieve an Hb rise�2.0 g/dl during the 42 days after baseline, than thosereceiving FeSuIf (82% versus 62%, respectively;p <0.001).

Other secondary efficacy endpoints included an in-crease in Hb �3.0 g/dI or an Hb level � 12.0 g/dl, meanHb increase, safety assessment, and Q0L scores. Pa-tients assigned to i. v. FCM were more likely than thosereceiving FeSuIf to achieve an Hb rise �3.0 gIdl (53%versus 36%; p <0.001 from baseline) or correction ofanemia (an Hb rise to �12.Og/dl [73% versus 50%;p <0.0011 from baseline). Patients treated with i.v.FCM achieved a greater mean Hb increase (3.3 versus2.6 g/dl; p < 0.001) and reported greater improvementin analog fatigue scales and SF-36 Q0L scores (p <0.05at day 14 and later) than those receiving FeSuIf. Therewere no hypotensive or serious adverse drug events(ADEs) in either treatment group. Study ADEs weredefined as all AEs that were possibly or probably related

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• Fernc carboxymaitoseo Ferrous sulfate

100

70

6050I40

110

Fernc Carboxymaltose

to study drug, as determined by the investigators. Nodeaths occurred during the study. There was no differ-ence between groups in the number of infections re-ported and no infection was thought to be related tostudy drug. Discontinuation of study drug due to AEsoccurred in five patients in the FCM arm and sevenpatients in the FeSuif arm. Patients assigned to oral irontherapy were more likely to experience GI ADEs, parti-cularly constipation (14.2% versus 3.0%) and nausea(11.9% versus 3.5 %). Those assigned to FCM were morelikely to report headache (6.5% versus 4.4%) and tran-sient fatigue (2.2% versus 0%). Transient, asymptomatichypophosphatemia was also observed after FCM ad-ministration; this resolved spontaneously without spe-cific treatment.

A potential limitation of this open-label trial is thatpatient-reported outcomes may have been affected byawareness of treatment assignment. This is particularlyrelevant of an i. v. versus an oral trial. However, health-related Q0L scores tend to increase with Hb level, re-gardless of treatment [231, and treatment-related im-provement in fatigue, specifically that seen in open-la-bel interventional trials, is also seen in trials in whichpatients are masked to treatment assignment 1241.

Patients who received FCM showed more rapid cor-rection of iron depletion, iron-deficient erythropoiesisand anemia; greater improvement in health-relatedQ0L and fewer adverse GI symptoms than patients re-ceiving oral FeSuIf. These responses were significantlydifferent by day 14 for the primary outcome (Hb in-crease >2.0 g/dl) and by day 28 for the secondary out-come (Hb increase >3.0 g/dl), demonstrating the valueof i. v. FCM in the early correction of iron deficiency inwomen post-partum, and in replacing ongoing bloodlosses in women with AUB.

5. FCM in patients with CHF [9]In patients with CHF, anemia is an independent riskfactor for hospital admission and mortality, and hasbeen shown to worsen as the severity of the CHF pro-gresses 125. 261. Beyond anemia, iron deficiency is be-coming recognized as an important factor in CHF,which can mimic the symptoms of CHF and impactnegatively on functional capacity and perceptions ofhealth 127. 281. Conversely, it is possible that iron reple-tion in iron-deficient patients with CHF may improvesymptoms as it has been shown to improve symptom-atic and exercise performance in patients without heartfailure 129, 301.

A recent study of iron repletion in patients with CHF(Ferinject® Assessment in patients with IRon deficiencyarid chronic Heart Failure [FAIR-HF)) demonstrated thatFCM can have a positive impact on functional symp-toms (measured using the New York Heart Association(NYHAJ class), patients' perceptions of their own health,and exercise capacity (six-minute walk test) 19]. FAIR-HF was a randomized, double-blind, placebo-controlled

trial of 200 mg of iron as FCM administered weekly untilpatients were iron replete per the Ganzoni formula, thenevery four weeks (31]. After 24 weeks, 50% of patients(147/292) reported themselves to be much or moder-ately improved compared with baseline, significantlymore than in the placebo group (28% 141/1491; oddsratio for improvement: 2.51 [95% confidence intervals:1.75, 3.611; p<0.OOl). Likewise, the improvement inNYHA class was significantly better in the FCM groupthan the placebo group (odds ratio for a one-NYHA-class improvement was 2.40 [95 % confidence intervals:1.55, 3.711; p<O.O0l). The impact of FCM on functionalsymptoms and quality of life was observed in patientsregardless of the presence of anemia (defined as� 12.0 g/dl hemoglobin), indicating a role for iron reple-tion beyond the management of anemia. Significant im-provements (p < 0.001) in quality of life, CHF symptomsand functional capacity were observed as early as studyweek 4 [9].

6. FCM in other therapy areasAn important limitation of the studies by Qunibi et al.171 and Schaefer et a!. 181, reported in the following sec-tion, is that they are currently only available in abstractform, therefore, only limited information is available inthe public domain at this stage. As information regard-ing definitions, statistical analyses and limitations arenot provided, the results should be interpreted accord-ingly.

6.1 FCM In patients with CKD and/or on HD with IDA17, 81

The management of patients with anemia and under-going dialysis has improved with the availability of ESAs1321. Patients undergoing dialysis and those with CM)often require iron treatment because of frequent blood(and thus iron) loss 1331. Anemia places a high burdenon patients with CKD not on dialysis [32, 34). For thesepatients, therapy consists of maintenance of iron storesduring ESA treatment [35, 361. The approval of safe andefficient i. v. iron preparations (such as ISC) has im-proved the management of anemia in patients on HDand in those with CKD. FCM offers specific advantagesto patients with NDD-CKD, as it offers the ability to de-liver up to 1000 mg of iron in a single 15-mm dose. Itwould be ideal to give 1000 mg of iron during a singleclinic visit, but concerns regarding hypotension andother AEs have precluded this approach in the past withtraditionally available i.v. iron preparations 171.

A multicenter, randomized, open-label, Phase III

study was conducted by Qunibi et al. 171 to comparethe efficacy and safety of large doses of i. v. FCM (max-imum first dose of 1000 mg of iron with up to two addi-tional doses of 500 mg iron, as determined by iron in-dices; (n = 147) administered over a short period oftime (15 mm) versus oral FeSulf (325 mg 165 mg iron],t.i.d., for 56 days; n = 103)) in patients with NDD-CKD

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Ferric Carboxymaltose

with IDA. Patients were randomly assigned to receivei. v. FCM or oral FeSulf. Randomization was stratifiedby the use of ESA, degree of CKD and baseline Hb level.Inclusion criteria were glomerular filtration rate �45 ml!min/1.73 m2, Hb � 11.0 g/dl, TSAT � 25% and serum fer-ritin � 300 igIl. ESA doses, if any, must have been stablefor at least 8 weeks prior to administration of iron andremain so throughout the study. Major exclusion criter-ia included documented history of discontinuation oforal iron therapy due to GI distress and i. v. iron useduring the 12 weeks prior to the study start. The primaryefficacy endpoint was the percentage of patients achiev-ing an increase in Hb � 1.0 g/dl at any time point be-tween baseline and the end of the study or the time ofintervention.

Baseline characteristics, Hb, iron parameters, andmean iron deficit at baseline were similar in bothgroups. Mean compliance with the prescribed oral ironregimen was 95.8% (unlike the "real-life" situation). Theprimary efficacy endpoint, the proportion of patientsachieving an Hb increase � 1 g/dl, was significantlygreater in the i. v. FCM group than in the FeSuif group(60.4% 187/1441 versus 34.7% 135/1011; p<O.OOl).

Other efficacy endpoints included the percentage ofpatients achieving � 1 g/dl increase in Hb by day 28;mean change to highest Hb; mean increase in Hb byday 42 and day 56; mean TSAT (%) and serum ferritin.FCM was also shown to be more efficacious than oralFeSuif across all ranked secondary endpoints. In pa-tients receiving FCM, the percentage of patientsachieving a � 1 g/dl increase in Hb by day 28, the meanchange to highest Hb (1.3 versus 0.8 gIdl, respectively;

p <0.001), and the mean increase in Hb by day 42 (1.0versus 0.5 g/dl, respectively; p <0.005) and 56 (1.0 versus0.7 g/dl, respectively; p < 0.034) were all higher com-pared with patients receiving FeSulf. In patients withCKD not on dialysis, FCM (1000 mg iron over 15 mm,with one or two additional 500 mg iron doses) was moreeffective than oral FeSulf therapy.

A multicenter, open-label, randomized, parallel groupPhase III study was conducted in 183 (PP population)adult patients (aged 18—80 years) undergoing HD orhaemofiltration with IDA (defined as Hb <11.5 gIdl;TSAT <20%; or serum fen-itin <200 ig!l) secondary toCKD (81. Patients received either 200 mg iron as FCM(n = 97; ITT population) given without dilution as a bo-lus-push injection or as ISC (n = 86; IT'!' population)given over 10 mm. Both treatments were administeredinto the HD venous line, 1 h after the start of each dialy-sis session, two-to-three times weekly, until the totalcumulative dose for each patient was reached. The max-imum treatment period was 4 weeks and patients werefollowed for an additional 4 weeks. Patients were pre-scribed an ESA at baseline and must have received thistreatment for at least 8 weeks prior to inclusion in thestudy. The ESA dose may have been decreased duringthe study, but no ESA dose increases were permittedduring the study period.

394 Bailie - Femc carboxymaltose

Fig. 4. Changes in serum ferritin levels from baseline to endof follow-up period In patients undergoing hemodialysls re-ceiving treatment with either ferric carboxymaltose or Ironsucrose (81.Note: The following values are reported for the per-protocolpopulation. Treatment had a statistically significant effectfavourable for FCM on serum ferritin changes from baselineto week 2 (p <0.01). Severity of IDA at baseline also had astatistically sIgnificant effect on serum ferritin changes frombaseline to follow-up (p < 0.05).Adapted from data cited in Schaefer et aL 2008 181. Copyright2008 wIth permission from ERA-EDTA (XLV ERA-EDTA Con-gress, Stockholm, Sweden, May 10—13 2008).

The primary response was defined as the percentageof patients reaching an Hb increase of at least 1.0 g/dlat 4 weeks post-baseline. The primary response wasmet by 46.4% (45/97) and 37.2% (32 /86) of patients inthe FCM and ISC groups, respectively. Other efficacyendpoints included mean Hb levels during follow-upand serum ferritin levels. Mean Hb levels increased atthe follow-up visit in both treatment groups: from9.3 g/dl to 10.6 g/dl and from 9.3 g/dl to 10.3 g/dl inthe FCM and ISC groups, respectively. Mean serumfenitin levels increased from baseline to week 2: from90.4 ig/l to 723.4 ig/l and from 93.1 jig/I and549.6 jig/I in patients treated with FCM and ISC, re-spectively (Fig. 4) (81. At the end of follow-up, meanserum ferritin values were 465.3 jig/i versus 397.7 jig/Ifor the FCM and ISC groups, respectively. As increaseddoses of ESA were not permitted during this rando-mized, controlled study, biases that may be introduceddue to uncontrollable influences of Hb level are pre-sumed to affect both groups equally, thus, the increasein Hb can be solely attributed to efficient iron utiliza-tion. There was a trend towards better response formost efficacy parameters for patients with IDA under-going HD allocated to FCM administered by push in-jection compared with ISC given over 10 mm. Thechoice of an open design without blinding and the lackof a placebo arm were the main limitations of thisstudy. An open design was necessary because of thedifferences in administration of the two study drugs;

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that is, injection of ISC over 10 mm. or a faster andsimpler bolus-push injection of FCM. However, as effi-cacy was assessed by monitoring changes in laboratoryparameters, it is unlikely that an open-label designcould introduce bias to these results.

In addition to these Phase III studies, a Phase II, mul-ticenter, open-label, single-arm study in 163 patientsundergoing maintenance HD demonstrated that FCMwas well tolerated and effective in the correction of Hblevels in patients with IDA 1371.

7. Overall safety of FCMSafety data are available from ten multiple-dose studies1381: one Phase I/IL pharmacodynamic study 1391, onePhase III IBD study 121, two HD studies (one Phase II1371 and one Phase LII 181), three Phase III post-partumstudies 13—51, one Phase III AUB study 161, and twoPhase III NDD-CKD studies [71, one of which is longterm. Safety evaluations included AE reporting, routinesafety laboratory tests (clinical chemistry and hematol-ogy), vital signs (blood pressure, heart rate and bodytemperature) and physical examinations. Only threestudies 12, 3, 81 included assessment of 12-lead electro-cardiograms. In three studies 12—41, laboratory tests in-cluded urinalysis, and the study by Kulnigg and collea-gues [2] also included markers of inflammation. Therecording of AEs was based on spontaneous reports bythe patients and observations by the study physician.AEs were defined along with categorization accordingto intensity, seriousness, and causality.

7.1 Ten multiple dose Phase 1-111 studIes: safety dataSafety data were combined and analyzed from ten mul-ticenter, Phase I—Ill FCM clinical trials involving ap-proximately 3000 patients with IDA secondary to a vari-ety of conditions (Table 2)1381. The majority of studiescompared FCM with oral iron (ferrous sulfate, 325 mg[65mg iron], t.i.d.). One study compared FCM withISC 181 and one study utilized a placebo-controlledcrossover design in which all patients received bothFCM and placebo 1101.

Of those patients receiving FCM (n = 1968), 93% com-pleted the study and approximately 88% (n = 1736) re-ceived a repletion dose of � 1000 mg iron. The disconti-nuation rate due to any AE was similar in both groups(FCM group 1.5%; oral iron group 1.8%). No serious orlife-threatening hypersensitivity (anaphylactoid) ADEswere reported with FCM. The most common ADE withFCM was headache (Table 3) 1381. Two non-serioushypersensitivity ADEs (0.1 %) were reported with nochanges in vital signs. No symptomatic hypotension oc-curred. Mild-to-moderate transient skin changes (rashes,urticaria and itching) were observed. A decrease in serumphosphorus was observed; the decreases were transientand asymptomatic (Table 3). The overall ADE rate waslower for the FCM group (302/1968 patients; 15.3%)compared with the oral iron group (218/834 patients;

Table 2: Number of patients by population and treatment ac-cording to analysis often, multicenter Phase I-Ill FCM clin-ical trIals 1381.

Population FCM Maximumsingle doseof iron asFCM(mg)

Oral iron ISC

NDD-CKDHD-CKDIBDAIJBPPAOther IDA

176300201352700239

1000200

1000100010001000

103NA63

226442NA

NA118NANANANA

FCM, femc carboxymaltose; HD-CKD, hemodialysis-dependentchronic kidney disease; AUB, abnormal uterine bleeding; IBD, in-flammatory bowel disease; IDA, iron-deficiency anemia; ISC, ironsucrose; NDD-CKD, non-dialysis-dependent chronic kidney dis-ease; PPA, post-partum anemia.Reproduced from Qunibi et aL 2008 [381. Copyright 2008 wIthpermission from ERA-EDTA (XLV ERA-EDTA Congress. Stock-holm, Sweden, May 10—13 2008).

Table 3: Drug-reiated adverse events (AEs) in patIents takingferric carboxymaltose (FCM) and oral Iron according to theanalysis of ten, multicenter, Phase I-Ill FCM clinical trials1381.

Patients, n (%)

FCM Oral iron(n = n = 834

One or more drug-related AE 302 (15.3) 218 (26.1)One or more drug-related serious AE 0 0Drug-related AEs at >2% incidence

Headache 50 (2.5) 18 (2.2)Drug-related AEs at <2% incidence'

Nausea 33 (1.7) 48 (5.8)L.ocal injection-site reactions 31(1.6) 0Decreased serum phosphorus 30 (1.5) 0Rash 21(1.1) 22 (0.2)Dizziness 20 (1.0) 5 (0.6)Increased alanine aminotransferase 19 (1.0) 9 (1.1)Constipation 17 (0.9) 94 (11.3)Diarrhea 10 (0.5) 23 (2.8)Abdominal pain (upper) 7 (0.4) 10 (1.2)Vomiting 6 (0.3) 12 (1.4)Abdominal pain 0 6 (0.7)Feces discolored 0 11 (1.3)

'Categorization of incidence refers to the FCM group.Reproduced from Qunibi et aL 2008 1381. Copyright 2008 wIthpermission from ERA-EDTA (XLV ERA-EDTA Congress, Stock-holm, Sweden, May 10—132008).

Table 4: Drug-telated adverse events (AEs) in patients under-going hemodlalysis taking ferric carboxymaltose (FCM) andIron sucrose (ISC) 1381.

. Patients n (%)

FCM ISC

One or more drug-related AEDrug-related AEs = 1% incidence

HypotensionAcute bronchitis

6 (5.0)

1 (0.8)0

12 (10.2)

5 (4.2)2 (1.7)

Reproduced from Quinibi et aL 2008 1381. Copyright 2008 wIthpermission from ERA-EDTA (XLV ERA- EDTA Congress, Stock-holm, Sweden, May 10—132008).

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26.1 %) (Table 3). In patients undergoing HD, FCM ad-ministration resulted in fewer overall ADEs as well asfewer cases of treatment-related hypotension than ISC(Table 4)138].

7.2 Safety In IDABailie et al. 1101 undertook a randomized, cross-over,double-blind, single-dose study comparing the safetyand tolerability of i. v. FCM or placebo in patients withIDA. Five-hundred and fifty-nine patients with IDA re-ceived a dose of either FCM (15 mg/kg, maximum1000 mg) over 15 mm or placebo on day 0. On day 7, pa-tients received the other agent. Safety evaluations wereperformed on days 7 and 14. The primary endpoint wasthe incidence of treatment-emergent AEs (TEAEs) dur-ing each 7-day study period. During the first 24 h andduring the 7-day treatment period, at least one TEAEwas experienced by 15.0% and 29.3% of patients afterFCM, and by 11.4% and 19.7% of patients after placebo,respectively. Most TEAEs were classified as Grade 1(mild [did not interfere with the patient's usual func-tion]) or 2 (moderate [interfered to some extent withthe patient's usual function]). Six patients had Grade 3(severe (interfered significantly with the patient's usualfunction]) TEAEs after FCM and nine patients afterplacebo. One patient had a Grade 4 (life-threatening[resulted in a threat to life or in an incapacitating dis-abilityl) TEAE of intestinal obstruction after FCM, andone patient had a Grade 5 TEAE of Aeromonas pneumo-nia and died 27 days post-FCM administration, butneither was considered related to study drug. Duringthe first 24 h of the treatment period, ADEs were re-ported in 9.3% of patients receiving FCM and 4.8% re-ceiving placebo. Of drug-related Grade 3 events, fourpatients received FCM and five received placebo. Theauthors concluded that administration of FCM (15 mg/kg, maximum of 1000 mg) over 15 mm was well toler-ated and associated with minimal risk of AEs in patientswith IDA 110]. The favorable safety profile of FCM wasfurther demonstrated in the two studies in patients withCHF plus iron deficiency and/or anemia (9, 40].

7.3 Safety in PPABreymann et al. 131 conducted an investigation of thesafety and tolerability of i. v. FCM compared with oralFeSulf and measurement of levels of iron in breast milkfrom a subset of patients in the study of PPA. Overall,AEs (excluding those relating to IDA or to the therapeu-tic effect of iron treatment, e. g., ferritin increase) wereexperienced by 26.0% (59 /227) of patients treated withFCM and by 22.2% (26/117) of patients treated withFeSulf (Fisher's Exact test; p = 0.5 10) in the breast milksubset study (Table 5). Except for infusion-site burning,FCM was better tolerated than FeSuIf. Statistically sig-nificant differences were seen in the following cases(FCM versus FeSuif): GI disorders (3.5% versus 10.3%;p = 0.015), general disorders and administration-site con-

396 Bailie — Femc carboxy maltose

ditions (6.2% versus 0%; p = 0.003), and musculoskeleta]and connective tissue disorders (0% versus 2.6%;p = 0.039). Constipation was less common in the FCMgroup (1 patient 10.4 %]) than in the FeSuif group (8 pa-tients (6.8 %]). In the FCM group, 2.2% of patients experi-enced infusion-site burning and 1.3% experienced infu-sion-site pain. Only 1.7% of patients in the control groupexperienced arthralgia. There were no safety concernsidentified in breast-fed infants of mothers receiving FCMor FeSuIf (Table 5).

A potential limitation of the pooled safety data forFCM and other i.v. iron treatments is that full assess-ment of the safety profiles of i. v. iron preparations isdifficult to acquire. There may be significant inter-ratervariability and possible subjectivity associated with thereporting of AEs by investigators across centers in amulticenter trial. Moreover, safety was assessed as asecondary endpoint in many of the trials. Clinical studydesigns are limited by exclusionary patient entry crite-ria, small numbers of exposed patients and short dura-tions of treatment [411. There are many examples ofimportant AEs that were not detected in clinical trialswith other medications, but that were only discoveredduring post-marketing surveillance 1421. Moreover,more serious idiosyncratic adverse reactions are rare,which makes case ascertainment difficult, even in largepatient populations.

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Table 5: TolerabilIty of ferric carboxymaltose (FCM) and fer-rous sulfate (FeSuif) In mothers with post-partum anemia(n = 344) and their breast-fed Infants (n = 346) 131

Adverse events (AEs)' in mothers" - = 227, n (%)At least one AEChanges in liver function tests3tNasopharyngitisHeadacheAlanine aminotransferaseincreaseInfusion-site burningC-reactive protein increaseUterine hemorrhageConstipation

AEs in breast-fed infants2At least one AEErythemaDiarrheaConstipationNasopharyngitisAbdominal painUpper respiratory tract infection

59 (26.0)8 (3.5)7 (3.1)6 (2.6)5 (2.2)

5 (2.2)4 (1.8)3 (1.3)1 (0.4)

n = 229, n (%)24 (10.5)5 (22)3 (1.3)3 (1.3)2 (0.9)1 (0.4)1 (0.4)

n= 117, n (%)26 (22.2)

3 (2.6)2 (1.7)2 (1.7)3 (2.6)

00

1 (0.9)8 (6.8)

n = 117, n(%)14 (12.0)

00

4 (3.4)1 (0.9)2 (1.7)2 (1.7)

AEs excluded events relating to iron-deficiency anemia or thetherapeutic effect of iron treatment (e.g., ferritin increase).2) Event terms reported in four or more mothers or in three ormore breast-fed infants in total, in descending order of frequency.

Reported as: elevated aspartate aminotransferase and/or alanineaminotransferase, biirubin or gamma-glutamyl transpeptidase.Adapted from Breymann et al. 2008 131. Reprinted with permissionfrom the International Federation of Gynecology and Obstetrics(FIGO): Breymann C, Gliga F, Bejenariu C, Strizhova N. Compara-tive efficacy and safety of intravenous ferric carboxymaltose in thetreatment of postpartum iron deficiency anemia. Intl GynaecolObstet. 2008;101:67—73.

Fernc Carboxymaltose

8. ConclusionsThe efficacy and safety of FCM in correcting irondeficiency have been investigated in a wide range of in-dications in the nine Phase III clinical studies reportedhere. Results of the available studies have demonstratedthat i. v. FCM can be administered at doses of up to1000 mg iron during a minimum administration timeof 15 mm and is effective in the correction of iron defi-ciency across diverse patient populations (includingIBD, PPA, AUB, CKD, HD and CHF), providing clear im-provement in all indices of anemia (rapid Hb increaseand rapid normalization of iron stores, as assessed byserum ferritin and TSAT). In addition, in two studies [6,7,1, i.v. FCM has been shown to be superior to oralFeSuIf in terms of the proportions of patients achieving"success" (in terms of Hb increase according to variousdefinitions). In patients with IBD 121 or PPA 151, in-creases in Hb indicated a faster response to treatmentwith FCM than with oral FeSulf, while in patients withIDA secondary to CKD [8), FCM demonstrated a com-parable efficacy to ISC in achieving an increase in Hb� 1.0 g/dl at 4 weeks post-baseline, although there wasa trend of more pronounced increases on most responseparameters in patients with FCM and with low baselineHb values compared with the ISC arm. In all Phase IIIstudies, FCM treatment led to a rapid and significantrise in mean serum fenitin, which remained elevatedfor several weeks alter the last infusion, indicating theutilization of stored iron during the weeks of hemato-poiesis following the infusions.

Safety data from more than 3000 patients has shownthat FCM is well tolerated with a low risk of immuno-genicity. The incidence of AEs and the discontinuationrate due to AEs was lower in patients receiving FCNIthan in patients receiving oral iron or i. v. ISC (in HD).No safety concerns have been identified in breast-fedinfants of mothers receiving FCM.

Overall, FCM is considered to be an optimal treat-ment for parenteral iron administration, providing avery efficient and convenient means of delivering ironin patients with IDA.

AcknowledgementsThe author takes full responsibility for the content of the paper,but thanks Nicola West, BSc (Hons) (Caudex Medical; sup-ported by Vifor International), for her assistance in preparingthe initial draft of the manuscript.

Conflict of InterestThe authorhas received honoraria from Vifor Pharma and beena member of the Speakers' Bureau. He has previously obtainedresearch funding from American Regent Inc. The author re-ceived no reimbursement for the development of this manu-script.

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121 Kulnigg S, Stoinov S, Simanenkov V, Dudar LV, Karnafel W,Garcia LC, et a!. A novel intravenous iron formulation fortreatment of anemia in inflammatory bowel disease: theferric carboxymaltose (FERINJEC'F) randomized controlledtrial. Am I Gastroenterol. 2008;103:1 182—92.

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[41 Seid MH, Derman RI, Baker JB, Banach W, Goldberg C,Rogers R. Ferric carboxymaltose injection in the treatmentof postpartum iron deficiency anemia: a randomized con-trolled clinical trial. Am I Obstet Gynecol. 2008;199:435—7.

151 Van Wyck DB, Martens MG, Seid MH, Baker JB, Man-gione A. Intravenous ferric carboxymaltose compared withoral iron in the treatment of postpartum anemia: a ran-domized controlled trial. Obstet GynecoL 2007;1 10:267—78.

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