FDA Advisory Committee Briefing Document
`
`Drug Safety and Risk Management Committee
`February 1, 2008
`
`Prepared by the Division of Medical Imaging and Hematology Products/Office of
`Oncology Drug Products/Office of New Drugs
`Consultative assistance from the Office of Clinical Pharmacology and the Office of
`Biostatistics
`
`New Drug Application (NDA) 22-054 for Injectafer (Ferric Carboxymaltose) for the
`treatment of iron deficiency anemia in patients with heavy uterine bleeding or
`postpartum patients
`
`Table of Contents
`
`Topics for discussion
`Executive summary
`Background
` Medical summary
` Clinical pharmacology summary
` Biometrics review
`Publication: Amanzadeh, J, Reilly, R. Hypophosphatemia: an
`evidence-based approach to its clinical consequences and management.
`Nature Clinical Practice Nephrology 2: 136-147; 2006.
`
`Page
`2
`3
`
`7
`50
`54
`
`64
`
`Pharmacosmos, Exh. 1013, p. 1
`
`

`

`Topics for Questions for Advisory Committee Members:
`
`1. The committee will be asked to discuss the importance of the mortality data in the
`Injectafer clinical development program.
`
`2. Based upon considerations of the overall risks and benefits of Injectafer, FDA plans to
`request advice regarding marketing approval of the drug for the proposed indication.
`
`3. FDA anticipates the marketing approval discussion to involve considerations of:
`the need for additional clinical studies (either prior to approval or as a post-
`(cid:120)
`marketing commitment),
`a risk management plan,
`(cid:120)
`(cid:120) modification of the proposed indication or dosage regimen to enhance safety.
`
`2
`
`Pharmacosmos, Exh. 1013, p. 2
`
`

`

`Executive Summary
`
`1. Product Background:
`Injectafer (Ferric Carboxymaltose, from Luitpold Pharmaceuticals, Inc.) is the subject of
`a New Drug Application (NDA) for the indication of, "treatment of iron deficiency
`anemia in: heavy uterine bleeding (or) postpartum patients."
`
`The proposed market population includes patients who might otherwise receive oral iron
`as a treatment option. Consequently, the bulk of the clinical data assessing Injectafer
`safety and efficacy were obtained from studies that compared Injectafer to oral iron.
`Injectafer is not specifically proposed for use as an alternative to other parenteral iron
`products or for patients who are intolerant of oral iron.
`
`The Injectafer dosage regimen allows potentially a full iron replenishment dosage with
`three or fewer intravenous administrations, contingent upon the body's estimated iron
`deficit and certain limits upon a single dosage. Specifically, the dose is determined by
`calculating the total iron requirement and dividing this total amount into one or more
`single dose(s). The proposed dose regimen allows for the rapid intravenous (IV) push
`injection (single dose (cid:148) 500 mg) or IV infusion of up to a maximum dose of 1,000 mg (or
`15 mg/kg) for the first dose. The maximum single doses may be administered every
`seven days until the total iron requirement has been administered or a maximum of 2,500
`mg has been administered. Consequently, a "cycle" may be viewed as consisting of the
`weekly dosage regimens that delivered the full iron replacement dose or a maximum of
`2,500 mg iron.
`
`2. Clinical and Drug Class Background
`Iron deficiency anemia, one of the most common forms of anemia, is generally due to the
`loss of body iron during hemorrhage or insufficient iron intake. In addition to treatment
`of the underlying cause of iron deficiency anemia (such as correction of bleeding), iron
`replenishment helps normalize blood hemoglobin levels and potentially lessen the
`duration or severity of anemia symptoms.
`
`Many clinical situations are associated with the development of iron deficiency anemia,
`such as chronic hemodialysis, gastrointestinal hemorrhage due to various lesions,
`pregnancy and the postpartum condition, inflammatory bowel disease as well as
`hemorrhage due to uterine bleeding. The pathophysiology of the anemia in many of
`these considerations involves the interaction of multiple factors, such as hemorrhage,
`nutrition and malabsorption. The Injectafer clinical development program examined the
`use of the product in patients with iron deficiency anemia associated with chronic kidney
`disease (including patients undergoing hemodialysis), inflammatory bowel disease, heavy
`uterine bleeding as well as post-partum iron deficiency.
`
`Iron replenishment may be necessary only for a short period of time; for example,
`following a single hemorrhage episode. Alternately, iron replenishment may be
`necessary over a long period of time due to on-going iron losses, as may occur with low-
`grade, recurrent hemorrhage. The Injectafer clinical development program for the
`
`3
`
`Pharmacosmos, Exh. 1013, p. 3
`
`

`

`proposed indication generally focused upon the short term replacement of iron (through a
`maximum of a 2,500 mg iron deficit). Clinical data supporting the safety and efficacy of
`repeat Injectafer "cycles" were supplied from studies of patients with chronic kidney
`disease, a market population not currently cited in the proposed Injectafer indication.
`
`While oral iron is probably the most common iron replacement product for the broad
`population of patients with iron deficiency, three iron products are currently marketed for
`intravenous use among some patients with iron deficiency anemia. These products
`consist of:
`
`a. Iron dextran (for example, Dexferrum®, InFed®), indicated for patients with iron
`deficiency anemia (any cause) "in whom oral administration [of iron] is unsatisfactory or
`impossible."
`
`b. Ferric gluconate (Ferrlecit®), indicated for patients with iron deficiency anemia who
`are undergoing chronic hemodialysis and receiving erythropoietin therapy.
`
`c. Iron sucrose (Venofer®), indicated for patients with iron deficiency anemia who are:
`
`-non-dialysis dependent chronic kidney disease patients (receiving an
`
`
`
`erythropoietin or not)
`
`-hemodialysis dependent chronic kidney disease patients receiving an
`
`
`erythropoietin
`
`-peritoneal dialysis dependent chronic kidney disease patients receiving an
`
`
`erythropoietin.
`
`
`
`3. Dosage Considerations:
`The maximum iron dose for administration at any one time (single dose) for most
`currently marketed parenteral iron products is generally 200 mg or less. However,
`Venofer is approved for use as a maximum of a 400 mg single dose administration to
`certain patients undergoing peritoneal dialysis. The maximum Venofer (single) dose is
`limited to 200 mg in other patient populations.
`
`If approved, Injectafer would be relatively unique among the parenteral iron products in
`that the maximum (single) Injectafer dose is 1,000 mg (or 15 mg/kg).
`
`4. Efficacy Data:
`The major efficacy outcomes in the Injectafer clinical development program related to
`detection of change in blood hemoglobin concentrations. In general, the studies enrolled
`patients with iron deficiency anemia and used changes in hemoglobin concentrations as
`the primary efficacy endpoints. The endpoints compared either the proportions of
`patients achieving a pre-specified definition of anemia correction or a comparison of the
`change in hemoglobin value between baseline and a pre-specified time point.
`
`The studies were not designed sufficiently to meaningfully assess potential clinical
`benefits beyond changes in hemoglobin concentration. For example, most studies were
`
`4
`
`Pharmacosmos, Exh. 1013, p. 4
`
`

`

`open label such that unbiased assessment of any changes in "health-related quality of life"
`in these studies is impossible due to knowledge of the treatment assignment.
`
`The efficacy studies consistently showed that Injectafer administration increased blood
`hemoglobin concentrations. Hence, the supplied data provide substantial evidence of the
`efficacy of Injectafer in iron replenishment.
`
`5. Safety
`The major safety concern from the clinical development program relates to a mortality
`safety signal as evidenced by three notable findings, as listed below.
`
`a. An imbalance in death rates:
`
`In the entire clinical development program, death occurred among 10 patients who
`received Injectafer while one death occurred among a patient who received a control drug
`(Venofer). Five of the 10 deaths among patients receiving Injectafer appeared to relate to
`a cardiac abnormality.
`
`Studies in the development program varied in design, including the use of a 1:1
`randomization for several controlled studies, a randomized cross-over design (placebo-
`Injectafer) for one major study, an uneven randomization ratio in some controlled studies
`as well as uncontrolled studies. Nevertheless, the deaths among patients receiving
`Injectafer were distributed among multiple studies.
`
`Within the pool of randomized, controlled studies (that included a placebo-controlled,
`randomized, cross-over study), six deaths occurred among patients in the Injectafer group
`and one death in a patient treated with Venofer. Exclusive of the randomized, cross-over
`study, deaths in randomized, controlled studies consisted of 5/1206 (0.4%) for Injectafer
`and 1/994 (0.1%) for the control iron product.
`
`b. An imbalance in reports of serious adverse events, especially serious cardiac
`events:
`
`Within the pool of active-controlled, multicenter studies, a serious adverse event was
`reported by 43/1206 (3.6%) of Injectafer-treated patients and 21/834 (2.5%) of patients
`receiving oral iron (control product). Serious "cardiac" events were reported in 13/1206
`(1.1%) of Injectafer-treated patients and 3/834 (0.4%) of patients receiving oral iron
`(control product).
`
`c. An imbalance in the occurrence of "clinically important" hypophosphatemia
`
`Serum phosphorus was not measured rigorously in all clinical studies. However, data are
`available for the proposed market population. Specifically, 8% of postpartum patients
`and 70% of heavy uterine bleeding patients experienced "clinically important
`hypophasphatemia" following Injectafer administration. "Clinically important"
`hypophaphatemia was not reported among patients receiving oral iron. "Clinically
`
`5
`
`Pharmacosmos, Exh. 1013, p. 5
`
`

`

`important" hypophasphatemia was defined as a serum phosphate concentration < 2
`mg/dL.
`
`Hence, the mortality safety signal is not based upon statistical comparisons. Instead, the
`clinical pattern of a numeric imbalance in mortality, combined with imbalances in serious
`adverse events (especially cardiac events) and clinically important hypophosphatemia
`suggest that the proposed Injectafer dose regimen may be associated with important
`safety concerns.
`
`6. Purpose of the Advisory Committee Discussion
`The Advisory Committee is convened to provide an independent assessment of the
`importance, if any, of the mortality safety signal detected in the Injectafer clinical
`development program. FDA anticipates asking the Committee to address topics related
`to the market approval of the product as well as considerations of additional clinical
`studies, potential dose modifications and potential alterations of the proposed indication.
`
`The Committee discussion is a component of the regulatory review of the Injectafer
`NDA. The NDA was originally submitted to FDA in June, 2006 with a proposed
`indication related to use of the product among four groups of iron deficient patients:
`-heavy uterine bleeding
`-postpartum
`-inflammatory bowel disease
`-hemodialysis patients.
`
`The original FDA review of the application culminated in issuance of a non-approvable
`letter related predominantly to the mortality safety signal. In response to the FDA letter,
`in September, 2007, the sponsor submitted a statistical assessment of the mortality data,
`study reports for two additional studies performed among patients with chronic kidney
`disease and responses to FDA questions. The proposed indication was also changed (in
`November, 2007) to indicate Injectafer only for patients with iron deficiency anemia in
`the post-partum condition or patients with heavy uterine bleeding.
`
`In general, the sponsor does not concur with the FDA concern regarding a mortality
`safety signal and the proposed product label does not address the mortality finding. The
`Advisory Committee is convened to independently assess the clinical data and
`specifically, the data pertinent to assessment of a mortality safety signal.
`
`6
`
`Pharmacosmos, Exh. 1013, p. 6
`
`

`

`Medical Summary Document
`This summary consists of the most pertinent components of the medical officer's draft
`review document
`December 28, 2007
`In this document, Injectafer is sometimes referred to by other names used during the
`clinical development program (Ferinject, FCM or Vit-45).
`
`7
`
`Pharmacosmos, Exh. 1013, p. 7
`
`

`

`Table of Contents
`
`1 Executive Summary................................................................................................................. 10
`2 Backgroud Information........................................................................................................... 13
`2.1 Product Information ............................................................................................................ 13
`2.2 Proposed Indication............................................................................................................. 13
`2.3 Proposed Dose Regimen ..................................................................................................... 13
`3 Clinical Studies......................................................................................................................... 14
`3.1 Table of Clinical Studies..................................................................................................... 14
`3.2 Major Inclusion Criteria and Study Treatment ................................................................... 15
`4 Efficacy Findings...................................................................................................................... 17
`4.1 In Women With Heavy Uterine Bleeding............................................................... ………17
`4.2 In Women With Post-Partum Anemia ................................................................................ 18
`5 Safety Findings......................................................................................................................... 20
`5.1 Extent Of Exposure............................................................................................................. 22
`5.2 Demographic Characteristics .............................................................................................. 23
`5.3 Deaths ................................................................................................................................. 24
`5.4 Serious Cardiac Events ....................................................................................................... 35
`5.5 Hypophosphatemia.............................................................................................................. 41
`5.6 Hypersensitivity Reactions ................................................................................................. 44
`5.7 Adverse Events Leading To Premature Discontinuation Of Study Drug ........................... 45
`5.8 Common Adverse Events ................................................................................................... 47
`6 Overall Assessment .................................................................................................................. 48
`6.1 Efficacy ............................................................................................................................... 48
`6.2 Safety................................................................................................................................... 48
`
`8
`
`Pharmacosmos, Exh. 1013, p. 8
`
`

`

`AE
`ALT
`b.w.
`CAD
`CHF
`CKD
`CI
`CRF
`CRP
`C-section
`CTCAE
`dL
`ECG/EKG
`EPO
`ESRD
`FCM
`Fe[III]
`FeS04
`G
`GFR
`GI
`GGT
`Hb
`HD
`Hct
`HUB
`IBD
`ICM
`IDA
`IND
`IRB
`ITT
`IV
`L
`LFT
`Mg
`MI
`MITT
`mL
`NaCl
`NDA
`ng
`NSS
`NYHA
`PP
`r-HuEPO
`RBC
`SAE
`SD
`TIBC
`TID
`TSAT
`VIT-45
`WBC
`
`LIST OF ABBREVIATIONS
`Adverse event
`Alanine aminotransferase
`Body weight
`Coronary artery disease
`Congestive heart failure
`Chronic Kidney Disease
`Confidence Interval
`Case report form
`C-reactive protein
`Cesarean Section
`Common Toxicity Criteria for Adverse Event
` Deciliter
`Electrocardiogram
`Erythropoietin
`End Stage Renal Disease
`Ferric carboxymaltose
`Ferric Iron
`Ferrous Sulfate
`Gram
`Glomerular filtration rate
`Gastrointestinal
`Gamma-glutamyl transpeptidase
`Hemoglobin
`Hemodialysis
`Hematocrit
`Heavy uterine bleeding
`Inflammatory Bowel Disease
`Iron Carboxymaltose
`Iron Deficiency Anemia
`Investigational New Drug
`Institutional Review Board
`Intent-To-Treat
`Intravenous
`Liter
`Liver function test
`Milligram
`Myocardial infarction
`Modified Intent to Treat
`Milliliter
`Sodium chloride
`New Drug Application
`Nanogram
`Normal Saline Solution
`New York Heart Association
`Per Protocol
`Recombinant human erythropoietin
`Red blood cell
`Serious adverse event
`Standard Deviation
`Total iron binding capacity
`Three times daily
`Transferrin saturation
`Ferinject/Injectafer
`White Blood Cell
`
`9
`
`Pharmacosmos, Exh. 1013, p. 9
`
`

`

`1. EXECUTIVE SUMMARY
`
`Injectafer (Ferinject) is a Type I polynuclear iron (III)-hydroxide carbohydrate complex
`being developed as an intravenous iron product for treatment of iron deficiency anemia.
`The currently proposed indication is the treatment for iron deficiency anemia in patients
`with heavy uterine bleeding or post-partum patients with iron deficiency anemia. The
`proposed dose regimen is 1,000 mg as a single maximum dose weekly until
`administration of the total calculated iron requirement or a maximum total cumulative
`dose of 2,500 mg is reached.
`
`Multiple clinical studies were performed during the Injectafer development program
`although four randomized controlled studies are especially pertinent to support the
`proposed indication for the treatment of iron deficiency anemia in women with heavy
`uterine bleeding (one study) or post-partum anemia (three studies). Of these four studies,
`efficacy results from two studies showed superiority of Injectafer to oral iron and two
`studies showed non-inferiority to oral iron. The supplied data indicates that Injectafer
`administration results in iron replenishment with improvement in blood hemoglobin
`concentrations.
`
`The integrated review of safety included the results from 14 completed clinical studies.
`A total of 2080 patients in completed clinical studies were exposed to Injectafer
`treatment. In these studies, 1571 patients received the control treatments, including 834
`who received oral iron product, 145 who received Venofer (iron sucrose) and 592 who
`received placebo (in a cross-over study and a single dose safety study).
`
`The safety review raised concerns for Injectafer due to evidence of a mortality signal. Of
`note, the clinical development program was not designed to thoroughly assess mortality
`due to the relatively small database sample size (given the overall low mortality rate) and
`the study design features. For example, more subjects were exposed to Injectafer than a
`control drug since randomization was not consistently one to one. Nevertheless, the
`overall imbalance and pattern of mortality raises concerns.
`
`The evidence of a mortality safety signal is based upon the numeric imbalance in deaths
`from a database insufficiently sized to rule out an important mortality risk for Injectafer
`as well as imbalances in serious adverse event rates (especially for cardiac events) and
`the excessive rate of hypophosphatemia among subjects receiving Injectafer.
`
`The clinical database for Injectafer is open to multiple interpretations as to which studies
`should be classified among the "randomized, controlled studies" as well as to how the
`data should be analyzed based upon comparisons to oral iron or Venofer. Hence, in
`presentations, the sponsor and FDA may occasionally refer to data presentations that
`differ based upon differences in data pooling, data interpretation and the approach to
`summarization of the data.
`
`Mortality
`
`10
`
`Pharmacosmos, Exh. 1013, p. 10
`
`

`

`There were 10 deaths in Injectafer-treated patients as compared to one death in the
`control patients in all completed clinical studies. The 10 deaths in Injectafer-treated
`patients consisted of: one postpartum woman, one patient with inflammatory bowel
`disease, three patients undergoing chronic hemodialysis, four patients with non-dialysis
`dependent chronic renal failure, and one patient with multi-factorial iron deficiency
`anemia.
`
`In randomized studies, six deaths were reported in Injectafer-treated patients and one
`death was reported in a control patient (a nominal rate of 0.33% vs. 0.06%). These
`randomized studies include a cross-over study (Study VIT05006) in which subjects were
`randomized between Injectafer and placebo, followed by the complimentary treatment
`one week later (one death occurred after "cross-over" to Injectafer in this study). Some
`analyses may eliminate this study from the group of "randomized, controlled" studies,
`given the cross-over nature of the study. In this situation, the data would be described as
`showing five deaths in the Injectafer group in "randomized, controlled" studies and one
`death in a control group.
`
`Five of the six deaths among Injectafer-treated patients in randomized studies occurred in
`studies using the proposed first-dose 1,000 mg dose regimen. Four of these five patients
`received a single 1,000 mg dose and one patient received an initial 1,000 mg dose
`followed by lower subsequent doses.
`
`Among the 10 Injectafer-treated patients who died, five had received a single dose of
`Injectafer (four received 1,000 mg and one received 200 mg) and five received two or
`more doses of Injectafer. The events leading to nine of 10 deaths occurred within 32
`days of the last Injectafer administration. The sponsor had clinical information reviewed
`by external reviewers to determine the "cause" of death. Nevertheless, determination of
`the "cause" of a death is commonly difficult or impossible and all putative "causes" of
`death are suspect. The FDA review team nominally assessed the "causes" of deaths to
`include five cardiac disorders (two cardiac arrests, one anterior myocardial infarction,
`one heart failure and one cardiac insufficiency), three infections (two cases of sepsis, one
`bowel abscess and perforation), one gastrointestinal bleeding and one motor-vehicle
`accident.
`
`Serious adverse events, especially "cardiac" events
`
`Within the pool of active-controlled, multicenter studies, a serious adverse event was
`reported by 3.6% of Injectafer-treated patients and 2.5% of patients receiving oral iron
`(control product). Serious "cardiac" events were reported in 1.1% of Injectafer-treated
`patients and 0.4% of patients receiving oral iron (control product).
`
`In general, the data pool especially pertinent to consideration of marketing approval
`consists of the group of controlled studies that examined the 1,000 mg (maximum) first
`dose Injectafer regimen. Within this data pool, the occurrence of serious adverse event as
`well as serious "cardiac" events was also unbalanced, with numerically more events
`among patients receiving Injectafer.
`
`11
`
`Pharmacosmos, Exh. 1013, p. 11
`
`

`

`Hypophosphatemia
`
`Serum phosphate decreased in Injectafer-treated patients as compared to oral iron-treated
`patients in the six clinical studies where serum phosphate levels were measured. The
`incidence of hypophosphatemia varied among the studies but the overall pattern indicates
`that Injectafer administration was associated with an increased risk of clinically
`significant hypophosphatemia, compared to control products. For example, 8% of
`postpartum and 70% of heavy uterine bleeding patients reached a nadir serum phosphate
`of < 2.0 mg/dL. The phosphate nadirs in the heavy uterine bleeding patients occurred at a
`median of 15 days and recovered at a median of 18 days.
`
`12
`
`Pharmacosmos, Exh. 1013, p. 12
`
`

`

`2. BACKGROUND INFORMATION
`
`2.1 Product Information
`
`Injectafer (Ferinject) is a Type I polynuclear iron (III)-hydroxide carbohydrate complex
`being developed as an intravenous iron product for treatment of iron deficiency anemia.
`
`Current available treatment for iron deficiency anemia includes oral iron products and
`intravenous iron products. Approved intravenous iron products include iron dextran,
`Ferrlecit (ferric gluconate) and Venofer (iron sucrose). With respect to the dose regimen
`for these other intravenous iron products, the generally recommended maximum single
`dose is 100 mg of elemental iron for iron dextran, 125 mg of elemental iron for Ferrlecit,
`and up to 400 mg for Venofer. Hence, the proposed maximum single dose of Injectafer
`(1,000 mg) is more than twice that of any currently approved intravenous iron product.
`
`2.2 Proposed Indication
`
`In the original NDA submission dated June 15, 2006, the proposed indication was the
`treatment of iron deficiency anemia in patients with heavy uterine bleeding, post-partum
`anemia, inflammatory bowel disease and hemodialysis. However, on November 14,
`2007, the sponsor revised the proposed indication to the treatment of iron deficiency
`anemia in women with heavy uterine bleeding or post-partum patients with iron
`deficiency anemia. Despite the alteration of the proposed indication to a more narrow
`population of patients who may be healthier and less likely to need repeat "cycles" of
`Injectafer iron replenishment, FDA maintains that the totality of the clinical data from the
`development program are important to the assessment of Injectafer's risks and benefits.
`
`2.3 Proposed Dose Regimen
`
`Injectafer is administered intravenously either by rapid intravenous (IV) push injection or
`by IV infusion. The dose is determined by calculating the total iron requirement and
`dividing this total amount into one to three doses.
`
`Total iron requirement (cumulative dose) in mgs: Patient weight in kg x (15 – current Hb
`g/dL) x 2.4 + 500. Maximum total dose not to exceed 2,500 mg.
`If patient is postpartum use pre-pregnancy weight
`(cid:120)
`If TSAT > 20% and ferritin > 50 ng/mL subtract 500 mg
`(cid:120)
`(cid:120) Round dose to nearest 100 mg
`
`Maximum single dose must not exceed 15 mg/kg per dose or 1,000 mg, whichever is
`lower. The single doses should be administered every 7 days until the total iron
`requirement or a maximum of 2,500 mg is reached.
`600 to 1,000 mg doses: Dilute in 250 mL of 0.9% Sodium Chloride, USP and
`(cid:120)
`administer by IV infusion over (cid:149) 15 minutes or undiluted IV push injection
`over 15 minutes
`(cid:120) < 500 mg doses: Administer undiluted by IV push injection at 100 mg per
`minute
`
`13
`
`Pharmacosmos, Exh. 1013, p. 13
`
`

`

`The sponsor's proposed label provides no specific recommendations regarding the
`Injectafer dosage for patients who may develop iron deficiency anemia following iron
`replenishment with a first "cycle" of Injectafer. Conceivably, additional "cycles" of
`Injectafer would be administered to these patients.
`
`Repeat "cycle" data were supplied from studies conducted among patients with iron
`deficiency anemia who also had chronic kidney disease. Repeat "cycle" data have not
`been supplied for other patient populations, including women with heavy uterine bleeding
`and iron deficiency anemia or women with post-partum iron deficiency anemia.
`
`3. CLINICAL STUDIES
`
`3.1 Table of Clinical Studies
`
`Fourteen clinical studies were completed to support the safety and efficacy of Injectafer
`for the indication for the treatment of iron deficiency anemia. The following table lists
`all completed clinical studies.
`
`Summary of completed clinical studies
`Studies
`Type of
`Injectafer
`studies
`group
`
`Study
`Populations
`
`Heavy Uterine
`Bleeding
`
`Post-partum
`Anemia
`
`Inflammatory
`Bowel Disease
`
`1VIT04002/
`1VIT04003
`
`VIT-IV-CL-
`009
`
`Randomized, open-
`label, parallel
`group, superiority
`study
`1VIT03001 Randomized, open-
`label, parallel
`group, non-
`inferiority study
`Randomized, open-
`label, parallel
`group, non-
`inferiority study
`1VIT06011 Randomized, open-
`label, parallel
`group, superiority
`study
`Randomized, open-
`label, parallel
`group, non-
`inferiority study
`Single arm,
`baseline-controlled
`study
`
`VIT-IV-CL-
`008
`
`VIT-IV-CL-
`003
`
`Control
`group
`
`231
`(oral iron)
`
`179
`(oral iron)
`
`118
`(oral iron)
`
`148
`(oral iron)
`
`63
`(oral iron)
`
`246
`
`182
`
`231
`
`143
`
`137
`
`46
`
`none
`
`Total
`patients
`enrolled
`477
`
`361
`
`349
`
`291
`
`200
`
`46
`
`14
`
`Pharmacosmos, Exh. 1013, p. 14
`
`

`

`Hemodialysis
`
`Non-dialysis
`Dependent chronic
` kidney disease
`
`Iron deficiency
`anemia
`(For safety only)
`
`Chronic heart
`failure
`
`Single dose, PK
`and safety study
`
`VIT-IV-CL-
`001
`
`Single dose, PK and
`safety study
`
`1VIT05006 Single dose, cross-
`over safety study
`Pilot, randomized,
`double-blind,
`controlled study
`
`FER-CARS-
`01
`
`VIT-IV-CL-
`015
`
`Randomized, open-
`label, parallel group
`study
`VIT-53214 Single arm,
`baseline-controlled
`study
`1VIT04004 Randomized, open-
`label, parallel group
`study
`Single arm,
`treatment extension
`safety study
`
`1VIT05005
`(extension
`of
`1VIT04004)
`VIT-IV-CL-
`02
`
`119
`
`162
`
`147
`
`127
`
`24
`
`6
`
`584
`
`30
`
`119
`(Venofer)
`
`none
`
`103
`
`none
`
`8
`(Placebo)
`
`-
`
`569
`(Placebo)
`27
`(Venofer)
`15
`(placebo)
`
`238
`
`162
`
`250
`
`127
`
`32
`
`6
`
`72
`
`3.2 Major Inclusion Criteria and Study Treatment
`
`The following table shows the major inclusion criteria and study treatment in each study.
`
`Major inclusion criteria and study treatment
`
`Study
`populations
`
`Heavy Uterine
`Bleeding
`
`Post-partum
`Anemia
`
`Studies
`
`Major inclusion criteria
`
`Study treatment and duration
`
`1VIT04002/ Hb (cid:148)11.4 g/dL and 2
`1VIT04003
`mean Hb (cid:148)11.0 g/dL
`TSAT (cid:148)25%.
`Ferritin (cid:148)100 ng/mL.
`History of heavy uterine
`bleeding within the past 6
`months
`1VIT03001 Hb (cid:148)10.0 g/dL
`TSAT (cid:148)50%.
`Ferritin (cid:148)500 ng/mL.
`
`Injectafer:
`Total (cumulative) dose=
`weight (kg) x (15- hemoglobin [g/dL]) x
`2.4 + 500 mg
`If TSAT >20% and Ferritin >50 ng/mL
`subtract 500 mg
`Maximum single dose: 1000 mg
`Maximum cumulative dose: 2,500 mg
`
`Administration:
`
`15
`
`Pharmacosmos, Exh. 1013, p. 15
`
`

`

`VIT-IV-CL-009
`
`Within 10 days of
`delivery
`Hb (cid:148)10.5 g/dL
`Within 6 days of delivery
`
`200 mg: undiluted IV push over 1-2
`minutes
`300-400 mg: in 100 cc NS over 6 minutes
`500-1,000 mg: in 250 cc NS over 15
`minutes
`
`1VIT06011 Hb (cid:148)10.0 g/dL
`TSAT (cid:148)25%.
`Ferritin (cid:148)100 ng/mL.
`Within 10 days of
`delivery
`
`Inflammatory
`Bowel Disease
`
`VIT-IV-CL-008Hb (cid:148)11.0 g/dL
`TSAT <20%.
`Ferritin <100 ng/mL.
`
`VIT-IV-CL-
`003
`
`Iron deficiency anemia
`with a calculated total
`iron requirement (cid:149)1000
`mg
`
`Hemodialysis
`
`VIT-IV-CL-015Hb (cid:148)11.5 g/dL
`TSAT <20%.
`Ferritin <200 ng/mL.
`
`VIT-53214 hemodialysis associated
`anemia
`1VIT04004 Hb (cid:148)11 g/dL
`TSAT <25%.
`Ferritin <300 ng/mL.
`
`Non-dialysis
`dependent chro
` kidney disease
`
`Oral iron:
`Ferrous sulfate 325 mg three times a day
`for 6 weeks for Studies 1VIT4002/04003
`and 1VIT03001
`
`Ferrous sulfate 100 mg twice daily for 12
`weeks for Study VIT-IV-CL-009
`Same as Study 1VIT04002/04003 and
`1VIT03001 except for administration:
`<500 mg: undiluted as a slow IV injection
`at a rate of 100 mg/minute
`600-1000 mg: either undiluted as slow IV
`injection over 15 minutes or as an IV
`infusion diluted in 250 cc NSS over 15
`minutes
`Injectafer: same as 1VIT04002/04003
`Oral iron:
`Ferrous sulfate 100 mg twice daily for 12
`weeks
` Injectafer:
`500 mg/weekly x 4 doses or
`1000 mg weekly x 2 doses
`Diluted in 250 cc NSS and infusion over
`15 minutes
`Injectafer or Venofer:
`Total dose=weight (kg) x (15- hemoglobin
`[g/dL]) x 2.4 + 500 mg
`Administered 200 mg as undiluted directly
`into dialysis line two or three times
`weekly during hemodialysis
`Injectafer: same as Study VIT-IV-CL-015
`
`Day 0: 1000 mg
`Day 17 and 31: 500 mg if TSAT <30%
`and ferritin <500 ng/mL
`
`Administration:
`201-500 mg: in 100 cc NS over 15
`minutes
`501-1,000 mg: in 250 cc NS over 15
`minutes
`
`Oral iron:
`Ferrous sulfate 325 mg three times daily
`
`16
`
`Pharmacosmos, Exh. 1013, p. 16
`
`

`

`Iron deficiency
`anemia
`(for safety
`only)
`
`Chronic heart
`failure
`
`for 8 weeks
`Enrolled in 1VIT04004 1000 mg if TSAT<25% and ferritin <300
`ng/mL
`500 mg if TSAT<30% and ferritin <500
`ng/mL
`Injectafer:
`1000 mg single dose
`
`Placebo
`
`Injectafer or Venofer:
`200 mg weekly until total calculated dose
`was reached.
`
`1VIT05005
`(