Research
`
`Original Investigation
`Comparative Risk of Anaphylactic Reactions Associated
`With Intravenous Iron Products
`
`Cunlin Wang, MD, PhD; David J. Graham, MD, MPH; Robert C. Kane, MD; Diqiong Xie, PhD; Michael Wernecke, BA;
`Mark Levenson, PhD; Thomas E. MaCurdy, PhD; Monica Houstoun, PharmD; Qin Ryan, MD, PhD;
`Sarah Wong, MPH; Katrina Mott, MPH; Ting-Chang Sheu, MPH; Susan Limb, MD; Chris Worrall, BS;
`Jeffrey A. Kelman, MD, MSc; Marsha E. Reichman, PhD
`
`Supplemental content at
`jama.com
`
`IMPORTANCE All intravenous (IV) iron products are associated with anaphylaxis, but the
`comparative safety of each product has not been well established.
`
`OBJECTIVE To compare the risk of anaphylaxis among marketed IV iron products.
`
`DESIGN, SETTING, AND PARTICIPANTS Retrospective new user cohort study of IV iron
`recipients (n = 688 183) enrolled in the US fee-for-service Medicare program from January
`2003 to December 2013. Analyses involving ferumoxytol were limited to the period
`January 2010 to December 2013.
`
`EXPOSURES Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as
`reported in outpatient Medicare claims data.
`
`MAIN OUTCOMES AND MEASURES Anaphylaxis was identified using a prespecified and
`validated algorithm defined with standard diagnosis and procedure codes and applied to
`both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis
`were estimated, adjusting for imbalances among treatment groups.
`
`RESULTS A total of 274 anaphylaxis cases were identified at first exposure, with an additional
`170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk
`for anaphylaxis at first exposure was 68 per 100 000 persons for iron dextran (95% CI,
`57.8-78.7 per 100 000) and 24 per 100 000 persons for all nondextran IV iron products
`combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100 000) , with
`an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when
`compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI,
`2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3).
`The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg
`administered within a 12-week period was highest with iron dextran (82 per 100 000
`persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100 000 persons, 95% CI,
`15.3- 26.4).
`
`CONCLUSIONS AND RELEVANCE Among patients in the US Medicare nondialysis population
`with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest
`for iron sucrose.
`
`JAMA. 2015;314(19):2062-2068. doi:10.1001/jama.2015.15572
`
`2062
`
`
`
`Copyright 2015 American Medical Association. All rights reserved.Copyright 2015 American Medical Association. All rights reserved.
`
`Author Affiliations: Author
`affiliations are listed at the end of this
`article.
`Corresponding Author: Cunlin
`Wang, MD, PhD, Division of
`Epidemiology I, Office of Surveillance
`and Epidemiology, Center for Drug
`Evaluation and Research,
`US Food and Drug Administration,
`10903 New Hampshire Ave,
`Silver Spring, MD 20903
`(cunlin.wang@fda.hhs.gov).
`
`(Reprinted)
`
`jama.com
`
`Downloaded From: http://jama.jamanetwork.com/ by Stine Primdahl on 11/18/2015
`
`Pharmacosmos, Exh. 1055, p. 1
`
`

`
`Anaphylactic Reaction and Intravenous Iron Products
`
`Original Investigation Research
`
`I n 2010, anemia affected one third of the global popula-
`
`tion, and iron deficiency was the most common cause.1 A
`model using data throughout 2010 estimated that moder-
`ateirondeficiencyanemia(IDA)affectsapproximately610mil-
`lion people worldwide.2 Oral iron replacement is the primary
`treatment strategy for iron deficiency anemia but may be in-
`adequate for some patients due to intolerance, impaired ab-
`sorption, significant ongoing bleeding, or nonadherence.3 For
`these patients, intravenous (IV) iron may be indicated. Com-
`pared with oral iron, IV iron can significantly increase levels
`of hemoglobin, serum ferritin, and transferrin saturation.4 As
`of June 2013, there were 5 IV iron products marketed in the
`United States. While their efficacy is established, the most im-
`portant safety concern relates to the risk of serious and fatal
`anaphylaxis,5-8 which may occur at both first and subsequent
`exposures.
`No sufficiently large randomized trials have been con-
`ducted to determine the comparative risk of anaphylaxis for
`IV iron products. Based on a meta-analysis of published stud-
`ies of iron dextran, the estimated incidence of anaphylaxis was
`0.61%.9 Although the newer IV iron products are purportedly
`safer,10,11 anaphylactic reactions also occur with these
`products.8,12 In a randomized, placebo-controlled trial involv-
`ing more than 2500 patients treated with iron gluconate, the
`incidence of life-threatening reactions was 0.04%.9 In an-
`other trial of 750 patients treated with ferumoxytol, 1 patient
`developed anaphylaxis.13
`To our knowledge, there have been no large population-
`based observational studies that evaluate the risk of anaphy-
`laxis among different IV iron products. Such a study is impor-
`tant because large head-to-head comparative safety trials to
`detect rare adverse reactions like anaphylaxis may not be fea-
`sible. The purpose of this study was to compare the risk of ana-
`phylaxis among patients receiving different IV iron products
`in a large, nondialysis, US Medicare patient population.
`
`Methods
`Study Population
`This study used a retrospective new user cohort design. Pa-
`tients enrolled in fee-for-service Medicare Part A (hospitaliza-
`tion) and Part B (office-based care) between January 2003 and
`December 2013 entered the IV iron new user cohort on the date
`of their first outpatient claim with a Healthcare Common Pro-
`cedure Coding System (HCPCS) code for an IV iron product
`(index date). Patients were included in the study if on their in-
`dex date they were not receiving dialysis, were continuously
`enrolled in Medicare A and B for the previous 12 months, had
`no IV iron exposure in the preceding 12 months, and were ex-
`posed to only 1 type of IV iron product. Also, patients who had
`a claim for a blood transfusion on the index date or a diagno-
`sis of anaphylaxis in the 30 days before the index date were
`excluded. Since ferumoxytol received US Food and Drug Ad-
`ministration (FDA) approval in mid-2009, analyses involving
`this agent were limited to the period from January 2010 to end
`of study (December 2013). This study was approved by the Re-
`search Involving Human Subjects Committee of the FDA prior
`
`to initiation. Patient consent was waived because the study
`used deidentified health care claims data.
`
`Exposure of Interest
`The primary comparison of interest was the use of dextran vs
`nondextran IV iron products. A secondary analysis compared
`anaphylaxis risk between iron dextran and 3 approved non-
`dextran products individually (iron gluconate, iron sucrose,
`and ferumoxytol). Although it was not possible to distin-
`guish between the 2 FDA-approved iron dextrans (high-
`molecular-weight dextran, low-molecular-weight dextran)
`based on claims data during most of the study interval be-
`causetheysharedthesameHCPCScode,allirondextranclaims
`were combined into 1 group.
`
`Outcome Definition and Identification
`Cases of anaphylaxis were identified using a predefined, vali-
`dated algorithm, based on International Classification of
`Diseases, Ninth Revision, Clinical Modification diagnosis/
`procedureandHCPCScodesforinpatientandoutpatientclaims,
`whichwasdevelopedusingtheNationalInstituteofAllergyand
`Infectious Diseases and Food Allergy and Anaphylaxis Net-
`work (NIAID/FAAN) criteria.14,15 The algorithm had a positive
`predictive value (PPV) of 63% for anaphylaxis, and 76% for the
`composite outcome of anaphylaxis or serious allergic reaction,
`the latter of which was defined as an allergic reaction that is
`highly likely to evolve into anaphylaxis if untreated. False-
`positiveeventsidentifiedasanaphylaxisbythisalgorithminthe
`validationstudyincludedmildallergicreactions,isolatedhives,
`rash,andrespiratorydistress.14Thisalgorithmwasusedtoiden-
`tify anaphylaxis cases when multiple procedure and diagnosis
`codes were present (eAppendix 1 in the Supplement). Because
`IViron-associatedanaphylaxiscasesreportedfromclinicaltrials
`andspontaneousadverseeventsindicatethatanaphylaxisgen-
`erally occurs within a few hours of IV iron administration,8,12
`anaphylaxis cases in this study were limited, for the primary
`analysis, to only those captured on the same date as the IV iron
`administration, which may plausibly increase the positive pre-
`dictive value of the algorithm.
`
`Cohort Follow-up and Censoring
`In addition to the analysis of anaphylaxis at the first admin-
`istration, patients were also followed up to identify the risks
`of anaphylaxis at subsequent administrations. Follow-up be-
`gan on index date. Censoring occurred for disenrollment from
`Medicare Part A or B, switching to another IV iron product, di-
`alysis initiation, occurrence of an anaphylaxis event, death, or
`end of study (December 31, 2013), whichever occurred first.
`
`Covariates
`In addition to age and sex, data on the following potential con-
`founders were collected from Medicare claims during the 12-
`month period preceding the index date: history of food aller-
`gies, history of drug allergy, asthma, chronic obstructive
`pulmonary disease, coronary heart disease, hypertension, and
`indications for IV iron use (eAppendixes 2 and 3 in the Supple-
`ment). In the sensitivity analysis that included patients with
`Medicare part D (prescription drug) coverage, concomitant use
`
`jama.com
`
`(Reprinted) JAMA November 17, 2015 Volume 314, Number 19
`
`2063
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`Copyright 2015 American Medical Association. All rights reserved.Copyright 2015 American Medical Association. All rights reserved.
`
`Downloaded From: http://jama.jamanetwork.com/ by Stine Primdahl on 11/18/2015
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`Pharmacosmos, Exh. 1055, p. 2
`
`

`
`Research Original Investigation
`
`Anaphylactic Reaction and Intravenous Iron Products
`
`Figure 1. Trend of First-Time Use by IV Iron Product
`
`Iron dextran (n = 247 500)
`Iron gluconate (n = 94 400)
`Iron sucrose (n = 264 166)
`Ferumoxytol (n = 82 117)
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`Count of First-time Users
`
`0
`Jan
`Jul
`Jan
`Jan
`Jul
`Jan
`Jan
`Jan
`Jan
`Jan
`Jul
`Jan
`Jan
`Jul
`Jul
`Jul
`Jan
`Jul
`Jul
`Jul
`Jul
`Jul
`2013
`2012
`2011
`2010
`2008
`2009
`2006
`2005
`2004
`2003
`2007
`Year
`
`IV indicates intravenous.
`
`ofantibiotics,β-blockers,nonsteroidalanti-inflammatorydrugs
`(NSAIDs), and angiotensin-converting enzyme inhibitors was
`also included.16,17
`
`Statistical Analysis
`The risk of anaphylaxis and corresponding 95% CIs was cal-
`culated for each IV iron product and for the combined non-
`dextran products.18 Imbalances in baseline characteristics be-
`tween treatment groups were assessed using standardized
`mean differences (SMDs). Multivariable logistic regression was
`used to estimate the risk of anaphylaxis at first administra-
`tionafteradjustingforimbalancedcovariates.TheTukeyrange
`test was used to adjust for multiple comparisons.19 The 95%
`CIs of the adjusted odds ratios (ORs) were estimated based on
`likelihood ratio tests. The combined nondextran group was
`used as the reference group when compared with iron dex-
`tran. Iron sucrose was used as the reference group for com-
`parisons involving individual IV iron products. Because IV iron
`products differ by iron dose per administration, the cumula-
`tive risk of anaphylaxis was analyzed based on a clinically rel-
`evant repletion level of iron (1000 mg) achieved within 12-
`weeks per recommended dose and schedule. First, the number
`of exposures necessary to achieve an iron repletion of 1000
`mg were obtained by calculating the average number of ad-
`ministrations required for each IV iron product (eTable 1 in the
`Supplement). Under the assumption that the first administra-
`tion carried a higher risk of anaphylaxis than subsequent ad-
`ministrations, logistic regression was used to model risk at the
`first administration. Poisson regression was used to model risk
`of subsequent administrations. The risk of anaphylaxis with
`95% CIs for each treatment regimen was calculated by multi-
`plying the observed number of exposures needed to receive
`1000 mg of iron with the risk of anaphylaxis at each admin-
`istration.
`Prespecified sensitivity analyses examined the robust-
`ness of the results to variations in the outcome definition, in-
`cluding (1) anaphylaxis cases diagnosed up to 2 days after IV
`iron administration, (2) anaphylaxis or death occurring on the
`
`same day as IV iron administration, (3) cases only meeting ana-
`phylaxis criteria A and B as defined in eAppendix 1 in the
`Supplement, and (4) restricting the population to patients with
`Medicare Part D information to account for potential imbal-
`ance on relevant concomitant medications. Furthermore, fol-
`lowing the approval of ferumoxytol, a generic code J3490 (un-
`classified drugs) was used temporarily for reimbursement
`before a specific HCPCS code was assigned. We also con-
`ducted sensitivity analysis that removed ferumoxytol users
`who had a J3490 code during the period of July 2009 through
`December 2009. P < .05 was considered the threshold for sta-
`tistical significance. All tests were 2-sided. All analyses were
`performed using SAS version 9.2 (SAS Institute Inc) and R 3.0.2
`(R Foundation for Statistical Computing).
`
`Results
`Therewere247 500irondextranand440 683nondextrannew
`IV iron users during the study period. New iron dextran use
`decreased slightly over time, while nondextran use in-
`creased, particularly for iron sucrose. Ferumoxytol use be-
`gan following its 2009 marketing approval (Figure 1). At base-
`line, patients receiving dextran or nondextran IV irons were
`comparable with age, sex, race, and relevant health condi-
`tions except for coronary heart disease and hypertension
`(Table 1). The products differed with respect to the underly-
`ing conditions leading to IV iron administration, reflecting dif-
`ferences in FDA-approved indications for use (iron dextran is
`approved for use in broad iron deficiency anemia indications
`and nondextran products are approved only for use in pa-
`tientswithchronickidneydisease).Amongtheindividualnon-
`dextran products, baseline demographics and anaphylaxis-
`related characteristics were similar, except for the ferumoxytol
`cohort, which had the highest proportion of patients with
`chronic kidney disease (60%) and lowest proportion of pa-
`tients with gastrointestinal tract and genitourinary tract bleed-
`ing (12%) (eTable 2 in the Supplement).
`
`2064
`
`JAMA November 17, 2015 Volume 314, Number 19 (Reprinted)
`
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`
`Copyright 2015 American Medical Association. All rights reserved.Copyright 2015 American Medical Association. All rights reserved.
`
`Downloaded From: http://jama.jamanetwork.com/ by Stine Primdahl on 11/18/2015
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`Pharmacosmos, Exh. 1055, p. 3
`
`

`
`Anaphylactic Reaction and Intravenous Iron Products
`
`Original Investigation Research
`
`Table 1. Baseline Characteristics for Incident Users Receiving Iron Dextran and Nondextran Intravenous Iron
`(2003-2013)
`
`No. (%) of Patients
`Iron Dextran
`(n = 247 500)
`
`Nondextran Intravenous Iron
`(n = 440 683)
`
`Standardized Mean
`Difference
`
`73.2 (11.3)
`
`83 312 (33.7)
`164 188 (66.3)
`
`74.0 (11.4)
`
`167 097 (37.9)
`273 586 (62.1)
`
`374 436 (85.0)
`48 449 (11.0)
`4222 (1.0)
`6926 (1.6)
`6650 (1.5)
`
`86 661 (19.7)
`119 670 (27.2)
`169 783 (38.5)
`63 529 (14.4)
`1040 (0.2)
`
`233 229 (52.9)
`63 956 (14.5)
`143 498 (32.6)
`
`60 044 (13.6)
`132 620 (30.1)
`207 127 (47.0)
`77 570 (17.6)
`33 355 (7.6)
`1968 (0.4)
`394 991 (89.6)
`
`211 132
`
`10 404 (4.9)
`5420 (2.6)
`86 856 (41.1)
`52 376 (24.8)
`
`0.07
`
`0.09
`0.09
`
`0.05
`0.05
`0.03
`0.01
`0.03
`
`0.26
`0.16
`0.33
`0.01
`0.00
`
`0.69
`0.19
`0.50
`
`0.01
`0.02
`0.12
`0.02
`0.04
`0.01
`0.20
`
`0.09
`0.02
`0.17
`0.00
`
`Abbreviations: ACE,
`angiotensin-converting enzyme;
`CKD, chronic kidney disease;
`COPD, chronic obstructive pulmonary
`disease; GI/GU, gastrointestinal tract
`and genitourinary tract;
`NSAIDs, nonsteroidal
`anti-inflammatory drugs.
`a Data on concomitant medications
`were collected for those patients
`who were enrolled in Medicare
`Part D (prescription drugs)
`in 2007-2013.
`
`Baseline Characteristicsa
`Age, mean (SD), y
`Sex
`Men
`Women
`Race
`White
`Black
`Asian
`Hispanic
`Other/unknown
`Regions
`Northeast
`Midwest
`South
`West
`Other
`Indications
`Anemia
`CKD
`GI/GU bleeding
`Other
`Conditions
`33 179 (13.4)
`Asthma
`72 391 (29.2)
`COPD
`101 419 (41.0)
`Coronary heart disease
`41 481 (16.8)
`Depression
`16 151 (6.5)
`Drug allergy
`958 (0.4)
`Food allergy
`204 701 (82.7)
`Hypertension
`Beneficiaries With Part D Enrollmenta
`No. of patients
`83 627
`Concomitant medications
`NSAIDs
`Antibiotics
`β-Blockers
`ACE inhibitors
`
`214 962 (86.9)
`23 683 (9.6)
`1718 (0.7)
`4231 (1.7)
`2906 (1.2)
`
`25 935 (10.5)
`50 782 (20.5)
`135 108 (54.6)
`35 106 (14.2)
`569 (0.2)
`
`53 141 (21.5)
`53 681 (21.7)
`140 678 (56.8)
`
`5977 (7.1)
`1916 (2.3)
`27 616 (33.0)
`20 692 (24.7)
`
`There were 274 anaphylaxis cases identified at first expo-
`sure to an IV iron product. The risk for anaphylaxis was 68 per
`100 000 persons (95%CI, 57.8-78.7/ per 100 000) in the iron
`dextran group compared with 24 per 100 000 persons (95%
`CI, 20.0-29.5 per 100 000) in the nondextran IV iron group.
`The OR was 2.6 (95% CI, 2.0-3.3 P < .001), after adjustments
`for age, indication, history of coronary heart disease, and hy-
`pertension.Comparedwithironsucrose,bothirondextranand
`iron gluconate were associated with an increased risk of ana-
`phylaxis (OR, 3.6; 95% CI, 2.4-5.4 and OR, 2.0; 95% CI, 1.2-
`3.5, respectively). Using data from 2010 to 2013, ferumoxytol
`was also associated with a higher risk of anaphylaxis com-
`pared with sucrose (OR, 2.2; 95% CI, 1.1-4.3; Table 2). Results
`
`of sensitivity analyses were consistent with the main results
`(eTables 3-6 and eFigures 1-4 in the Supplement). We found
`less than 1% (548 of 82 117) ferumoxytol users had the ge-
`neric J3490 code during the June 2009-December 2009 pe-
`riod. Removing these patients had little change to the results
`(eTable 7 and eFigure 5 in the Supplement).
`Anadditional170anaphylaxiseventswereobservedatsub-
`sequent IV iron administrations. For all IV iron products, the
`rate of anaphylaxis was highest at the first administration and
`decreased thereafter. The decrease was particularly pro-
`nounced for iron gluconate and iron sucrose (Figure 2). The
`cumulative risk of anaphylaxis over multiple administrations
`was highest for iron dextran, followed in decreasing order by
`
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`Pharmacosmos, Exh. 1055, p. 4
`
`

`
`Research Original Investigation
`
`Anaphylactic Reaction and Intravenous Iron Products
`
`ferumoxytol, iron gluconate, and iron sucrose (eFigure 6 in the
`Supplement). To reach an aggregate iron dose of 1000 mg in
`the cumulative dose analysis, dextran and ferumoxytol users
`required 2 administrations on average, whereas sucrose us-
`ers needed 5 and iron gluconate users needed 7. For cumula-
`tive doses of 1000-mg iron administered, as estimated from
`modeling, iron dextran was also associated with the highest
`risk of anaphylaxis (82 per 100 000 persons, 95% CI, 70.5- 93.1
`per 100 000), whereas iron sucrose was associated with the
`lowest risk (21 per 100 000 persons, 95% CI, 15.3- 26.4 per
`100 000) (Figure 3).
`The 2 marketed iron dextran products (high-molecular-
`weightdextran,low-molecular-weightdextran)sharedthesame
`HCPCS code during most of the study period. Thus, the indi-
`vidual risk of each iron dextran product could not be fully stud-
`ied.However,duringabriefintervalfromJanuary2006toMarch
`2008, separate HCPCS codes were used for each dextran prod-
`uct.Duringthisperiod,of53 914newirondextranusers,48 772
`(90.5%)receivedlow-molecular-weightdextranand5142(9.5%)
`received high-molecular-weight dextran, suggesting that dur-
`ing the study period, most dextran use in this population was
`low-molecularweight.Amongfirstadministrationsofirondex-
`tran during this period, a total of 43 anaphylaxis events were
`observed, of which 40 (93%) were in those taking low-
`molecular-weight dextran (eTable 8 in the Supplement).
`
`Discussion
`Among more than 680 000 US Medicare nondialysis benefi-
`ciaries who initiated IV iron use from 2003 to 2013, iron dex-
`tran was associated with increased anaphylaxis risk com-
`pared with nondextran formulations at first administration.
`Amongthenondextranproducts,theriskofanaphylaxisatfirst
`administration was higher with both iron gluconate and feru-
`moxytol than with iron sucrose. Because each IV iron prod-
`uct has a specific recommended dose and schedule of admin-
`istration,thecumulativeriskofanaphylaxiswasalsocalculated
`based on both the number of administrations and clinically rel-
`evant repletion level of iron (1000 mg) achieved within 12
`weeks. Both analyses showed iron dextran was associated with
`the highest cumulative risk of anaphylaxis and iron sucrose
`with the lowest risk.
`AllIVironformulationsstudiedconsistofanelementaliron
`core surrounded by a carbohydrate shell intended to shield the
`iron core and facilitate iron delivery to the reticuloendothe-
`lial system following intravenous administration. The formu-
`lations differ from each other in the size of the iron core and
`the identity and density of the carbohydrate shell.20 Al-
`though iron dextran is asserted to have a greater risk of seri-
`ous adverse events than the more recently approved nondex-
`tran IV iron products, most of the clinical trials that supported
`the approval of nondextran IV irons used a placebo or oral iron
`comparator and not iron dextran. Only a few head-to-head
`trials prospectively compared IV iron formulations, and they
`were small in sample size, had few or no anaphylaxis events,
`and were not designed to establish comparative safety.9,21,22
`To our knowledge, the present study represents the largest
`
`bPvalueadjustedformultiplecomparisons.
`aAdjustedforage,indication,coronaryheartdisease,andhypertension.
`Abbreviation:AOR,adjustedoddsratio.
`
`.001
`(1.4-6.5)
`3.0
`
`<.001
`(3.0-9.8)
`5.4
`
`(27.8-78.2)
`47.0
`
`(66.0-108.4)
`84.7
`
`34029
`
`77935
`
`.02
`(1.1-4.3)
`2.2
`
`(23.1-50.0)
`34.1
`
`82117
`
`Reference]
`
`1[
`
`(9.9-24.3)
`15.6
`
`134836
`
`.005
`(1.2-3.5)
`2.0
`
`<.001
`(2.4-5.4)
`3.6
`
`Reference]
`
`1[
`
`<.001
`(2.0-3.3)
`2.6
`
`(25.3-50.9)
`36.0
`
`(57.8-78.7)
`67.5
`
`(12.6-23.0)
`17.0
`
`(57.8-78.7)
`67.5
`
`94400
`
`247500
`
`264166
`
`247500
`
`16
`
`66
`
`28
`
`21
`
`34
`
`167
`
`45
`
`167
`
`IronGluconate
`
`IronDextran
`
`Ferumoxytol
`
`IronSucrose
`
`IronGluconate
`
`IronDextran
`
`IronSucrose
`
`IronDextran
`
`2010-2013
`
`2003-2013
`
`Reference]
`
`1[
`
`(20.0-29.5)
`24.3
`
`440683
`
`107
`
`Nondextran
`
`2003-2013
`
`Pvalueb
`
`AOR(95%CI)a
`(95%CI)
`per100000persons
`Rate
`
`No.ofnewusers
`anaphylaxiscases
`No.of
`IntravenousIron
`
`Table2.RiskofAnaphylaxisatFirstAdministrationbyIntravenousIronProducts
`
`2066
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`

`
`Anaphylactic Reaction and Intravenous Iron Products
`
`Original Investigation Research
`
`Figure 2. Rate of Anaphylaxis by IV Iron Products and Number
`of Administrations
`
`No. of times
`administered
`
`1 2
`
`3 4
`
`-5
`≥6
`
`
`
`Iron DextranIron Dextran
`
`Ferumoxytol
`
`Iron Gluconate
`
`Iron Sucrose
`
`No. of users
`247 500
`126 678
`90 874
`129 799
`495 851
`
`No. of users
`82 117
`48 359
`12 244
`13 173
`8778
`
`No. of users
`94 400
`72 464
`64 834
`105 438
`312 971
`
`No. of users
`264 166
`196 201
`169 788
`251 284
`550 444
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Rate of Anaphylaxis per 100 000 Administrations
`
`No. of times
`administered
`
`1234
`
`-5
`≥6
`
`IV indicates intravenous.
`
`Figure 3. Adjusted Predicted Risk of Anaphylaxis at Cumulative Dose
`of 1000 mg
`
`Iron
`Dextran
`
`Ferumoxytol
`
`Iron
`Gluconate
`
`Iron
`Sucrose
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Predicted Risk of Anaphylaxis
`
`per 100 000 Persons
`
`Adjusted for age, coronary heart disease, and hypertension. Error bars indicate
`95% CIs.
`
`ting, physicians may code severe or textbook anaphylaxis as
`anaphylaxis but code less severe or atypical anaphylaxis in
`terms of its component symptoms or as an allergic reaction.
`Compared with anaphylaxis criteria used in the adjudication
`of clinical trial data, our algorithm might have missed the cases
`presenting with skin and mucosal symptoms that could have
`been treated with corticosteroids, which may be milder in na-
`ture than cases presenting with systemic symptoms (such as
`respiratory compromise, syncope). The skin and mucosal
`symptoms were not included in our algorithm because they
`are not specific to anaphylaxis, so including them would nega-
`tively affect the positive predictive value. While balancing be-
`tween positive predictive value and sensitivity, our algo-
`rithm should have captured the typical and severe anaphylaxis
`cases diagnosed by the physician. The validity of our analy-
`ses should not be biased by the under ascertainment of ana-
`phylaxis cases since it seems unlikely that physician coding
`practices for completing Medicare billing claims would differ
`
`comparative safety assessment of anaphylaxis risk for the IV
`iron products. In contrast to prior efforts to assess safety,23-25
`our study was not based on postmarket passive case report-
`ing, such as the FDA’s spontaneous adverse events reporting
`system, which is limited in its ability to support comparative
`safety analyses due to different approval dates and indica-
`tion of IV iron products, variations in reporting over time,
`choice of denominator used, and variations in the diagnostic
`criteria of anaphylaxis. Our study provides a more reliable es-
`timate of the relative risk between individual IV iron prod-
`ucts based on a prespecified algorithm for anaphylaxis, a well-
`defined and characterized population at risk, and adjustment
`for imbalances in baseline risk factors for anaphylaxis.
`The mechanism of anaphylactic reaction after IV iron re-
`mains unknown. Dextran may be immunogenic, even to pa-
`tientswhohavenotbeenpreviouslyexposed,becauseofcross-
`reactivity of dextran to native polysaccharide antibodies.21 The
`mechanism of anaphylaxis associated with nondextran IV iron
`is also unclear. Possibilities include reactions to the carbohy-
`drate shell or to release of unbound iron into the circulation
`that then may cause oxidative stress, hypotension, and car-
`diac failure in addition to the typical anaphylactic reaction. A
`recent review of ferumoxytol suggested that the structure of
`carbohydrate coating surrounding the iron oxide core also may
`be associated with immunogenicity.26 The possible adverse ef-
`fects of more rapid administration of higher doses of IV iron
`are also not well characterized.
`This study has several limitations. The study population
`consisted of US Medicare beneficiaries not receiving dialysis
`treatment; thus, our results may not extend to dialysis pa-
`tients or younger age populations. Patients receiving dialysis
`were not included because iron dextran and ferumoxytol were
`rarely used in this population. Another limitation was that the
`low- and high-molecular-weight dextran products could not be
`individually identified during most of study period. However,
`the very low use of high-molecular-weight iron dextran from
`January2006throughMarch2008,duringwhichwecoulddis-
`tinguish the use of 2 dextran products, suggests that our re-
`sults likely represent the risk of the low-molecular-weight dex-
`tran, especially the most recent data from 2010-2013.
`Based on the incidence rates observed in clinical trials of
`ferumoxytol, in which the rate of anaphylaxis or serious hy-
`persensitivity reaction varied between 0.2% and 0.9%, de-
`pending on the patient population,27 our results may indi-
`cate low sensitivity (8%-35%) in detecting anaphylaxis. One
`possible explanation is that the patient populations included
`in the randomized clinical trials and our large observational
`study were different. The ferumoxytol trial that reported an
`anaphylaxis incidence of 0.9% was conducted in a general
`population of patients with iron deficiency anemia to sup-
`port an unapproved indication (Miya Paterniti, MD, US FDA,
`written communication, July 10, 2015), whereas the majority
`of patients in our study had anemia related to chronic kidney
`disease per approved indication, and the baseline risk of ana-
`phylaxis may have been different in these 2 populations. Also,
`anaphylaxis can present in a variety of ways with varying de-
`grees of severity. In clinical trials, there is generally a well-
`defined case definition, whereas in the general practice set-
`
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`
`2067
`
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`Pharmacosmos, Exh. 1055, p. 6
`
`

`
`Research Original Investigation
`
`Anaphylactic Reaction and Intravenous Iron Products
`
`depending on which IV iron product was used. Although ran-
`dom variation in the sensitivity could create a spurious dif-
`ference between products, especially at very low levels of sen-
`sitivity, this is unlikely to have affected this study because the
`relative risks between individual IV iron products were all
`greater than 2, and greater than 5 in the comparison between
`iron dextran and sucrose.
`Inaddition,giventhedifferenceinindicationbetweeniron
`dextran and nondextran products, patients treated with dex-
`tran and nondextran IV iron may be different relative to the
`risk of anaphylaxis. We examined important baseline charac-
`
`teristics that are relevant to the risk of anaphylaxis and ad-
`justed for those that were not balanced in the final analysis.
`However, residual confounding is possible due to additional
`factors not captured by this study.
`
`Conclusions
`AmongpatientsintheUSMedicarenondialysispopulationwith
`first exposure to IV iron, the risk of anaphylaxis was highest
`for iron dextran and lowest for iron sucrose.
`
`ARTICLE INFORMATION
`Author Contributions: Dr MaCurdy had full access
`to all of the data in the study and takes
`responsibility for the integrity of the data and the
`accuracy of the data analysis.
`Study concept and design: All authors.
`Acquisition, analysis, or interpretation of data: All
`authors.
`Author Affiliations: Office of Surveillance and
`Epidemiology, Center for Drug Evaluation and
`Research, US Food and Drug Administration,
`Silver Spring, Maryland (Wang, Graham, Mott,
`Reichman); Office of New Drugs, Center for Drug
`Evaluation and Research, US Food and Drug
`Administration, Silver Spring, Maryland (Kane,
`Houstoun, Ryan, Limb); Dr Kane is now retired.
`(Kane); Office of Biostatistics, Center for Drug
`Evaluation and Research, US Food and Drug
`Administration, Silver Spring, Maryland (Xie,
`Levenson); Acumen LLC, Burlingame, California
`(Wernecke, MaCurdy, Wong, Sheu); Harvard School
`of Public Health, Boston, Massachusetts (Mott);
`Genentech Inc, San Francisco, California (Limb);
`Centers for Medicare & Medicaid Services,
`Washington, DC (Worrall, Kelman).
`Conflict of Interest Disclosures: All authors have
`completed and submitted the ICMJE Form for
`Disclosure of Potential Conflicts of Interest. The
`authors are employees or contractors of the
`Centers for Medicare & Medicaid Services or the US
`Food and Drug Administration. No other disclosures
`were reported.
`Funding/Support: This study was funded through
`an intraagency agreement between the Centers for
`Medicare & Medicaid Services and the US Food and
`Drug Administration.
`Role of the Funder/Sponsor: The Centers for
`Medicare & Medicaid Services and the US Food and
`Drug Administration had no role in the design and
`conduct of the study; the collection, analysis, and
`interpretation of the data; the preparation of the
`manuscript; or the decision to submit the
`manuscript for publication.
`Disclaimer: The views expressed are those of the
`authors and not necessarily those of the
`Department of Health and Human Services, the
`Centers for Medicare & Medicaid Services, or the US
`Food and Drug Administration.
`
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