CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203565Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`Clinical Pharmacology
`NDA
`
`203-565
`
`
`
`Submission Date:
`
`30 September 2011; 21 June 2012
`
`INJECTAFER®
`Brand Name:
`
`
`Generic Name:
`
`Ferric carboxymaltose
`
`
`
`Formulation:
`solution for injection
`OCP Reviewers:
`
`Bahru A Habtemariam, Pharm.D.
`
`OCP Acting Team Leader:
`Bahru A Habtemariam, Pharm.D.
`OCP Division:
`
`
`Division of Clinical Pharmacology V
`ORM Division:
`
`
`Division of Drug Hematology Products
`Sponsor:
`
`
`
`Luitpold
`Submission Type; Code:
`
`NDA, Original
`Dosing regimen:
`15 mg/kg up to a maximum single dose of 750 mg
`of iron on two occasions separated by at least 7 days
`up to a cumulative dose of 1500 mg of iron 750 mg
`Iron Deficiency Anemia (IDA)
`
`Indications
`
`NDA 203-565 for Injectafer (Ferric carboxymaltose (FCM)) is a new application for a
`previous NDA (#22-054) that received a complete response on July 9, 2007 due to safety
`issues. NDA 22-054 was submitted on June 15, 2006 but was not approved because 10
`deaths were reported among subjects exposed to FCM while no deaths were reported
`among subjects exposed to comparator iron replacement products.
`
`The clinical pharmacology aspects of FCM were reviewed previously and are available in
`DARRTS (C John, 5/30/2007). The clinical pharmacology aspects of the NDA were
`found to be acceptable during the original NDA 22-054 submission and no specific
`clinical pharmacology studies were requested.
`
`In the current NDA submission, the sponsor conducted two phase three clinical studies to
`address the safety issues outlined in the complete response letter for NDA 22-054. No PK
`data were submitted with the new NDA (NDA 203-565) submission. However, it was
`brought to the attention of our division that previously submitted (06/15/2006) breast
`milk PK data collected among nursing mothers who took part in study VIT-IV-CL-009
`were not reviewed. On the other hand, the findings of the breast milk PK study were
`described in section 8.3 of the proposed labeling. Electronic copy of study VIT-IV-CL-
`009 report was submitted on 6/21/2012 for review by the agency.
`
`This review summarizes results of the breast milk PK sub-study that was conducted as
`part of study VIT-IV-CL-009. Study VIT-IV-CL-009 was a multi-centre, controlled,
`phase 3 clinical trial that compared the safety and efficacy of intravenous infusions of
`FCM (n=227) and ferrous sulfate (n=117) in women with post-partum anemia (N= 344).
`Patients received three doses of either up to 1000 mg of FCM, given via IV infusion, or
`200 mg of iron sulfate. See Appendix 1 for details of the study design. As part of study
`VIT-IV-CL-009, the sponsor conducted a breast milk PK sub-study where iron levels
`
`Reference ID: 3149371
`
`

`

`were measured in breast milk following treatment with either FCM or ferrous sulfate
`(n=25).
`
`Breast milk sample collection was performed manually during a two week treatment
`period. Approximately 2-4 mL (minimum 2 mL) of breast milk was collected from
`patients in both treatment groups at each of the following time-points:
`
`0 Week 0: Pre-dose, l to 3 hours, 24i3 hours and 48i3 hours post-dose
`. Week 1: Pre-dose and l to 3 hours post—dose
`0 Week 2: Pre-dose
`
`At each of these time—points, patients participating in this sub-study were asked to
`breast-feed their children, or use a breast pump to empty their breast, prior to infusion of
`VIT-45 or ingestion of oral ferrous sulfate. All post-dose breast milk samples were
`collected at the start of a feeding period, if possible.
`
`Results:
`
`Breast milk iron level data were available from 25 subjects; 11 following FCM
`treatment and 15 following iron sulfate treatment. Mean, standard deviation, and range
`of iron level values were calculated for each PK sampling time described above
`(Appendix 2). Following treatment with either FCM or iron sulfate, mean iron levels
`post baseline were higher compared to mean baseline (week 0, predose) iron levels. It
`appears that breast milk iron levels were higher in women treated with FCM than those
`treated with iron sulfate (Figure 1). In the breast milk sub-study, the maximum iron
`level observed was 9.96 mg/kg, which was observed in a patient who received FCM.
`
`Figure 1. Mean (SE) breast milk iron levels in mothers treated with either FCM
`(injectafer) or ferrous sulfate.
`
`ai
`
`‘a)
`
`5i
`
`‘ E ’
`
`5‘
`
`9m .
`
`Sampling Time
`
`N ooo
`
`P onoo
`
`+ Injectafer
`
`—I— Femous
`Sulfate
`
`Ec g E
`
`?
`in.
`
`c«
`
`Ia 2
`
`Week 0, Week 0, Week 0, Week 0, Week 1, Week 1, Week 2,
`
`pre-dose
`
`1-3 h post 24 h post 48 h post
`
`pre-dose
`
`1-3 h post
`
`pre-dose
`
`Reference ID: 3149371
`
`

`

`
`Based on the above data, the sponsor made the following conclusion:
`Assuming an infant weighs 4 kg and consumes breastmilk at about 1/6 of his b.w. [27], an
`infant receiving breastmilk with 1.44 mg iron per kg breastmilk (average value in the
`substudy) may have ingested up to 0.96 mg iron/day (0.24 mg/kg b.w./day). An infant
`receiving breastmilk with 9.96 mg iron per kg breastmilk (highest value measured in a
`single sample in the substudy) may have ingested up to 6.64 mg iron/day (1.66 mg/kg
`b.w./day) for 1 day due to parenteral iron treatment of the mother (assuming a specific
`weight of mature breastmilk of 1.031 lg/L). Recommendations for iron intake are 1
`mg/kg/day for full-term infants and 2-4 mg/kg/day for low birth-weight infants, starting no
`later than 4 months of age in full term infants [28]. The US recommended dietary
`allowance (RDA) of iron in children from 0-3 years of age is 6-10 mg/day [29]. The US
`RDA maximum iron intake for infants from birth to age 6 months is 40 mg iron/day [30].
`The highest concentration of breastmilk iron measured in the study would therefore result
`in iron intake well below the recommended maximum US RDA iron intake.
`
`The reviewer agrees with the sponsor that the highest iron level measured in the breast
`milk sub-study was well below 40 mg. However, we defer to clinical reviewers regarding
`the appropriate threshold of iron levels in breast milk.
`
`Reviewer’s Note:
`The breast milk PK data were not submitted by the time this review was completed. The
`review was completed using sponsor’s PK analysis as described in the clinical study
`report for study VIT-IV-CL-009. The sponsor will submit breast milk PK data at a later
`date and an addendum will be made to this review. From reviewer’s perspective, the
`submitted clinical study report provides sufficient information to complete the labeling
`for injectafer.
`
`
`Reviewer: Bahru A Habtemariam,
`Pharm.D.
`Division of Clinical Pharmacology 5
`
`Cc: DDOP: CSO - A Baird; MTL - K Robie Suh; MO - M Lu
`DCP-5: Reviewers - B Habtemariam, TL - J Bullock, DDD - B Booth,
`
` DD - A Rahman
`
` Acting Team Leader:
`Bahru A Habtemariam, Pharm.D.
` Division of Clinical Pharmacology 5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3149371
`
`

`

`Appendix 1: Study Design
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3149371
`
`
`
`

`

`Appendix 2: Breast milk Iron levels in breast feeding mothers.
`
`
`
`Reference ID: 3149371
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BAHRU A HABTEMARIAM
`06/21/2012
`
`Reference ID: 3149371
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`
`
`
`Office of Clinical Pharmacology
`New Drug Application Filing and Review Form
`NDA 203-565 for Injectafer (Ferric carboxymaltose (FCM)) is a new application for a previous
`NDA (#22-054) that received a complete response on July 9, 2007, due to safety issues. NDA 22-
`054 was submitted on June 15, 2006 but was not approved because 10 deaths were reported
`among subjects exposed to FCM while no deaths were reported among subjects exposed to
`comparator iron replacement products.
`
`The clinical pharmacology aspects of FCM were reviewed previously and are available in
`DARRTS (C John, 5/30/2007). The clinical pharmacology aspects of the NDA were found to be
`acceptable during the original NDA 22-054 submission and no specific clinical pharmacology
`studies were requested.
`
`In the current NDA submission, the sponsor conducted two phase three clinical studies to address
`the safety issues outlined in the complete response letter for NDA 22-054. No PK data were
`collected in these two studies.
`
`
`
`
`NDA/BLA Number
`OCP Division (I, II, III, IV, V)
`Medical Division
`OCP Reviewer
`
`OCP Team Leader
`Pharmacometrics Reviewer
`
`Information
`203,565
`5
`Oncology
`Bahru A Habtemariam,
`Pharm.D
`Julie Bullock, Pharm.D
`NA
`
`
`Brand Name
`Generic Name
`Drug Class
`Indication(s)
`
`Dosage Form
`Dosing Regimen
`
`Information
`Injectafer
`Ferric carboxymaltose (FCM)
`Hematology
`Injectafer is indicated for the treatment of
`iron deficiency anemia
`solution
`15 mg/kg up to a maximum single dose of
`750 mg of iron on two occasions separated
`by at least 7 days up to a cumulative dose of
`1500 mg of iron.
`Intravenous
`
`Luitpold
`Standard
`
`
`
`Date of Submission
`
`Estimated Due Date of OCP Review
`Medical Division Due Date
`
` PDUFA Due Date
`
`September 30, 2011
`
`May 29, 2011
`June 29, 2011
`
`
` August 3, 2012
`
`Route of
`Administration
`Sponsor
`Priority
`Classification
`
`
`
`
`STUDY TYPE
`Table of Contents present and sufficient to
`locate reports, tables, data, etc.
`Tabular Listing of All Human Studies
`HPK Summary
`Labeling
`Reference Bioanalytical and Analytical
`Methods
`I. Clinical Pharmacology
` Mass balance:
`
`Clin. Pharm. and Biopharm. Information
`“X” if included
`Number of
`at filing
`studies
`submitted
`
`
` 2
` 2
`
`
`
`
`
`
` X
`X
`
`X
`
`
`Number of
`studies
`reviewed
`
` 2
`
` 2
`
`
`
`
`Critical Comments If any
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`
`Reference ID: 3054584
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`
` Isozyme characterization:
` Blood/plasma ratio:
` Plasma protein binding:
` Pharmacokinetics (e.g., Phase I) -
`
`Healthy Volunteers-
`
`Patients-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`single dose:
`multiple dose:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`single dose:
`multiple dose:
`
` Dose proportionality -
`fasting / non-fasting single dose:
`fasting / non-fasting multiple dose:
` Drug-drug interaction studies -
`In-vivo effects on primary drug:
`In-vivo effects of primary drug:
`In-vitro:
`
` Subpopulation studies -
`
`ethnicity:
`gender:
`pediatrics:
`geriatrics:
`renal impairment:
`hepatic impairment:
`
`Phase 2:
`Phase 3:
`
`Data rich:
`Data sparse:
`
` PD -
`
` PK/PD -
`
` Population Analyses -
`
`Phase 1 and/or 2, proof of concept:
`Phase 3 clinical trial:
`
`II. Biopharmaceutics
` Absolute bioavailability
` Relative bioavailability -
`
`solution as reference:
`alternate formulation as reference:
` Bioequivalence studies -
`traditional design; single / multi dose:
`replicate design; single / multi dose:
` Food-drug interaction studies
` Bio-waiver request based on BCS
` BCS class
` Dissolution study to evaluate alcohol induced
` dose-dumping
`III. Other CPB Studies
` Genotype/phenotype studies
` Chronopharmacokinetics
` Pediatric development plan
` Literature References
`Total Number of Studies
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`2
`
`
`
`
`
`
`127
`2
`
`
`
`
`
`
`-
`2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`This is a very small study
`(n=7) of which 6 and 1
`patients had Child Pugh
`classification classes B and C,
`respectively
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`
`Reference ID: 3054584
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`On initial review of the NDA/BLA application for filing:
`
`
`Yes No N/A Comment
`
`Content Parameter
`
`Criteria for Refusal to File (RTF)
`1 Has the applicant submitted bioequivalence data comparing to-be-
`marketed product(s) and those used in the pivotal clinical trials?
`2 Has the applicant provided metabolism and drug-drug interaction
`information?
`3 Has the sponsor submitted bioavailability data satisfying the CFR
`requirements?
`4 Did the sponsor submit data to allow the evaluation of the validity of
`the analytical assay?
`5 Has a rationale for dose selection been submitted?
`6
`Is the clinical pharmacology and biopharmaceutics section of the
`NDA organized, indexed and paginated in a manner to allow
`substantive review to begin?
`Is the clinical pharmacology and biopharmaceutics section of the
`NDA legible so that a substantive review can begin?
`
`7
`
`8
`
`Is the electronic submission searchable, does it have appropriate
`hyperlinks and do the hyperlinks work?
`
`
`Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality)
` Data
`9 Are the data sets, as requested during pre-submission discussions,
`submitted in the appropriate format (e.g., CDISC)?
`
`
`
`
`
`
`
`
`
`
`
`
`There are no
`PK data
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` X
`
` X
`
` X
`
` X
`
`
`X
`
`
`
`
`
`
` X
`
`
`
` X
`
`
`
`
`
`
`
`
` X
`
`
`
`X
`
`
` X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` X
`
` X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` X
`
` X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` x
`
`
`
`
`
` X
`
`10
`
`If applicable, are the pharmacogenomic data sets submitted in the
`appropriate format?
` Studies and Analyses
`11
`Is the appropriate pharmacokinetic information submitted?
`12 Has the applicant made an appropriate attempt to determine
`reasonable dose individualization strategies for this product (i.e.,
`appropriately designed and analyzed dose-ranging or pivotal
`studies)?
`13 Are the appropriate exposure-response (for desired and undesired
`effects) analyses conducted and submitted as described in the
`Exposure-Response guidance?
`Is there an adequate attempt by the applicant to use exposure-
`response relationships in order to assess the need for dose
`adjustments for intrinsic/extrinsic factors that might affect the
`pharmacokinetic or pharmacodynamics?
`15 Are the pediatric exclusivity studies adequately designed to
`demonstrate effectiveness, if the drug is indeed effective?
`16 Did the applicant submit all the pediatric exclusivity data, as
`described in the WR?
`Is there adequate information on the pharmacokinetics and exposure-
`response in the clinical pharmacology section of the label?
`
`14
`
`17
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`
`Reference ID: 3054584
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`
`
`
`
`
`
`X
`
`
`
`
` X
`
`
`
` X
`
`
`
`
`
` General
`18 Are the clinical pharmacology and biopharmaceutics studies of
`appropriate design and breadth of investigation to meet basic
`requirements for approvability of this product?
`
`19 Was the translation (of study reports or other study information)
`from another language needed and provided in this submission?
`
`
`
`
`
`
`
`
`
`
`
`
`
`IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE?
`Yes
`
`
`
`If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and provide
`comments to be sent to the Applicant.
`
`
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter.
`
`
`Bahru A. Habtemariam, Pharm.D.
`Reviewing Clinical Pharmacologist
`
`Julie Bullock, Pharm.D.
`Team Leader/Supervisor
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` December 1, 2011
`
`
`Date
`
` December 1, 2011
`
`
`Date
`
`
`
`
`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`
`Reference ID: 3054584
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BAHRU A HABTEMARIAM
`12/14/2011
`
`JULIE M BULLOCK
`12/19/2011
`
`Reference ID: 3054584
`
`

`

`NDA 22-054 Ferinject®
`
`
`
`
`
`
`
`
`
`
`NDA
`
`22054
`
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`OCP Division
`ORM Division
`
`Sponsor
`Relevant IND(s)
`Submission Type; Code
`Formulation;
`Strength(s)
`
`Indication
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`
`
`
`
`June 16, 2006;
`February 16, 2007
`
`Submission
`Date(s)
`Ferinject
` N/A
`Christy S. John, Ph.D
`Young Moon Choi, Ph.D.
`V
`Division of Medical Imaging and
`Hematology Drug Products
`Luitpold Pharmaceuticals, Inc
`63,243
`1
`S
`Intravenous infusion, 15 mg/kg body weight
`IV infusion, not exceeding 1000 mg Fe/week
`or 200 mg iron given as bolus injection up to
`3 times a weeks
`For the treatment of iron deficiency anemia
`(IDA) secondary to pregnancy/childbirth
`(postpartum anemia), heavy uterine bleeding
`(HUB), and inflammatory bowel disease
`(IBD) and hemodialysis.
`
`
`
`
`

`

`
`
`2
`
`
`
`
`
`NDA 22-054 Ferinject®
`
`
`
`
`
`
`
`Table of Contents
`1 Executive Summary..................................................................................3
`1.1 Recommendations............................................................................. 4
`1.2 Phase IV Commitments .................................................................... 4
`1.3 Summary of Clinical Pharmacology Findings.................................. 5
`2 Question-Based Review............................................................................8
`2.1 General Attributes of the drug .......................................................... 8
`2.2 General Clinical Pharmacology ...................................................... 10
`2.3
`Intrinsic Factors............................................................................... 15
`2.4 Extrinsic Factors ............................................................................. 15
`2.5 General Biopharmaceutics.............................................................. 15
`3
`Detailed Labeling Recommendations............................................. 16
`4 Appendices..............................................................................................17
`4.1 Proposed Package Insert (Original and Annotated)........................ 18
`4.2.
`Individual Study Reviews............................................................... 18
`4.3 Consult Reviews (including Pharmacometric Reviews) ................ 51
`4.4 Cover Sheet and OCP Filing/Review Form.................................... 52
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 22-054 Ferinject®
`
`
`
`3
`
`
`
`
`
`
`
`Executive Summary
`
` 1
`
`
`
`
`
`
`
`VIT-45 (Ferinject also known as iron carboxymaltose) is a complex of polynuclear
`iron(III)-hydroxide with 4®-(poly-(1-4)O-α-D- glucopyranosyl)-oxy-
`2®,3(S),5®,6-tetrahydroxy-hexanoate, having a relative molecular weight of
`approximately 150,000 Dalton. Ferinject is indicated for the treatment of iron
`deficiency anemia (IDA) secondary to pregnancy/childbirth (postpartum anemia),
`heavy uterine bleeding (HUB), and inflammatory bowel disease (IBD) and
`hemodialysis.
`
`Four clinical pharmacology studies were conducted. An imaging study (VIT-IV-
`CL-001) used Fe-52 with positron imaging tomography (PET) and Fe-59 to assess
`the pharmacokinetics of VIT-45. The study showed that from 0 to 8 hours post-
`injection most of the VIT is found in the liver, spleen, and a much higher amount
`in bone marrow. Fe-59 was used to show the radio-iron utilization by the red blood
`cells (RBC). Incorporation of radioiron in RBC increased rapidly during first 6-9
`days indicated the potential use of VIT-45 as iron supplement. A dose escalation
`PK Study (VIT-IV-CL-02) in patients with mild iron deficiency anemia was
`performed to study safety and tolerability of the drug. The study included single IV
`doses of 100, 500, 800, and 1000 mg via a bolus IV injection or IV infusion. The
`increase in geometric mean Cmax for total serum iron concentration did not
`increase linearly with dose (particularly in 800 mg dose group). The average
`terminal half-life (t1/2) of VIT-45 (injected or infused) ranged from 10.3 h to 17.7
`hours.
`
`The pharmacodynamic variables evaluated included total serum iron concentration,
`ferritin and transferrin concentrations, transferrin receptor concentrations,
`reticulocyte count and hemoglobin concentrations. No single pharmacodynamic
`variable was established as the primary pharmacodynamic factor. The percent
`increase in transferrin saturation for 500, 800, 1000 mg was 76, 63, 71%,
`respectively at 24-36 hrs post-dose. Iron binding capacity was fully utilized (as
`shown by 90% transferrin saturation) after doses of 500, 800 and 1000 mg. Mean
`hemoglobin concentrations 8 days post dosing for different treatment arms and
`placebo were not significantly different. Thus, optimal dosing was not fully
`explored by the sponsor based on pharmacodynamic variables or clinical endpoint
`(hemoglobin level). The highest dose level 1000 mg was selected for weekly
`injection and its use was not justified.
`
`The drug-related treatment-emergent adverse events reported by at least 2% of
`VIT-45 subjects in the first-dose 1,000 mg studies were headache (3.9%) and
`blood phosphate decrease (3.4%) as compared to zero for oral iron. A total of 9
`subjects died during VIT-45 clinical development program. According to the
`sponsor no death in Ferinject trials was consistent with hypophosphatemia.
`
`
`
`
`

`

`
`
`
`
`4
`
`NDA 22-054 Ferinject®
`
`
`1.1.1 Recommendations:
`
`The NDA 22-054, Ferinject for intravenous use is acceptable from the Clinical
`Pharmacology and Biopharmaceutics perspective. However, the relationship between dose
`and various pharmacodynamic variables indicate that Ferinject dose has not been optimized.
`Therefore, the following comment should be sent to the applicant:
`
`Based upon the pharmacodynamic variables, such as, unsaturated iron binding capacity and
`mean changes in transferrin saturation from baseline at 24-36 hours data, it appears that a
`lower dose such as 500 mg and 800 mg may be equally efficacious clinically. It is noted that
`higher serum ferritin concentrations have been linked to increased risk of cardiovascular
`disease and oxidative stress (G. Aronoff. J. Am. Soc. Neph. 15, 99-106, 2004; Lim, PS. et.
`al. Nephrol. Dial. Transplant. 14, 2680-2687, 1999; Drueke T. et. al. Circulation 106, 2212-
`2217, 2002). Therefore, the applicant should conduct a pharmacokinetic-pharmacodynamic
`study to explore the effectiveness and safety of lower doses of Ferinject.
`
`
`
`1.2 Phase IV Commitments
`
`Not applicable
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 22-054 Ferinject®
`
`
`
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings:
`
`VIT-45 (Ferinject also known as iron carboxymaltose) is a complex of polynuclear iron(III)-
`hydroxide. Ferinject is indicated for the treatment of iron deficiency anemia (IDA)
`secondary to pregnancy/ childbirth (postpartum anemia), heavy uterine bleeding (HUB), and
`inflammatory bowel disease (IBD) and hemodialysis. Four clinical pharmacology studies
`were conducted (Table I) in support of this NDA.
`
`Table I. Summary of Clinical Pharmacology Studies Performed
`
`Study Number
`
`Number
`of
`Subjects
`VIT-IV-CL-001 6
`
`VIT-IV-CL-02
`
`32
`
`VIT-IV-03
`
`46
`
`1VIT05006
`
`10
`
`
`
`
`
`
`
`
`
`
`5
`
`
`
`
`
`Objectives
`
`Type of Study
`
`To prove the safety and
`efficacy of iron(III)-
`hydroxide dextrin complex
`by measuring the
`distribution of Fe-52 by
`PET imaging and the
`incorporation of Fe-59 in
`RBCs in subjects with
`iron-deficiency anemia or
`renal anemia
`To obtain PK/PD and
`safety information on
`ascending single doses of
`VIT-45 in subjects with
`mild iron-deficiency
`anemia.
`To obtain PK/PD and
`safety information after
`multiple doses of VIT-45
`in subjects with moderate
`iron-deficiency anemia
`To obtain PK and safety
`information after a single
`dose of VIT-45 in
`postpartum subjects with
`iron-deficiency anemia
`
`PET Imaging
`study of
`ferrokinetics and
`RBC iron
`utilization
`
`Dose-Finding,
`placebo-
`controlled,
`blinded
`
`Dose-finding,
`non-controlled
`
`Sub-study; non-
`controlled
`
`
`
`

`

`
`
`6
`
`
`
`
`
`NDA 22-054 Ferinject®
`
`
`
` A
`
` dose escalation PK Study (VIT-IV-CL-02) in patients with mild iron deficiency anemia
`was performed to study safety and tolerability of the drug. The study included single IV
`doses of 100, 500, 800, and 1000 mg via a bolus IV injection or IV infusion. The increase
`in geometric mean Cmax for total serum iron concentration did not increase linearly with
`dose (particularly in 800 mg dose group). The average terminal half-life (t1/2) of VIT-45
`(injected or infused) ranged from 10.3 h to 17.7 hours.
`
`The intravenously injected iron complex VIT-45 100 mg led to a maximum total serum
`iron of 37 μg/mL (geometric mean Cmax). A short infusion of VIT-45 at doses of 500,
`800, 1000 mg led to mean maximum total serum iron concentrations of 156, 319 and 331
`μg/mL, respectively. Particularly, the 800 mg dose deviated from the dose-linear
`increase, while the maximum levels after 1000 mg VIT-45 were approximately doubled
`when compared to the 500-mg dose. Similarly, average AUC was 426 μg-h/mL for 100
`mg VIT-45. The increase in AUC values with incremental dose of VIT-45 was higher
`than expected for dose-proportional increases; the geometric means for 500, 800 and
`1000 mg doses were 2443, 5218, 6311 μg-h/mL, respectively. The Tmax was about 30
`minutes for the lower doses (100 and 500 mg). However, increasing VIT-45 doses led to
`a shift of Tmax that was about 1 h or longer at 800 to 1000 mg VIT. The average terminal
`half-life (t1/2) of the injected or infused iron complex solution was calculated to be in the
`range of 10.3 h (1000 mg) to 17.7 h (100 mg VIT-45). The geometric mean residence
`time (MRT) was less than a day (16.9 h to 23.6 h). The total body clearance, CL, was low
`and averaged at approximately 3.4 mL/min for the 100- and 500-mg doses and at
`approximately 2.6 mL/min for the two higher doses. The majority of administered iron
`complex was utilized or excreted within 24 h after a low dose of 100 mg and within 72 h
`after higher doses of 500-1000 mg.
`
`The pharmacodynamic variables included the measurement of serum iron concentrations,
`serum ferritin and transferrin concentrations, transferrin receptor concentrations, iron
`binding capacity and transferrin saturation (TfS). In addition, the hemoglobin levels and
`reticulocyte counts were also measured. The sponsor has not established a primary
`pharmacodynamic variable. There is no correlation defined between pharmacokinetic
`profile and a primary pharmacodynamic variable. For example, iron binding
`capacity (TSAT >95%) was almost fully utilized after the doses of 500 mg, 800 mg and
`1000 mg iron and lasted for 2 to 3 days. A dose optimization and justification of dose
`based on pharmacodynamic variables has not been provided by the sponsor.
`
`Based upon the pharmacodynamic variables, such as, unsaturated iron binding capacity
`and mean changes in transferrin saturation from baseline at 24-36 hours data, it appears
`that a lower dose such as 500 mg and 800 mg may be equally efficacious clinically.
`Based upon applicant’s data, the maximum serum ferritin concentration after
`administration of VIT-45 increased significantly for 500, 800 and 1000 mg dose groups
`to 423, 488, 652 ng/mL, respectively. Higher serum ferritin concentrations have been
`linked to increased risk of cardiovascular disease and oxidative stress (G. Aronoff. J. Am.
`
`
`
`
`
`
`

`

`
`
`
`
`7
`
`NDA 22-054 Ferinject®
`
`
`Soc. Neph. 15, 99-106, 2004; Lim, PS. Et al. Nephrol. Dial. Transplant. 14, 2680-2687,
`1999; Drueke T. et. al. Circulation 106, 2212-2217, 2002). The applicant should conduct
`a pharmacokinetic-pharmacodynamic study to explore the effectiveness and safety of
`lower doses of Ferinject.
`
`The clinical efficacy of VIT-45 was demonstrated in treatment of IDA in a variety
`of patient populations. In the clinical program, the effectiveness of VIT-45 was
`evaluated in 7 studies; a) Patients with postpartum IDA (2 Studies) b) Anemic
`patients undergoing regular hemodialysis (2 Studies); c) Patients with IDA
`secondary to GI disorders (2 Studies); d) Patients with IDA secondary to heavy
`uterine bleeding. Four of the seven studies provide the primary evidence of
`effectiveness of VIT-45 for the treatment of IDA. Responder analyses were based
`on an increase from baseline in hemoglobin of >2.0 g/dL, an increase from
`baseline in hemoglobin >3.0 g/dL, and hemoglobin level >12 g/dL on or before
`Week 4. These criteria represent increasing magnitude of hemoglobin response,
`and hemoglobin levels >12 g/dL indicate that subjects have achieved hemoglobin
`levels within or approaching normal range. Among subjects in the Modified Intent-
`to-Treat Population in the pivotal studies (1VIT03001, VIT-IV-CL-009, VIT-IV-
`CL-008, and 1VIT04002/1VIT04003) combined, a statistically significant greater
`proportion of VIT-45 subjects (485/748; 64.8%) achieved a >12 g/dL hemoglobin
`up to Week 4 compared to oral iron subjects (266/563; 47.2%).
`
`The drug-related treatment-emergent adverse events reported by at least 2% of
`VIT-45 subjects in the calculated dose/first-dose 1,000 mg studies were headache
`(3.9%) and blood phosphate decrease (3.4%) as compared to zero for oral iron. A
`total of 9 subjects died during VIT-45 clinical development program.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 22-054 Ferinject"
`
`8
`
`2
`
`Question-Based Review
`
`2.1 General Attributes of the drug
`
`VIT-45 is a complex of polynuclear iron(III)-hydroxide with 4®-(poly—(l-4)-O-aD-
`glucopyranosyl)-oxy—2®, 3(S),5®,6-tetrahydroxy—hexanoate, having a relative molecular
`weight of approximately 150,000 Da corresponding to the empirical formula:
`[Fer(OH)y(H20)z]n[{C6H1007}l]k, where n=103, m =