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

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`
`203565
`SD 20
`January 30, 2013
`January 30, 2013
`Ferric carboxymaltose (Injectafer)
`Iron deficiency anemia
`Luitpold Pharmaceuticals Inc.
` Division of Hematology Oncology Toxicology
` (for Division of Hematology Products)
` Brenda J. Gehrke, Ph.D.
` Haleh Saber, Ph.D.
` John Leighton, Ph.D., DABT
` Ann Farrell, M.D. (DHP)
` Amy C. Baird
`
`Project Manager:
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203565 are owned by Luitpold Pharmaceuticals
`Inc. or are data for which Luitpold Pharmaceuticals Inc. has obtained a written
`right of reference. Any information or data necessary for approval of NDA
`203565 that Luitpold Pharmaceuticals Inc. does not own or have a written right to
`reference constitutes one of the following: (1) published literature, or (2) a prior
`FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s
`approved labeling. Any data or information described or referenced below from
`reviews or publicly available summaries of a previously approved application is
`for descriptive purposes only and is not relied upon for approval of NDA 203565.
`
`
`Reference ID: 3330782
`
`

`

`Background:
`The current submission, Supporting Document 20 for NDA 203565, is a Class 2
`Resubmission. NDA 203565 was submitted in September 2011 as a new NDA
`for Injectafer (ferric carboxymaltose) by Luitpold Pharmaceuticals Inc. for the
`indication of iron deficiency anemia and a complete response letter was issued in
`July 2012 due to deficiencies with the manufacturing facility. There were no
`pharmacology/toxicology concerns with the application, and a review of the
`impurity and heavy metal acceptance criteria that also contained the proposed
`labeling recommendations for the pharmacology/toxicology sections (8.1, 12.1,
`and 13.1) was completed on June 13, 2012. There is no new
`pharmacology/toxicology information in this resubmission. The proposed
`
`acceptance criteria for
`are the same as those proposed in the 2012 submission and found
`acceptable; see the previous pharmacology/toxicology review.
`
`Recommendation:
`Recommending approval. There are no pharmacology/toxicology issues for NDA
`203565 to preclude approval of the drug for the proposed indication.
`
`
`Reference ID: 3330782
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRENDA J GEHRKE
`06/24/2013
`
`HALEH SABER
`06/25/2013
`
`Reference ID: 3330782
`
`

`

`MEMORANDUM
`
`
` ferric carboxymaltose (Injectafer)
`
`Date: June 13, 2012
`To:
`File for NDA 203565
`From: John K. Leighton, PhD, DABT
`
`Acting Director, Division of Hematology Oncology Toxicology
`
`Office of Hematology and Oncology Products
`
`
` I
`
` have examined pharmacology/toxicology supporting review of Dr. Chopra
`(secondary signoff by Dr. Adebayo Laniyonu) and review memorandum and
`labeling provided by Dr. Gehrke. I agree with Dr Gehrke’s conclusion that
`Injectafer may be approved and that no additional nonclinical studies are needed
`for the proposed indication.
`
`Reference ID: 3145148
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN K LEIGHTON
`06/14/2012
`
`Reference ID: 3145148
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`
`203565
`SD 1
`September 30, 2011
`October 3, 2011
`Ferric carboxymaltose (Injectafer)
`Iron deficiency anemia
`Luitpold Pharmaceuticals Inc.
` Division of Hematology Oncology Toxicology
` (for Division of Hematology Products)
` Brenda J. Gehrke, Ph.D.
` Haleh Saber, Ph.D.
` John Leighton, Ph.D.
` Ann Farrell, M.D. (DHP)
` Amy C. Baird
`
`Project Manager:
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203565 are owned by Luitpold Pharmaceuticals
`Inc. or are data for which Luitpold Pharmaceuticals Inc. has obtained a written
`right of reference. Any information or data necessary for approval of NDA
`203565 that Luitpold Pharmaceuticals Inc. does not own or have a written right to
`reference constitutes one of the following: (1) published literature, or (2) a prior
`FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s
`approved labeling. Any data or information described or referenced below from
`reviews or publicly available summaries of a previously approved application is
`for descriptive purposes only and is not relied upon for approval of NDA 203565.
`
`
`Reference ID: 3145032
`
`

`

`MEMORANDUM
`
`
`MEMO DATE: 6/13/2012
`
`TO: To the file for NDA 203565
`FROM: Brenda J. Gehrke, Ph.D., Pharmacologist; Division of Hematology
`Oncology Toxicology, OHOP
`THROUGH: Haleh Saber, Ph.D., Supervisory Pharmacologist; Division of
`Hematology Oncology Toxicology, OHOP
`
`Background
`
`Ferric carboxymaltose injection was originally submitted by Luitpold
`Pharmaceuticals Inc. under NDA 22054 on June 15, 2006 for the indication of
`treatment of iron deficiency anemia in heavy uterine bleeding, postpartum,
`inflammatory bowel disease and hemodialysis patients. A Not Approvable letter
`was issued on July 9, 2007 with clinical deficiencies. The nonclinical studies for
`Ferric carboxymaltose were reviewed during this initial submission of NDA
`22054. Studies reviewed included pharmacology; safety pharmacology;
`pharmacokinetics; general toxicology studies including 13-week studies in rats
`and dogs; genetic toxicology; fertility, embryo-fetal and peri and postnatal
`development toxicology studies; and local tolerance studies. Carcinogenicity
`studies were not submitted nor are they needed per ICH S1A due to the short-
`term intermittent nature of the clinical dosing. There were no
`pharmacology/toxicology issues at that time, and approval was recommended for
`ferric carboxymaltose by the pharmacology/toxicology review team (Dr. Yash
`Chopra and Dr. Adebayo Laniyonu). The NDA was resubmitted on September
`12, 2007 and a second Not Approvable letter was issued on March 11, 2008 with
`clinical deficiencies. Since the indication was changed from the original NDA,
`NDA 203565 was submitted on September 30, 2011 as a new NDA for Injectafer
`(ferric carboxymaltose) by Luitpold Pharmaceuticals Inc. for the indication of iron
`deficiency anemia. No additional pharmacology/toxicology studies are needed
`for the proposed indication and none were submitted to NDA 203565. The
`Applicant is cross-referencing the nonclinical data in NDA 22054.
`
`Injectafer (ferric carboxymaltose) is an intravenous formulation of polynuclear
`iron III hydroxide in complex with 4(R)-(poly-(1→4)-O-α-D-glucopyranosyl)-oxy-
`2(R),3(S),5(R),6-tetrahydroxy-hexanoate. The drug will be administered
`intravenously as an undiluted slow intravenous push injection or by drip infusion.
`According to the dosage and administration section of the label, the
`recommended dosage is 15 mg/kg body weight 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. Treatment with iron may be repeated if iron deficiency
`reoccurs. Based on this information, the drug will be administered twice (one
`week apart), however, repeated dosing is possible and the number of
`administrations a patient will receive is unknown.
`
`Reference ID: 3145032
`
`

`

`Impurities/heavy metals
`
`The drug substance of ferric carboxymaltose contains high levels of the heavy
`metals
`“"0. For each heavy metal, the proposed drug
`substance acceptance criteria, the level of the heavy metal for the maximum iron
`dose of 750 mg, and the permitted daily exposure (PDE) recommended in the
`revised USP guidelines (USP 35-NF 30) are shown in the table below.
`
`
`
`Heavy metal
`
`Acceptance
`criteria in D3
`(pg/g Fe)
`
`Level of heavy metal
`(pg) per iron dose of
`750 mg
`
`USP Parenteral
`PDE
`(pg/day)
`
`(b) (4)
`
`DS: drug substance.
`
`"m present in a single 750 mg dose of iron
`The levels of
`are much higher than the permitted daily exposure values. Patients will receive
`two doses of ferric carboxymaltose at least 7 days apart. Since repeated dosing
`of ferric carboxymaltose will be permitted according to the proposed label, the
`number of administrations a patient will receive is unknown.
`If multiple
`administrations of ferric carboxymaltose are administered to a patient, the patient
`may receive relatively high exposures to
`"M. Based on
`this information, the proposed acceptance criteria for
`"M
`are not acceptable. The following comment was sent to the Applicant on May 10,
`2012:
`
`Your proposed acceptance criteria for the heavy metals in the drug
`substance specification
`“m
`appear to be too high. Based on a
`maximum iron dose of 750 mg for a single injection of ferric
`carboxymaltose, these acceptance criteria result in approximately
`per dose. These levels are
`higher than the permitted daily exposure (PDE) limits for parenteral
`administration listed in the USP and EMA guidelines (please see the links
`below for more information). Lower the acceptance criteria for these
`heavy metals.
`
`(b) (4)
`
`“"9 the drug
`Your proposed acceptance criteria of
`product is equivalent to
`“m content in the drug product, which
`results in
`“M" This level is higher than the PDE limit for
`parenteral administration listed in the EMA guideline document. Please
`provide justification for the safety of the proposed acceptance criteria for
`“m Yourjustification could include exposure to
`“"0 patients
`who receive your approved drug Venofer.
`
`Reference ID: 3145032
`
`

`

`USP:
`
`http://www.usgorg/sites/defauItlfiles/usp pdf/EN/hottogics/232 Elementall
`mpuritiesLimits.pdf
`EMA:
`
`http://wwwema.europaeu/docs/en GB/document "brag/Scientific guidel
`ine/2009/09NVC500003587.Qdf
`
`A response to the comment was received on May 16, 2012. The Applicant
`emphasized that both the USP and EMA guidelines state that the PDE limits are
`based on chronic use, and that ferric carboxymaltose is not administered daily
`and is not intended for chronic use. Based on the eriodic short-term use of the
`
`with at least 7 da s
`drug with a maximum daily iron dose of 750 mg
`
`between doses, the A licant used the formula Limit—
`
`
`e
`va ues from
`
`
`the guidelines used in the formula, the new acceptance criteria, and the level of
`the heavy metal for the maximum iron dose of 750 mg are shown in the table
`below.
`
`Acceptance criteria
`in D3
`(pg/g Fe)
`
`Level of heavy
`metal (pg) per
`iron dose of 750
`
`(pg/day)
`
`USP Parenteral
`PDE
`
`For the new acceptance criteria, the levelsof— present
`in a single 750 mg dose of iron are still higher than the USP permitted daily
`exposure recommendations. It is noted that discussions on safety-based
`acceptable levels of heavy metals are ongoing as part of the ICH Q3D
`discussions. However, for the metals listed above, the acceptance criteria
`provided above are acceptable for the following reasons.
`
`
`
`Reference ID: 3145032
`
`

`

`"M"
`Thus, the revised drug substance acceptance criteria for
`ferric carboxymaltose are
`acceptable from a pharmacology/toxicology perspective.
`
`Also in the response was the following justification for the safety of the proposed
`acceptance criteria for
`“x":
`
`(b) (4)
`
`“m present in the
`Based on this justification explaining the higher levels of
`“m is
`approved drug Venofer, the acceptance criteria of
`acceptable from a pharmacology/toxicology perspective. At this time there are
`no pharmacology/toxicology issues for NBA 203565 to preclude approval of the
`drug for the proposed indication.
`
`Comments on Proposed Labeling:
`
`The pharmacologic class under “Indications and Usage” of the HIGHLIGHTS is
`"iron replacement produc which is consistent with the pharmacologic class for
`the other intravenous iron products (Feraheme, Ferrlecit, and Venofer).
`
`Ferric caroboxymaltose was administered daily in the embryo-fetal development
`studies (data presented in section 8.1 of the label) and 3 times per week, on
`Days 0, 3, and 7 in the fertility and early embryonic development study (data
`presented in section 13.1 of the label), which differs from the weekly
`administration in humans. Due to this difference in administration schedules and
`lack of PK data, dose-to-dose comparisons based on body surface area (mg/m2)
`were made to compare the human and animal doses.
`
`Since there are clinical data in nursing women exposed to lnjectafer, the
`maternal health team was consulted for section 8.3 (Nursing Mothers). The
`maternal health team and the clinical team will be making the labeling
`recommendations for section 8.3, which has been omitted below.
`
`It
`Journal articles, e.g. Park and Park (2011), suggest that iron is genotoxic.
`appears that the genotoxic potential of iron is due to iron overload in the studies
`published. This observation is not relevant to the current iron product lnjectafer,
`
`Reference ID: 3145032
`
`

`

`since Injectafer will be administered to patients with iron deficiency anemia.
`Administration of Injectafer is not expected to cause iron overload. Additionally,
`genotoxicity studies with ferric carboxymaltose and other iron products (see
`labels for Feraheme and Venofer) were compliant with ICHS2 and were negative
`for genotoxicity. Therefore, information on the potential genotoxicity of iron from
`overload will not be added to the label.
`
`Reference:
`
`Park, J. and Park, E. (2011). Influence of iron-overload on DNA damage and its
`repair in human leukocytes in vitro. Mutation Research/Genetic Toxicology and
`Environmental Mutagenesis, 718: 56-61.
`
`The proposed draft FDA labeling for ferric carboxymaltose for the
`pharmacology/toxicology sections is presented below.
`
`Proposed Labeling:
`
`HIGHLIGHTS
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Injectafer is an iron replacement product indicated for the treatment of iron
`deficiency anemia.
`
`---------------------------USE IN SPECIFIC POPULATIONS----------------------
`• Nursing Mothers:
`exercise when
`administered to a nursing woman. (8.3)
`
`
`
` 8
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`Pregnancy Category C
`Adequate and well controlled studies in pregnant women have not been
`conducted. In
` studies, administration of ferric carboxymaltose to
`rabbits during the period of organogenesis caused fetal malformations and
`increased implantation loss at maternally toxic doses; approximately 12% to 23%
`of the human weekly dose of 750 mg (based on body surface area). Injectafer
`should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus.
`
`Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion
`up to 30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse
`embryofetal findings. This daily dose in rats is approximately 40% of the human
`weekly dose of 750 mg based on body surface area. In rabbits, ferric
`carboxymaltose was administered as a one-hour infusion on gestation days 6 to
`19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day.
`
`
`Reference ID: 3145032
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

` Malformations were seen
`starting at the daily dose of 9 mg/kg (23% of the human weekly dose of 750 mg).
`Abortion occurred starting at the daily iron dose of 4.5 mg/kg (12% of the human
`weekly dose based on body surface area). Pre-implantation loss was at the
`highest dose.
`
` pre- and post-natal development study was conducted in rats at intravenous
`doses up to 18 mg/kg/day of iron (approximately 23% of the weekly human dose
`of 750 mg on a body surface area basis). There were no adverse effects on
`survival of offspring, their behavior, sexual maturation or reproductive
`parameters.
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with
`carboxymaltose, a carbohydrate polymer, that releases iron.
`
`NONCLINICAL TOXICOLOGY
`13
`13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility:
`Carcinogenicity studies have not been performed with ferric carboxymaltose.
`
`Ferric carboxymaltose was not genotoxic in the following genetic toxicology
`studies: in vitro microbial mutagenesis (Ames) assay, in vitro chromosome
`aberration test in human lymphocytes, in vitro mammalian cell mutation assay in
`mouse lymphoma L5178Y/TK+/- cells, in vivo mouse micronucleus test at single
`intravenous doses up to 500 mg/kg.
`
`In a combined male and female fertility study, ferric carboxymaltose was
`administered intravenously over one hour to male and female rats at iron doses
`of up to 30 mg/kg. Animals were dosed 3 times per week (on Days 0, 3, and 7).
`There was no effect on mating function, fertility or early embryonic development.
`The dose of 30 mg/kg in animals is approximately 40% of the human dose of 750
`mg based on body surface area.
`
`
`
`
`
`
`
`
`
`
`
` A
`
`Reference ID: 3145032
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRENDA J GEHRKE
`06/13/2012
`
`HALEH SABER
`06/13/2012
`
`Reference ID: 3145032
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`NDA/BLA Number: 203565 Applicant: Luitpold
`Pharmaceuticals Inc.
`NDA/BLA Type: NDA 505 b1
`
`Stamp Date: 10/03/2011
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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` 2
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` 3
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` 4
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` 5
`
`
`
` 6
`
`
`
`
`Drug Name: Ferric
`carboxmaltose
`
`On initial overview of the NDA/BLA application for filing:
`
`
`
`
`
`Content Parameter
`Yes
`No
`1 Is the pharmacology/toxicology section
`organized in accord with current regulations
`and guidelines for format and content in a
`manner to allow substantive review to
`begin?
`
`Is the pharmacology/toxicology section
`indexed and paginated in a manner allowing
`substantive review to begin?
`
`Is the pharmacology/toxicology section
`legible so that substantive review can
`begin?
`
`Are all required (*) and requested IND
`studies (in accord with 505 b1 and b2
`including referenced literature) completed
`and submitted (carcinogenicity,
`mutagenicity, teratogenicity, effects on
`fertility, juvenile studies, acute and repeat
`dose adult animal studies, animal ADME
`studies, safety pharmacology, etc)?
`
`If the formulation to be marketed is
`different from the formulation used in the
`toxicology studies, have studies by the
`appropriate route been conducted with
`appropriate formulations? (For other than
`the oral route, some studies may be by
`routes different from the clinical route
`intentionally and by desire of the FDA).
`Does the route of administration used in the
`animal studies appear to be the same as the
`intended human exposure route? If not, has
`the applicant submitted a rationale to justify
`the alternative route?
`7 Has the applicant submitted a statement(s)
`that all of the pivotal pharm/tox studies
`have been performed in accordance with the
`GLP regulations (21 CFR 58) or an
`explanation for any significant deviations?
`
`
`
`
`Comment
`There is no pharmacology/toxicology
`section in this NDA; nonclinical studies
`were submitted and reviewed under NDA
`22054; there is a cross-reference to the non-
`clinical data in NDA 22054 (paper
`submission)
`
`Not applicable
`
`
`Not applicable
`
`
`Nonclinical studies were reviewed under
`NDA 22054
`
`
`Not applicable
`
`
`Not applicable
`
`Nonclinical studies were reviewed under
`NDA 22054 and applicant is cross-
`referencing nonclinical studies in NDA
`22054
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement
`010908
`
`Reference ID: 3052544
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`
`
`
`
`
`Content Parameter
`Yes
`No
`
`Comment
`
`8 Has the applicant submitted all special
`Nonclinical studies were reviewed under
`studies/data requested by the Division
`NDA 22054 and applicant is cross-
`during pre-submission discussions?
`referencing nonclinical studies in NDA
`22054
`
`
`
`
`
`
`
`
`9 Are the proposed labeling sections relative
`to pharmacology/toxicology appropriate
`(including human dose multiples expressed
`in either mg/m2 or comparative
`serum/plasma levels) and in accordance
`with 201.57?
`10 Have any impurity – etc. issues been
`addressed? (New toxicity studies may not
`be needed.)
`11 Has the applicant addressed any abuse
`potential issues in the submission?
`
`12 If this NDA/BLA is to support a Rx to OTC
`switch, have all relevant studies been
`submitted?
`
`(cid:57)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`No known impurity issues at this time
`
`
`
`Not applicable
`
`
`
`Not applicable
`
`
`
`IS THE PHARMACOLOGY/TOXICOLOGY SECTION OF THE APPLICATION
`FILEABLE? __Yes______
`
`If the NDA/BLA is not fileable from the pharmacology/toxicology 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.
`
`
`
`
` Brenda J. Gehrke, Ph.D.
`Reviewing Pharmacologist
`
`
` Haleh Saber, Ph.D.
`Team Leader/Supervisor
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 12/1/2011
`
`
`Date
`
`
`
`
` 12/1/2011
`
`Date
`
`File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement
`010908
`
`Reference ID: 3052544
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRENDA J GEHRKE
`12/01/2011
`
`HALEH SABER
`12/01/2011
`
`Reference ID: 3052544
`
`

`

`NDA No. 22-054
`
`Ferinject
`
`1
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`INTENDED CLINICAL POPULATION:
`
`SPONSOR:
`
`DOCUMENTS REVIEWED:
`
`REVIEW DIVISION:
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`22-054
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`000
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`June 15, 2006
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`Ferinject (Iron carboxymaltose Injection, VIT-45)
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`Post-partum /IBS/Hemodialysis Anemia
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`Luitpold Pharmaceuticals, Inc., Norristown, PA.
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`Vol. 1:8 to 1:13, 1.15-1.17, 1.28 to 1.53
`
`Division of Medical Imaging & Hematology Drug
`Products (HFD-160)
`
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`PHARM/TOX REVIEWER:
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`PHARM/TOX SUPERVISOR:
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`ACTING DIVISION DIRECTOR
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`PROJECT MANAGER:
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`Date of review submission to Division File System (DFS): June 5, 2007.
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`Yash M. Chopra, M.D., Ph.D.
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`Adebayo Laniyonu, Ph.D.
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`R. Dwaine Rieves, M.D.
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`Hyon-Zu, Lee, Pharm.D.
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`

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`NDA No. 22-054
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`Ferinject
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`2
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`TABLE OF CONTENTS
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`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................... 5
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`2.6.1 INTRODUCTION AND DRUG HISTORY........................................................5
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`2.6.2 PHARMACOLOGY..............................................................................................9
`2.6.2.1
`Brief summary ........................................................................................................................ 9
`2.6.2.2
`Primary pharmacodynamics ................................................................................................... 9
`2.6.2.3
`Secondary pharmacodynamics ............................................................................................... 9
`2.6.2.4
`Safety pharmacology ............................................................................................................ 10
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`2.6.3 PHARMACOLOGY TABULATED SUMMARY............................................16
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`2.6.4 PHARMACOKINETICS/TOXICOKINETICS ...............................................16
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`2.6.6 TOXICOLOGY....................................................................................................37
`2.6.6.1
`Overall toxicology summary ................................................................................................ 37
`2.6.6.2
`Single-dose toxicity .............................................................................................................. 38
`2.6.6.3
`Repeat-dose toxicity ............................................................................................................. 42
`2.6.6.4
`Genetic toxicology................................................................................................................ 62
`2.6.6.5
`Carcinogenicity..................................................................................................................... 68
`2.6.6.6
`Reproductive and developmental toxicology........................................................................ 68
`2.6.6.7
`Local tolerance ..................................................................................................................... 98
`2.6.6.8
`Labeling.............................................................................................................................. 100
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`2.6.7 TOXICOLOGY TABULATED SUMMARY .................................................100
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`OVERALL CONCLUSIONS AND RECOMMENDATIONS..................................102
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`2
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`NDA No. 22-054
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`Ferinject
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`I.
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`EXECUTIVE SUMMARY
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`Recommendations
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`A. Recommendation on approvability: From the preclinical pharmacology and
`toxicology view point, VIT-45 should be approved.
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`B. Recommendation for nonclinical studies: None.
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`C. Recommendations on labeling:
`The changes in the following sections of the non-clinical portions of the proposed label
`with edits are shown below: The underlined italics represent addition in the original
`version by the reviewer.
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` 8
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` USE IN SPECIFIC POPULATIONS
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`Summary of nonclinical findings
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`II.
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`VIT-45, an intravenous hematinic preparation liberates utilizable iron in the body for
`intermittent use in iron deficient anemia. The released iron binds with iron binding
`proteins and accumulates mainly in animal’s blood cells with about 76% in red cells,
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`(b) (4)
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`(b) (4)
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`

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`NDA 22-054
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`Ferinject
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`4
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`11% in liver and 2% in spleen and 1% in kidney. Single intravenous dose of 1 g/kg and
`0.24 g/kg in rats and dogs, respectively were not lethal but 2 g dose in mice was lethal.
`The repeat dose 13—week intravenous infusion toxicity study in rats and dogs showed iron
`deposition in multiple organs including liver, spleen, lymph nodes and kidneys. The dose
`of 9 mg/kg/week was tolerated well in these species. Similar tissue deposition was also
`seen in a chronic continuous intravenous infusion 26-week study in dogs,
`9 mg/kg/week was identified as a well tolerated dose. VIT—45 was not genotoxic in a
`battery of tests including,
`in vitro microbial mutagenesis assay, in vitro chromosome
`aberration test in human lymphocytes, in vitro mammalian cell mutation assay in mouse
`lymphoma L5178Y/TK+/— cells, in vivo mouse micronucleus test. VlT—45 exerted no
`adverse effect on the fertility and general reproductive performance in rats. It did not
`produce a teratogenic defect in pregnant rats but at a maternal toxic dose in rabbits, it
`caused doomed cranium with hydrocephaly. It did not produce perinatal and postnatal
`developmental defects in rat pups.
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`A.
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`Pharmacologic activity
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`VIT-45, an intravenous hematinic preparation liberates utilizable iron in the body for
`intermittent use in iron deficient anemia. Sponsor did not submit any new preclinical
`study to demonstrate the hematinic effects of the compound. VIT—45 is
`@(4)
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`These breakdown products are GRAS listed agents. Malotetriose is synthesized
`in kidneys from maltose and is hydrolyzed by amylase. Maltotetrose is a metabolite of
`dextrins and icodextrin used in peritoneal dialysis. It is metabolized into matotetraose,
`maltotriose, maltose and glucose.
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`The sponsor submitted a battery of neurological tests, including Irwin tests. VlT—45 did
`not exert significant effects on body temperature and spontaneous locomotor activity up
`to 90 mg/kg dose. No significant changes occurred in the respiratory parameters of
`conscious rats up to 90 mg/kg dose. The renal function test in conscious rats suggested a
`treatment related transient 33 to and 46 % decrease in urine output in male and female
`rats at 90 mg/kg dose with a slight decrease in urinary sodium, potassium, and chloride
`excretion. The total iron binding capacity and plasma iron of the animals were increased
`in a dose dependent manner.
`In telemetric dogs, an intravenous dose of up to 90 mg/kg
`VIT-45 produced a decrease in RR interval and, no significant changes in QT- and QTc-
`intervals.
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`B.
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`Nonclinical safety issues relevant to clinical use: None
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`NDA 22-054
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`Ferinject
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`5
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`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
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`2.6.1 INTRODUCTION AND DRUG HISTORY
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`NDA number: 22-054
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`Review number: 000
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`Information to sponsor: Yes ( ) No ( )
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`Sponsor and/or agent: Luitpold Pharmaceuticals, Norristown, PA.
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`Manufacturer for drug substance: Luitpold Pharmaceuticals, Norristown, PA.
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`Reviewer name: Yash M. Chopra, M.D., Ph.D.
`Division name: Division of Medical Imaging & Hematology Drugs Products
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`HFD #: 160
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`Review completion date: June 5, 2007
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`Drug:
`Trade name: Ferinject Injection
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`Generic name: Iron Carboxmaltose
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`Code name: VIT-45
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`Chemical name: The drug substance is a complex of polynuclear iron (III)
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`hydroxide with 4(R)-(poly-(1-->4) –O-〈-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-
`tetrahydroxy-hexanoate.
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`CAS registry number:
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`Molecular formula/molecular weight: 150,000 Daltons (Approximately)
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`Structure:
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`NDA 22-054
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`Ferinject
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`6
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`Relevant INDs/NDAs/DMFS: IND 63,243
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`Drug class: Hematopoeitic Agent/Hematinic Agent
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`Intended clinical population: For Iron Overload Patients
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`Clinical formulation: VIT-4S contains
`hydroxide, sodium chloride and less than
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`(mo-
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`on
`(5)“) ll'
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`Route of administration: Intravenous Injection
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`Intended clinical dose: The proposed maximum single dose of Fen'njectw (iron
`carboxymaltose) injection is 1000 mg or 15 mg/kg on day 0 and. maximum repeat doses is 2500
`mg/week for the treatment of iron deficiency anemia secondary to Pregnancy/Childbirth (Post-
`partum Anemia), Heavy Uterine Bleeding (HUB). In chronic hemodialysis patients, the intended
`clinical dose is 200 mg/dialysis session 2 or 3 times a week.
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`Disclaimer: Tabular and graphical information are constructed by the reviewer rmless
`cited otherwise.
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`[For (b)(2) applications:
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`Data reliance: Except as specifically identified below, all data and information
`discussed below and necessary for approval of NDA 22-054 are owned by Luitpold
`Pharmaceuticals, Norristown, PA. Any information or data necessary