The Safety of Intravenous Iron Dextran
`(Dexferrum®) During Hemodialysis in Patients
`with End Stage Renal Disease
`Sally A. Hood
`Marg(lTet. O'Brien
`Regina Higgins
`
`In patients. with end stage renal dis(cid:173)
`
`ease (ESRD) who undergo routine
`hemodialysis, the presence of sub-
`optimal iron stores imfu:':n their
`ery-
`response to recombinant
`tbropoietin (epoetin) therapy (Van
`Wyck, 1989). De Nationil Kithuy
`Foraulation - Dialjsis Outcomes ~
`lnitiati1J1
`(NKF-DOQr') ClinicOl
`GuitlelifllS For tlu Treatment Of .Anemia of
`Chronic Rmal Failm, published in
`1997, state that regu1ai intravenous
`(IV) administration of iron will pre(cid:173)
`vent iron deficiency and, thus, pro(cid:173)
`mote better erythropoiesis than oral
`iron therapy among patients who
`undergo hemodialysis.
`Intravenous iron dextran has been
`shown to improve erythropoiesis and
`r~duce epoetin re~ements in
`hemodialySis patients (F'ishbane, Frei,
`& Maesaka, 1995; FJShbane & Lynn,
`1995). However, some clinicians are
`concemed about adverse events asso(cid:173)
`ciated with this mode of therapy. In
`this retrospective study, adverse reac(cid:173)
`tions to the iron dexttan. product
`Dexferrum® ·· (American Regent
`Laboratories, Inc., Shirley, NY) were ·
`evaluated among ESRD patients at
`an outpatient dialysis cliniC over a 6-
`month period. _
`
`Patients and Methods
`The records of all 62 . ESRD
`patients who reeeived Dexfemun at
`t:he Merrimack Valley· Dialysis
`Center, a hospital-based dialysis unit
`in Methuen, Massachus~tts from
`August 1, 1997 to January 31, 1998
`were studied. Patient characteristics
`are summarized in 'Tuble 1. Each
`patient chart was eYllmined for demo(cid:173)
`graphic and clinical data and any doc(cid:173)
`umentation of adverse· reactions that
`occmred during DexfemJ.Jn infusion.
`We noted the type of adverse reac(cid:173)
`tion, the severif¥ of the reaction, and
`the treatment actions taken. Each case
`in which a reaction occurred was ·
`evaluated to determine the probabili(cid:173)
`ty that the reaction ·was caused by
`administration of Dexfemnn.
`We calculated the incidence of
`adverse events as a percentage of the
`total number of. patients treated with
`Dexfemnn. Due to the small number
`of adverse events, we did not analyze
`potential predicton of such events.
`
`Methodology
`. A. complete retrospective review
`of all dialysis nm sheets and nursing
`progress notes of patients who
`received Dexferrum was conducted.
`Dexferrum was administered
`to
`
`patients' accOrding to the irori moni- · .. ·
`taring parameters recommended by
`NKF-DOQJ in its Clinical Practkl
`Guidelinll for tlll Tnatmmt of A.nemia of
`Clmmic RinalFailure (National Kidn ey
`Foundation, 1997).
`·
`Acci>iding to our protocol, a 25
`mg test dose diluted in 100 ml normal
`saline was administered over 30 min(cid:173)
`utes •. If DO reaction OCCUired within 1
`hour, the remainder of the therapeu(cid:173)
`tic dose (75 mg) diluted in 100 ml nor(cid:173)
`mal saline was administered over 1
`hour. Cfhe ~ of Dexfermm diluted
`in an IV solution is not in the product
`~·'
`Results
`·or the 62 patients .studied, 2
`{3.2%) experienced adverse events.
`The first, a moderate reaction, was
`judged to be related to Dexferrum,
`while the second, a cardiac arrest, was
`judged not to be related. We desaibe
`each case below.
`·
`The adverse event associated with
`Dexferrum therapy occmred in an
`84-year-old, white, male with a histo(cid:173)
`ry of coronary artery disease. He was
`recei~ an angiotensin-convertm~
`enzyme (ACE) inhibitor (Captopril®J
`and had a history of a prior course of
`IV ,iron therapy. The adverse event
`
`::
`
`Sall] .L B"°'4 MB, ~ PRCPC, is metlkal
`tlirraor, Ml1'fima« Ji11e] Dialysis MllAan, llflll
`Mmittuzlk Valle] Neplaroloa llflll u....-...:-
`. "1r·-.. -·~
`MetAuor,, MA..
`
`Margaret O~ RN, CNN, is fomwrl111&1111
`coordinator, Mmittuzdc Va/Uy DWpis Milluun,
`Mttluun, MA..
`Rqlu maw, RN, is a sttzff RN, Mminuuk
`Valky Dial]~ Metlulen, Mttluun, MA.
`
`Not.e: Suppurtd in part 1'y A.mmam Regmt
`Lllboraloria, Inc.
`
`NEPHRoLeGY NURSING JOURNAL. February 2000• Vol. 27, No. 1
`
`41
`
`Luitpold Pharmaceuticals, Inc., Ex. 2020, p. 1
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
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`'"\ . !
`
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`
`I;
`
`Table 1
`Patient Characteristics
`
`Total.medical records included in analysis
`Mean age (range)
`Race
`Asian
`African-American
`Hispanic
`Native American
`White
`History of diabetes mellitus
`History of 2 or more comorbid diagnoses·
`Concurrent treatment with an ACE inhibitor
`History of prior course. of iron dextran~ : ..
`
`'·,·
`
`62
`60.8 yrs (16-92 yrs)
`
`14 (23%)
`
`. 48 (77%)
`16 (26%)
`22 (35%) ..
`10 (16%)
`53 (85%)
`
`occurred during the second dose of a
`course of Dexferrum
`treatment
`(dosage= 100 mg). After initiation of
`· the Dexferrum infusion, the patient
`experienced chest pain and hypoten(cid:173)
`sion. Review of the patient's history
`revealed that the reaction was likely
`to be related to Dexferrum. The
`patient usually developed hypoten(cid:173)
`sion, without chest pain, during the
`second hour of dialysis when iron was
`not administered. In this instance, the
`drop in blood pressure occurred less
`than 30 minutes after initiation of
`Dexferrum. The patient also experi(cid:173)
`enced chest pain and was treated with
`nitroglycerin. He was not hospital(cid:173)
`ized
`A cardiac arrest that was judged to
`have been related to a primary car(cid:173)
`diac ischemic event rather than to
`De:·.ien;::m ccamed i~ a 68-year-old,
`white, male with a history of diabetes
`mellitus, coronary artery disease,
`peripheral vascular disease, car(cid:173)
`diomyopathy, severe left ventricular
`dysfunction (he had an implanted
`pacemaker), and a history of recent
`sepsis. He had no history of drug
`allergy. He was receiving an ACE
`inhibitor (Lisinopril®) and had no
`prior course of IV iron therapy. The
`adverse event occurred during the
`first dose of Dex:ferrum during the
`first therapeutic course. A 25 mg test
`dose was administered with no com(cid:173)
`plications; however, approximately
`25 :a::Unutes after initiation of the
`remaining Dexferrum dose (75 mg),
`the patient was noted to be hypoten(cid:173)
`sive and unresponsive. He had no
`preceding symptoms to indicate ana(cid:173)
`phylaxis, although, on presentation to
`
`the dialysis unit that day, he felt
`unwell in a nonspecific way. Despite
`resuscitatiop effodc;, including admin(cid:173)
`iStration of epinephrine. and. solume(cid:173)
`dro~ the patient expired. In a review
`of the events and in light of the
`patient's history of severe ~ac dys(cid:173)
`function, it was likely that his death
`was not related to Dexferrum.
`Overa]], no patient developed ana(cid:173)
`phylactic rea.cti.ons or associat.ed reac(cid:173)
`tions, such as dyspepsia, dyspnea/whee-z(cid:173)
`ing, headache, nausea/vomiting, skin
`:flushing, or swelling, that were associated
`with Dexferrum therapy.
`
`Discussion
`Jn addressing at;lvme events associ(cid:173)
`ated with . IV iron preparations, the
`NKF-DOQJ: cited reports documenting
`low incidence rates of ~tlireatening or
`serious· arute reactions associated with
`IV iron dextran. In a prospective study
`of Jmferon® (F:asons PLC, Cheshire,
`England), no longer marketed in the
`United States, the incidence of immedi(cid:173)
`ate life-threatening reactions was 0.620/o
`(3 of 481 general patients) (Hamstra,
`Block, & Schocket, 1980). Jn a retrospec-
`. tive chart review ·of patients receiving
`lnFed® (Schein Pharmaceutical, Inc.,
`Floral Parle, NJ), the incidence of serious
`adverse events was 0.70/o (4 of 573 dialy(cid:173)
`sis patients). Overall 27 of 573 patients
`(4.70/o) ~enced an adverse reaction
`to InFed (FJSbbane et al, 1996).
`Our 6-month retrospective study
`revealed that adverse events occurred
`in 3.2% ofhemodialysis patients treat(cid:173)
`ed with Dexferrum. Excluding the
`event judged to be unrelated to iron
`dextran administration, only 1 patient
`in our series, or 1.60/o, experienced an
`
`adverse reaction associated with
`Dexferrum.
`Due to the small number of events
`that occurred in this series of patients
`treated with Dexferrum, analysis of
`potential predictors of adverse reac- ·
`tions would not have been meaning(cid:173)
`ful. The study of InFed found signifi(cid:173)
`cant predictors of adverse reactions to
`be a history of drug allergy (odds ratio
`[OR], 2.4; P-=.03) and a histoxy of
`multiple drug allergies (OR 5.5;
`.P-=.0004) (FIShbane et al., 1996).
`Limitations of our study include its
`retrospective nature and the fact that
`our stut;iy population (77% white, 230/o
`Hispanic) lacked a more inclusive
`ethnic representation. Nonetheless,
`our :findings add to the evidence that
`serious reactions associated with IV
`iron dexf:ra:n therapy, in this case
`Dexferrum., in ESRD patients on
`hemodialysis are infrequent
`
`References
`Fishbane, S., Frei, G.L., & Maesaka, J.K.
`(1995). Reduction in recombinant
`human eiythropoietin doses by the
`use of chronic intravenous iron stip(cid:173)
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`Fishbane, S., & Lynn, R.I. (1995). The effi(cid:173)
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`of iron deficiency in hemodialysis
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`Fishbane, S., Ungureanu, V.D., Maesaka,
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`dextran in hemodialysis patients ..
`.American Journal of IUd.ney Diseases,
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`. . . . . .
`. ..
`Hamstra, RD., Block, MH., & Schocket,
`AL. (1980). Intravenous irOn dextran
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`42
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`NEPHROLOGY NURSING JOURNAL 11 February 2000 w Vol. 27, No. 1 -
`
`Luitpold Pharmaceuticals, Inc., Ex. 2020, p. 2
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495