Kidney International, Vol. 68 (2005), pp. 1801–1807
`
`The safety and efficacy of ferumoxytol therapy in anemic chronic
`kidney disease patients
`
`BRUCE S. SPINOWITZ, MICHAEL H. SCHWENK, PAULA M. JACOBS, W. KLINE BOLTON,
`MARK R. KAPLAN, CHAIM CHARYTAN, and MARILYN GALLER
`
`Division of Nephrology and Hypertension, The New York Hospital Medical Center of Queens, Flushing, New York; Advanced
`Magnetics, Inc., Cambridge, Massachusetts; University of Virginia Health System, Charlottesville, Virginia; and Nephrology
`Associates, Nashville, Tennessee
`
`The safety and efficacy of ferumoxytol therapy in anemic
`chronic kidney disease patients.
`Background. Administration of safe and effective iron ther-
`apy in patients with chronic kidney disease is a time consuming
`process. This phase II clinical trial studied ferumoxytol, a semi-
`synthetic carbohydrate-coated iron oxide administered by rapid
`intravenous injection to anemic chronic kidney disease patients
`(predialysis or undergoing peritoneal dialysis).
`Methods. Inclusion criteria included hemoglobin ≤12.5 g/dL
`and transferrin saturation ≤35%. Twenty-one adult patients
`were randomized to receive ferumoxytol in a regimen of 4 doses
`of 255 mg iron in 2 weeks or 2 doses of 510 mg iron in 1 to 2
`weeks. Ferumoxytol was administered at a rate of up to 30 mg
`iron/sec.
`Results. The maximum hemoglobin response following feru-
`moxytol administration occurred at 6 weeks, increasing from a
`baseline of 10.4 ± 1.3 g/dL to 11.4 ± 1.2 g/dL (P < 0.05). Ferritin
`increased from a baseline of 232 ± 216 ng/mL to a maximum
`of 931 ± 361 ng/mL at 2 weeks (P < 0.05), while the baseline
`transferrin saturation increased from 21 ± 10% to 37 ± 22%
`at 1 week (P < 0.05). Seven adverse events in 5 patients during
`this trial were deemed possibly related to ferumoxytol, none
`serious. These events included constipation, chills, tingling, a
`gastrointestinal viral syndrome, delayed pruritic erythematous
`rash, and transient pain at the injection site.
`Conclusion. Although larger studies are required, this small
`study demonstrates that ferumoxytol can be safe and effec-
`tive in increasing iron stores, is associated with an increased
`hemoglobin response, and is well tolerated at a rapid infusion
`rate.
`
`Providing adequate bioavailable iron to patients with
`chronic kidney disease (CKD) is necessary to ensure
`an efficient response to erythropoietic hormone therapy
`[1]. Additionally, there are data supporting a significant
`
`Key words: ferumoxytol, anemia, hemoglobin, iron, ferritin, transferrin
`saturation.
`
`Received for publication August 27, 2004
`and in revised form March 18, 2005, and April 27, 2005
`Accepted for publication May 13, 2005
`
`C(cid:1) 2005 by the International Society of Nephrology
`
`hemoglobin response in this population with parenteral
`iron therapy alone [2]. Oral iron administration is rel-
`atively ineffective in supporting erythropoiesis in CKD
`patients [3–5], and many patients have gastrointestinal
`intolerance of these compounds. As a result, intravenous
`iron is commonly used to achieve and maintain adequate
`iron levels in this patient population.
`Until recently, iron dextran was the only intravenous
`iron preparation available in the United States [6].
`Adverse reactions have been reported in 4.7% to
`43% of patients administered intravenous iron dextran
`[7–9]. Most of these reactions are mild, with 38% of pa-
`tients given a total dose infusion exhibiting delayed re-
`actions of arthralgia, myalgia, and fever. Some patients
`experience anaphylactoid-type reactions (defined as dys-
`pnea, wheezing, chest pain, hypotension, urticaria, or an-
`gioedema), which can be serious and life threatening [9].
`Comparative data on the safety of the currently avail-
`able parenteral iron preparations are difficult to evaluate
`since information on the number of patients treated, the
`specific product and dosage regimen utilized, previous ex-
`posure to other iron preparations, and current diagnoses
`are often not available. Reports are typically retrospec-
`tive, and neither blinded nor comparative. A recent retro-
`spective analysis concluded that the rate of adverse drug
`events was lowest in patients receiving a low-molecular-
`weight iron dextran preparation compared to a higher-
`molecular-weight iron dextran or sodium ferric gluconate
`[10].
`Newer parenteral iron preparations such as sodium
`ferric gluconate and iron sucrose are effective and
`considered safer [11, 12], but require multiple and/or
`relatively time-consuming administration regimens.
`Currently, in the United States, according to the Food
`and Drug Administration labeling, intravenous iron re-
`placement is generally given as a slow infusion of 125 mg
`sodium ferric gluconate over 10 minutes or 100 to 200 mg
`of iron sucrose over approximately 5 minutes. These de-
`livery modes incur significant expense for supplies, such
`
`1801
`
`Pharmacosmos, Exh. 1012, p. 1
`
`

`
`1802
`
`Spinowitz et al: Ferumoxytol therapy in chronic kidney disease
`
`as tubing and infusate, costly nursing time, and patient in-
`convenience. To achieve iron repletion with these newer
`agents, commonly a total dose of 1 g ofiron requires 5 to
`10 sessions over an extended period of time.
`Ferumoxytol (Advanced Magnetics, Cambridge, MA,
`USA) is an investigational, semi-synthetic carbohydrate-
`coated, magnetic iron oxide preparation. It is one of a
`class of compounds originally developed as magnetic res-
`onance imaging (MRI) contrast agents, and is adminis-
`tered for MR angiography as a rapid intravenous bolus
`[13, 14]. Ferumoxytol was designed to minimize potential
`immunologic reactions, such as those seen with commer-
`cially available iron dextran products, and to minimize
`free iron during dosing.
`The purpose of this open label study was to evalu-
`ate the safety and efficacy of ferumoxytol in stimulating
`hemoglobin synthesis in anemic CKD patients on stable
`dosing regimens of erythropoietic hormones.
`
`METHODS
`Subjects were recruited from 3 centers in the United
`States for this prospective open-label phase 2 dose esca-
`lation study. The primary purpose of the study was to
`evaluate the safety of 2 dose regimens in this patient
`population, while a secondary purpose was to gather ex-
`ploratory data on efficacy to permit the design of larger
`studies. The study was conducted in accord with the
`Declaration of Helsinki and approved by an Institutional
`Review Board for each site. After granting informed con-
`sent, each subject had screening laboratory tests, a med-
`ical history, and a physical examination performed to
`establish a baseline and confirm inclusion criteria and
`exclusion criteria. Patients included had been diagnosed
`with CKD and could be on peritoneal dialysis therapy
`but not hemodialysis. Other inclusion criteria included
`an age of 18 years or greater, hemoglobin level less than
`or equal to 12.5 g/dL, and a transferrin saturation of 35%
`or less.
`Exclusion criteria included women who were pregnant
`or lactating, the use of parenteral or oral iron therapy
`in the previous 2 weeks, transfusions or active bleed-
`ing in the previous 2 months, major surgery within the
`previous month, active infections, inflammatory condi-
`tions, multiple drug sensitivities, autoimmune disease,
`immunodeficiencies, androgen therapy within the past
`12 weeks, iron overload (transferrin saturation 50% or
`greater, serum ferritin 800 ng/mL or greater), severe hy-
`perparathyroidism (parathyroid hormone greater than
`1500 pg/mL), serum AST or ALT greater than 2 times
`the upper limit of normal, and receipt of an investiga-
`tional drug in the previous 30 days.
`Patients were allowed, but not required, to be on ery-
`thropoietic hormone therapy and the dose was allowed
`
`to be modified in accordance with each site’s established
`protocol for therapy.
`Serum aluminum and parathyroid hormone concen-
`trations and occult blood in the stool were determined at
`screening. Serum chemistries, prothrombin time, and ac-
`tivated partial thromboplastin times were obtained prior
`to drug administration, and repeated one week follow-
`ing completion of the dosing regimen. A complete blood
`count and measures of body iron status (serum iron, to-
`tal iron binding capacity, transferrin saturation, ferritin,
`and transferrin) were obtained at screening and weekly
`for 8 weeks following the first dose, using routine clinical
`chemistry and hematology testing
`The study drug, ferumoxytol (Advanced Magnetics,
`Inc.), is a superparamagnetic iron oxide (magnetite)
`nanoparticle coated with a semi-synthetic carbohydrate
`designed to minimize immunologic sensitivity. The drug
`has an average colloidal particle size of 30 nm by light
`scattering and a molecular weight of 750 kD. Ferumoxy-
`tol is a sterile liquid formulated to contain 30 mg/mL of
`elemental iron and 44 mg/mL of mannitol. It is isotonic
`and neutral pH.
`Patients were to receive either 4 intravenous doses of
`ferumoxytol at 255 mg of iron (group 1) or 2 intravenous
`doses of ferumoxytol at 510 mg of iron (group 2). All
`patients in group 1 were dosed and evaluated for safety
`prior to enrolling any patients in group 2. Group 1 doses
`were given every 2 to 3 days, while group 2 doses were
`administered one week apart. An intravenous line (but-
`terfly) was placed into a peripheral vein and 0.9% NaCl
`was infused to keep the vein open. The appropriate dose
`of ferumoxytol was administered by intravenous injection
`into the peripheral vein at a rate of 1 mL/sec (30 mg/sec)
`(i.e., 9 seconds for the 255 mg dose or 17 seconds for the
`510 mg dose). A 10 to 20 mL normal saline intravenous
`flush was given after drug administration.
`Safety monitoring during drug administration included
`measurement of blood pressure, heart rate, respiratory
`rate, and oral temperature prior to drug administration,
`and repeated at 15, 30, and 60 minutes after ferumoxy-
`tol administration, as well as at weekly visits for 8 weeks
`thereafter, along with evaluation for adverse events. Ad-
`verse events were defined as illnesses, signs, or symp-
`toms that appeared or worsened after the implemen-
`tation of study procedures; evaluated as serious or not
`serious; as mild, moderate, or severe; as definitely, prob-
`ably, possibly, unlikely, or definitely not related to drug
`administration.
`Primary efficacy outcomes included changes from
`baseline of hemoglobin, transferrin saturation, and serum
`ferritin levels. The time to maximum response was evalu-
`ated, as well as epoetin alfa and darbepoetin alfa dosing
`regimens in the 4 weeks prior to and 8 weeks post feru-
`moxytol administration. Safety data were gathered and
`adverse events noted and evaluated for their association
`
`Pharmacosmos, Exh. 1012, p. 2
`
`

`
`Spinowitz et al: Ferumoxytol therapy in chronic kidney disease
`
`1803
`
`Table 1. Subject demographic and baseline clinical values
`
`Gender
`Age
`
`Dose groups
`2 × 510 mg
`4 × 255 mg
`Total
`(N = 21)
`(N = 11)
`(N = 10)
`9M/12F
`5M/6F
`4M/6F
`63.2 ± 15.4
`58.0 ± 17.8
`68.9 ± 10.4
`(28–76)
`(28–78)
`(51–86)
`16/4/1
`7/3/1
`9/1/0
`4.3 ± 3.3
`3.2 ± 1.6
`5.5 ± 4.2
`(0.6–15.4)
`(0.6–6.0)
`(1.5–15.4)
`10.4 ± 1.3
`10.0 ± 1.3
`10.9 ± 1.3
`(8.3–12.7)
`(8.3–12.7)
`(8.8–12.6)
`232 ± 216
`266 ± 215
`252 ± 259
`(2–782)
`(2–637)
`(74–782)
`21 ± 10
`21.0 ± 9.8
`20.2 ± 7.3
`(3–47)
`(3–35)
`(14–36)
`23 ± 25a
`31 ± 31a
`15 ± 14
`(4–117)
`(10–117)
`(4–38)
`1/0/3/10/7
`1/0/2/6/2
`0/0/1/4/5
`CKD stage 1/2/3/4/5
`GFR, glomerular filtration rate, as estimated by the Modification of Diet in Renal Disease formula, (http://www.hdcn.com/calcf/gfr.htm). Values are given as mean ±
`standard deviation. The range is stated in parentheses.
`aOne patient with membranous nephropathy had a creatinine of 0.6 and GFR of 117. If this patient is excluded, the 2 × 510 group averages 23 ± 14 (10–53) and the
`combined group is 19 ± 12 (4–53).
`
`Race (white/black/Hispanic)
`Serum creatinine mg/dL
`
`Hemoglobin g/dL
`
`Ferritin ng/mL
`
`Transferrin saturation %
`
`GFR mL/min/1.73m2
`
`with ferumoxytol. Efficacy data were evaluated for each
`individual dosing group as well as the combination of both
`groups.
`
`Statistics
`All results are expressed as mean ± standard devi-
`ation. Changes from baseline for the hematologic and
`iron parameters were examined over time using one-way
`repeated measures analysis of variance (ANOVA), with
`post-hoc Dunnet’s test.
`
`RESULTS
`Twenty-one patients enrolled and completed this study,
`18 of whom were predialysis CKD patients and 3 patients
`(all in group 1) who were receiving chronic peritoneal
`dialysis therapy. Of the 21 patients, 20 had a history of
`hypertension, 14 with diabetes, and 2 with polycystic kid-
`ney disease. The 10 patients in group 1 (4 × 255 mg iron)
`received 40 doses of ferumoxytol and the 11 patients in
`group 2 (2 × 510 mg iron) received 22 doses of feru-
`moxytol. All patients completed dosing as planned. Pa-
`tient demographics and baseline clinical characteristics
`are presented in Table 1. Group 1 patients had a higher
`hemoglobin (10.9 g/dL) at baseline than group 2 (10.0),
`but this difference was not statistically significant.
`Hematologic parameters and measures of iron status
`are presented in Table 2, including baseline and maxi-
`mal values, and the time in weeks at which the peak re-
`sponse was observed. Since the 2 dosing groups received
`the same total iron dosage, they were also combined
`to form 1 group for statistical analysis. Changes in iron
`status as reflected in ferritin and transferrin saturation
`(Figs. 1 and 2) were maximal after 1 to 2 weeks, as was
`
`the reticulocyte count, while hemoglobin and hematocrit
`peaked later, at 5 to 6 weeks. Nine patients exhibited
`transient ferritin values over 1000 (4 in group 1, 5 in
`group 2). At 8 weeks after dosing was completed, 2 pa-
`tients still had ferritin values greater than 1000, while the
`other 7 patients had ferritin values that had decreased to-
`ward baseline. The mean maximal change in hemoglobin
`concentration (at 6 weeks after ferumoxytol administra-
`tion) was 1 g/dL (Fig. 3). Although the 2 groups had
`different baseline hemoglobin values, the hemoglobin
`response was parallel and equivalent in magnitude.
`Among the individual patients, 8 patients in each group
`exhibited an increase in hemoglobin of greater than 0.5
`g/dL. The maximum increase in reticulocyte count was
`seen at 2 weeks.
`In the 4-week period prior to ferumoxytol adminis-
`tration, 13 of the subjects received stable hematopoietic
`hormone therapy (10 subjects received epoetin alfa, 3
`patients received darbepoetin alfa), while 8 subjects did
`not receive either treatment (Table 3). In the 8 weeks af-
`ter ferumoxytol dosing, 15 patients had their dosing regi-
`mens unchanged, 4 patients had their mean weekly doses
`decreased, and 2 patients had increases in their mean
`weekly doses, 1 from 2000 to 3450 units (with no change
`in hemoglobin concentration after ferumoxytol therapy)
`and 1 from 10,000 to 20,000 units (with a maximal change
`in hemoglobin post-ferumoxytol therapy of 0.7 g/dL, less
`than the mean change in the 2 dosing groups). In patients
`receiving epoetin alfa, the pre-ferumoxytol mean weekly
`dosage was 9650 units, compared with the mean weekly
`dose post-ferumoxytol dosage of 9100 units, not statis-
`tically different. The mean weekly darbepoetin dosage
`decreased from 30 lg to27.8 lg after ferumoxytol ad-
`ministration, not statistically different.
`
`Pharmacosmos, Exh. 1012, p. 3
`
`

`
`1804
`
`Spinowitz et al: Ferumoxytol therapy in chronic kidney disease
`
`Table 2. The hematologic and iron indices responses to ferumoxytol compared with baseline
`
`Hematocrit %
`
`Hemoglobin g/dL
`
`Reticulocyte count %
`
`Ferritin ng/mL
`
`Transferrin saturation %
`
`Group
`4 × 255 mg
`(N = 10)
`2 × 510 mg
`(N = 11)
`Total
`(N = 21)
`4 × 255 mg
`(N = 10)
`2 × 510 mg
`(N = 11)
`Total
`(N = 21)
`4 × 255 mg
`(N = 10)
`2 × 510 mg
`(N = 11)
`Total
`(N = 21)
`4 × 255 mg
`(N = 10)
`2 × 510 mg
`(N = 11)
`Total
`(N = 21)
`4 × 255 mg
`(N = 10)
`2 × 510 mg
`(N = 11)
`Total
`(N = 21)
`a P < 0.05 compared with baseline value. None of the values for group 1 were different from those of group 2.
`
`Baseline
`33.9 ± 3.3
`30.3 ± 3.4
`32.0 ± 3.8
`10.9 ± 1.3
`10.0 ± 1.3
`10.4 ± 1.3
`1.8 ± 0.6
`1.7 ± 0.9
`1.74 ± 0.8
`252 ± 259
`212 ± 177
`232 ± 216
`20 ± 7
`22 ± 12
`21.3 ± 10
`
`Peak
`36.3 ± 2.2
`33.5 ± 3.8
`34.8 ± 3.4a
`11.8 ± 0.7
`11.0 ± 1.4
`11.4 ± 1.2a
`2.1 ± 1.0
`2.6 ± 1.4
`2.36 ± 1.3
`988 ± 353a
`885 ± 378a
`931 ± 361a
`40 ± 8a
`35 ± 14a
`37.2 ± 22.1a
`
`Time to peak
`
`6 weeks
`
`5 weeks
`
`5 weeks
`
`4 weeks
`
`6 weeks
`
`6 weeks
`
`2 weeks
`
`2 weeks
`
`2 weeks
`
`2 weeks
`
`2 weeks
`
`2 weeks
`
`1 week
`
`2 weeks
`
`1 week
`
`Group I
`Group II
`Group I/II
`
`6
`
`7
`
`8
`
`9
`
`4 W
`
`5
`eeks
`
`1200
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`ng/mL
`
`Group I
`Group II
`Group I/II
`
`0
`
`2
`
`4
`
`6
`
`Weeks
`
`8
`
`10
`
`0
`
`0
`
`1
`
`2
`
`3
`
`45
`40
`35
`30
`25
`20
`15
`10
`
`50
`
`%
`
`Fig. 1. TSAT response to ferumoxytol.
`
`The only statistically significant change in vital signs
`was a decrease of the mean heart rate in the 4 × 255 mg
`dose group from 73 to 68 following ferumoxytol dosing.
`Routine serum chemistry values (apart from ferritin and
`transferrin saturation) were unchanged in the postdose
`observation period. There were a total of 7 nonserious
`adverse events in 5 patients that were deemed possibly
`related to ferumoxytol; no adverse event was considered
`to be definitely or likely related, and none led to discon-
`tinuation of dosing. These included solitary instances of
`mild constipation a day later (group 1), mild chills an hour
`after dosing (group 2), mild tingling a day after dosing
`(group 1), moderate gastrointestinal upset of presumed
`
`Fig. 2. Ferritin response to ferumoxytol.
`
`viral etiology a day after dosing (group 1), mild delayed
`pruritic, erythematous rash 3 days after dosing (group 2),
`and mild pain at the injection site that resolved after rein-
`sertion of the intravenous line in a different site (group
`2). No adverse event led to discontinuation of dosing.
`
`DISCUSSION
`Ferumoxytol was effective in rapidly increasing mea-
`sures of body iron status (ferritin and transferrin satura-
`tion), in both dosing groups, with a maximal effect seen
`at 1 to 2 weeks. These increases demonstrate that the
`
`Pharmacosmos, Exh. 1012, p. 4
`
`

`
`Spinowitz et al: Ferumoxytol therapy in chronic kidney disease
`
`1805
`
`5-minute period with relative safety, and in a dosage of
`up to 500 mg diluted in 250 to 500 mL over a 2- to 6-hour
`dosing duration [3–5, 12, 17–22]. One small, uncontrolled
`study concluded that a regimen of iron sucrose 500 mg in-
`travenously over a 2-hour duration had an unacceptably
`high rate of adverse effects (e.g., hypotension requiring
`hospitalization) [23]. In contrast, a study evaluating the
`same dosing regimen in peritoneal dialysis patients noted
`no adverse drug effects [18].
`Sodium ferric gluconate has generally been diluted in
`100 mL of 0.9% sodium chloride, at a dose of 125 mg,
`and given intravenously over a 10-minute interval. Re-
`cently, experience has been reported with 250 mg and up
`to 500 mg dosages (not FDA approved), generally given
`at slower administration rates (up to 5 hours). While one
`study concluded that this could be done without appar-
`ent adverse effects [24], others have noted significant
`untoward reactions (e.g., severe nausea/vomiting, hy-
`potension, and syncope) in 10% to 30% of patients with
`this dosing regimen [25, 26]. If our data and experience
`with ferumoxytol are confirmed in larger cohorts, feru-
`moxytol would clearly represent an improvement in the
`logistic aspects of intravenous iron delivery.
`All adverse events considered possibly related to feru-
`moxytol in this open label, uncontrolled study were mild
`to moderate, and qualitatively similar to other iron prepa-
`rations. No adverse event was serious, and none were
`considered definitely or likely related to drug adminis-
`tration. Anaphylaxis and immediate hypotension were
`not observed in this small study, but the number of ex-
`posures is too small to draw any definitive conclusions.
`Other small studies of ferumoxytol in normal subjects,
`hemodialysis patients, and patients undergoing cardio-
`vascular MRI have reported nausea and metallic taste,
`respectively [13; abstract; Jacobs P et al: J AmSoc Nephrol
`14:27A, 2003].
`The current study was of relatively short duration (less
`than 12 weeks), and, thus, was not designed to address
`the question of potential chronic toxicities of ferumoxy-
`tol. With other parenteral iron preparations, the risks of
`increased infection rates and oxidative stress have been
`noted as possible toxicities. A recent review concluded,
`however, that no studies exist that provide reliable con-
`clusions linking parenteral iron therapy and infection in
`dialysis patients [27]. While oxidative stress may be linked
`to cardiovascular morbidity and mortality, careful mon-
`itoring and avoidance of excessive serum ferritin levels
`may minimize this risk [27].
`
`CONCLUSION
`Intravenous ferumoxytol in a dosage of up to 510 mg
`can be given safely as a rapid intravenous bolus. It is ef-
`fective in providing bioavailable iron to increase body
`iron stores, as evidenced by improvements in ferritin and
`
`Group 1
`Group II
`Group I/II
`
`0
`
`1
`
`2
`
`3
`
`4
`Weeks
`
`5
`
`6
`
`7
`
`8
`
`12.00
`
`11.50
`
`11.00
`
`10.50
`
`10.00
`
`9.50
`
`9.00
`
`8.50
`
`Hgb g/dL
`
`Fig. 3. Hemoglobin response to ferumoxytol.
`
`iron contained in ferumoxytol is bioavailable, and is used
`to promote increased hemoglobin synthesis and retic-
`ulocytosis. Ferumoxytol administration was effective in
`stimulating erythropoiesis without a significant increase
`in dosage of hematopoietic hormone therapy, and in pa-
`tients who had “normal” body iron stores (as evidenced
`by the mean serum ferritin concentration of 232 ng/mL
`and mean transferrin saturation of 21%). For the com-
`bined groups there was a mean increase in hemoglobin
`of 1 g/dL, maximally manifested at 6 weeks, while for the
`individual dosing groups there was a similar and paral-
`lel change. This is in keeping with the concept of func-
`tional iron deficiency, seen frequently in patients with
`chronic kidney disease, and which is responsive to ex-
`ogenous iron.
`This study demonstrates that ferumoxytol can be ad-
`ministered as a rapid bolus of 30 mg of iron per second in
`a concentrated form of 30 mg/mL, and in a dosage of up to
`510 mg. In contrast, both iron sucrose and ferric sodium
`gluconate require a much slower rate of administration
`and/or much lower dose, mandating a longer period of
`time and more clinic visits to administer equivalent doses.
`Thus, ferumoxytol has the advantage of requiring fewer
`patient visits and a shorter administration time than these
`commonly used iron therapies, with benefit to the clini-
`cian, ancillary staff, and patient.
`A preparation of iron dextran, which was recalled by
`the FDA in 1990, was the first available parenteral iron
`preparation in the United States. Intravenous infusion
`rates of 100 to 300 mg/min have been reported [15], al-
`though subsequently a maximum rate of 100 mg/minute
`was recommended [16]. Typical dosages reported ranged
`from 500 to 3000 mg, although it is not clear how many of
`the almost 2400 patients actually received (and tolerated)
`the higher dosages/infusion rates. Since serious adverse
`reactions to iron dextran may be induced by relatively
`low doses, it is not possible to accurately describe serious
`adverse reaction rates in this relatively small cohort.
`Iron sucrose has been administered intravenously and
`undiluted in dosages of 100 to 200 mg (5–10 mL) over a
`
`Pharmacosmos, Exh. 1012, p. 5
`
`

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`1806
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`Spinowitz et al: Ferumoxytol therapy in chronic kidney disease
`
`Table 3. Summary of erythropoietin dosing by dose group and time point
`
`Time point
`Descriptive statistics
`
`Baseline
`Mean ± SD
`Day 7 (week 1)
`Mean ± SD
`Change from baseline (mean ± SD)
`Day 14 (week 2)
`Mean ± SD
`Change from baseline (mean ± SD)
`Day 21 (week 3)
`Mean ± SD
`Change from baseline (mean ± SD)
`Day 28 (week 4)
`Mean ± SD
`Change from baseline (mean ± SD)
`Day 35 (week 5)
`Mean ± SD
`Change from baseline (mean ± SD)
`Day 42 (week 6)
`Mean ± SD
`Change from baseline (mean ± SD)
`Day 49 (week 7)
`Mean ± SD
`Change from baseline (mean ± SD)
`Day 56 (week 8)
`Mean ± SD
`Change from baseline (mean ± SD)
`
`4 × 255 mg iron
`N = 10
`7200.0 ± 8066.4
`N = 10
`7000.0 ± 8232.7
`−200.0 ± 632.5
`Not recorded
`
`N = 10
`9245.0 ± 8015.3
`2045.0 ± 5590.5
`N = 10
`7745.0 ± 8219.6
`545.0 ± 8788.5
`N = 10
`7745.0 ± 8219.6
`545.0 ± 8788.5
`N = 10
`4745.0 ± 6689.6
`−2455.0 ± 6479.3
`N = 10
`4745.0 ± 6689.6
`−2455.0 ± 6479.3
`N = 10
`6795.0 ± 6467.3
`−405.0 ± 5019.0
`
`Ferumoxytol
`2 × 510 mg iron
`N = 11
`6272.7 ± 9381.8
`N = 11
`4090.9 ± 7435.8
`−2181.8 ± 12944.6
`N = 9
`6111.1 ± 9360.1
`−1555.6 ± 9043.1
`N = 9
`3888.9 ± 7912.7
`−2666.7 ± 8000.0
`N = 11
`5000.0 ± 8729.3
`−1272.7 ± 8112.8
`N = 7
`4428.6 ± 7345.2
`−2000.0 ± 10392.3
`N = 10
`3000.0 ± 6342.1
`−1500.0 ± 8527.7
`N = 9
`4444.4 ± 6839.4
`−555.6 ± 9837.6
`N = 6
`3333.3 ± 8165.0
`−2333.3 ± 11343.1
`
`Total
`N = 21
`6714.3 ± 8574.0
`N = 21
`5476.2 ± 7769.3
`−1238.1 ± 9219.0
`N = 10
`5500.0 ± 9033.9
`−1400.0 ± 8540.1
`N = 19
`6707.9 ± 8215.8
`−186.8 ± 7064.9
`N = 21
`6307.1 ± 8395.0
`−407.1 ± 8278.3
`N = 17
`6379.4 ± 7814.5
`−502.9 ± 9252.7
`N = 20
`3872.5 ± 6407.1
`−1977.5 ± 7387.4
`N = 19
`4602.6 ± 6571.8
`−1555.3 ± 8059.3
`N = 16
`5496.9 ± 7093.2
`−1128.1 ± 7676.8
`
`transferrin saturation, and in raising hemoglobin levels in
`anemic CKD patients. Compared with other parenteral
`iron preparations, it may provide efficiencies of time,
`and perhaps cost, for patients and clinicians. Definitive
`conclusions, including chronic toxicities, will be drawn
`based upon the results of larger clinical trials, currently
`in progress.
`
`ACKNOWLEDGMENTS
`This study was funded by Advanced Magnetics Incorporated,
`Cambridge, MA. Part of this work was presented at the 37th Annual
`Meeting of the American Society of Nephrology, San Diego, November
`2003.
`
`Reprint requests to Michael H. Schwenk, PharmD, The New York
`Hospital Medical Center of Queens, Division of Nephrology and Hyper-
`tension, 56–45 Main Street, Flushing, NY 11355.
`E-mail: mhschwen@nyp.org
`
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