CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
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`APPLICATION NUMBER:
`203565Orig1s000
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`MEDICAL REVIEW(S)
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`M E M O R A N D U M
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`July 21, 2013
`
`Kathy M. Robie-Suh, M.D., Ph.D.
`Medical Team Leader, Hematology
`Division of Hematology Products
`Office of Hematology and Oncology Products, CDER
`
`Medical Team Leader Secondary Clinical Review
`NDA 203565, submitted 1/30/2013 (received 1/30/2013); updated clinical
`safety information, submitted 3/13/2013 and 3/20/2013 (received 3/13/2013 and
`3/20/2013)
`Injectafer (VIT-45, ferric carboxymaltose injection; FCM) for the treatment of
`iron deficiency anemia
`Sponsor: Luitpold Pharmaceuticals, Inc.
`
`
`NDA 203565
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`
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`
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`To:
`
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`This application seeks approval of Injectafer (ferric carboxymaltose) for the broad indication
`of the treatment of iron deficiency anemia. The proposed dosing is 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 delivered by intravenous infusion or injection.
`
`Background:
`This is a resubmission for this application which was initially submitted on September 30,
`2011. Clinical review of the original submission found the application acceptable for approval
`from a clinical viewpoint (M. Lu, 6/8/2012; K. Robie Suh, 7/20/2012). However, the
`application was not able to be approved due to Chemistry, Manufacturing and Controls (CMC)
`deficiency for the drug product manufacture leading to an overall withhold recommendation
`for the inspections of the manufacturing and testing facilities (see CDTL review, 7/21/2012).
`A Complete Response (CR) letter for the application was issued on July 23, 2012.
`
`The current resubmission is intended to address all the CMC concerns in the July 23, 2012 CR
`letter. In addition on March 13, 2013 and March 20, 2013 the sponsor provided updated safety
`information for the drug (Periodic Safety Update Report (PSUR) from Luitpold covering June
`18, 2011-June 17, 2012 and PSUR Addendum from Vifor Pharma covering June 18, 2012-
`January 31, 2013). The initial clinical review (M. Lu, 6/8/12) included safety data up to June
`17, 2011. The primary clinical review of this resubmission and Safety Updates has been
`conducted by M. Lu, (signed 7/9/2013).
`
`Ferric carboxymaltose (brand name FerinjectR) is currently approved in the European Union
`and a number of other countries (first approval 7/6/2007 in The Netherlands), mainly for the
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`Date:
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`From:
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`Subject:
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`Reference ID: 3344953
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`NDA 203565
`Page 2 of 6
`indication stated as “for treatment of iron deficiency when oral iron preparations are
`ineffective or cannot be used. The diagnosis must be based on laboratory tests.” Generally the
`product is labeled that use is contraindicated in cases of known hypersensitivity to Ferinject or
`to any of its excipients, in anemia not attributed to iron deficiency, and where there is evidence
`of iron overload or disturbances in utilization of iron. In some countries it is also
`contraindicated in pregnant women in the first trimester.
`
`Safety Update:
`June 18, 2011 through June 17, 2012 PSUR (3/13/2013 submission): From June 18, 2011
`through June 17, 2012 the sponsor reports 1,004 patients randomized to Ferinject and 485
`patients exposed to Ferinject in clinical trials. Postmarketing exposure was estimated to be
`197,291 patient years during this time with estimated total of 482,868 patient years of
`exposure. The sponsor reports in total 700 new cases of adverse events. Of these cases 149
`patients experienced serious events of which 53 were unlisted.
`There were 9 deaths reported during this time all due to serious unlisted adverse events. Two
`cases (both postmarketing) were considered related to Ferinject. These were:
`• A 56 year old woman with “asiderotic anaemia”who received 100 mg of Ferinject over
`15 minutes and began to experience dyspnea, agitation, bronchospasm and
`cardiorespiratory arrest beginning 5 minutes after start of the infusion. The infusion
`was stopped and patient received adrenaline, ketamine and other interventions but
`suffered neurological damage due to severe ischemia and she expired several days
`later. Event was considered related to Ferinject. The patient had also received
`pneumococcal vaccination 15 minutes prior to start of event which sponsor states as
`alternative explanation for the event.
`• An 80 year old woman with multiple medical problems including global heart failure,
`chronic heart disease, hypertension and hyperthyroidism received 500 mg of Ferinject
`diluted in 250 mL administered over 30 minutes for iron deficiency anemia. She
`presented 6 hrs later with left hemiparesis and was confirmed as having a partial middle
`cerebral artery stroke. She died approximately
` later. Event was considered
`possibly related to Ferinject.
`
`
`The other fatal events (not considered drug-related) were: myocardial infarction (3 patients);
`increasing respiratory insufficiency in 1 patient with lung neoplasm; severe respiratory tract
`infection and cardiorespiratory arrest in 1 patient; 1 patient due to cardiac failure
`
`after receiving Ferinject; 1 patient due to cardiac failure, pulmonary edema, and renal failure
`after receiving Ferinject.
`
`
`The sponsor indicates that cumulatively through December 31, 2011 there have been 236
`hypersensitivity associated cases of which 178 were serious (sponsor calculated rate of 0.045%
`for serious hypersensitivity cases). The events were reported as occurring within 30 minutes
`post dose in 56.4% (133/236) of cases; however, in 21.6% of cases timing of the
`hypersensitivity reaction was not reported. The sponsor states no patients died due to
`hypersensitivity reactions. Hypersensitivity events occurred at single doses ranging from
`50-1,500 mg iron in most cases (155/236). From June 18, 2011 through June 17, 2012 there
`were 13 new reports of hypersensitivity reactions, 8 serious. The sponsor indicates there were
`no reported deaths due to hypersensitivity. Outcome was not reported for 3 cases.
`
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`Reference ID: 3344953
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`(b) (6)
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`(b) (6)
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`(b) (6)
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`(b) (6)
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`NDA 203565
`Page 3 of 6
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`June 18, 2012 through January 31, 2013 PSUR Bridging Report (3/20/2013 submission):
`From June 18, 2012 through January 31, 2013 the sponsor reports an additional 194,300
`patient years of exposure to give an estimated total cumulative postmarketing exposure
`through January 31, 2013 of 677,168 patient years. During this time also an additional 326
`patients were enrolled in clinical trials (163 receiving Ferinject [53 pregnant women, 17
`patients with chronic heart failure and an additional estimated 93 (blinded) patients with
`chronic heart failure]). The sponsor reports a total 544 new cases of adverse events (108
`serious)(excludes 17 cases [4 serious] from consumers). There were 47 serious unlisted cases.
`There were 7 fatal cases, including 2 fetal deaths. Only one fatal case was deemed related to
`Ferinject: a 58 year old woman with pulmonary non-Hodgkin’s lymphoma, post-actinic
`cardiomyopathy, and other illnesses who experienced Grade IV hypersensitivity reaction and
`anaphylactic shock with dyspnea, hypotension, and bradycardia beginning 3 minutes after start
`of Ferinject infusion (received about 36 mg iron in 30 mL saline) and died.
`
`Pregnancy-related cases of serious unlisted events including fetal deaths are described in Dr.
`Min Lu’s Medical Officer Review (July 9, 2013). There were 7 pregnancy-related serious
`unlisted event cases and 6 fetal deaths. One patient died as described above and one recovered
`with unspecified sequelae. There were 18 cases of hypersensitivity that had some unlisted
`event term among the listed events. These are shown in the table below.
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`Reference ID: 3344953
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`NDA 203565
`Page 4 of 6
`No increases in frequency of certain identified events, including hypersensitivity,
`hemosiderosis, cardiotoxicity, hyperphosphatemia, overdose or hypertension were identified.
`
`The data in the safety updates did not raise new safety concerns or change the overall benefit-
`risk assessment. Post-marketing data should be reflected in the labeling.
`
`Sponsor’s proposal to address Pediatric Research Equity Act (PREA):
`No pediatric patients were studied for the current NDA. To address PREA (Pediatric Research
`Equity Act) the sponsor requests a waiver for patients less than years of age and requests a
`deferral for studies in pediatric patients
`to 17 years of age.
`
`
`Waiver Request (ages birth to less than years):
`The sponsor has requested a waiver for pediatric patients birth to
`group the sponsor states:
`
`“Based on our previous pediatric experience with our other approved IV iron
`(Venofer), recruiting patients from birth to
`years of age into our Phase III trials
`(Post marketing study) was waived by the Division.
`
` years. Regarding this age
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`
`
`
`Luitpold Pharmaceuticals, Inc., respectfully requests a waiver from conducting a
`pediatric study in the 0- years of age group due to logistical challenges associated with
`subjects of this age range. This request for a waiver is to meet the requirements of
`Pediatric Research Equity Act (PREA).”
`
`
`It should be noted that pediatric studies of Venofer for iron deficiency anemia in patients age
`<2 years with non-dialysis dependent chronic kidney disease (CKD) receiving or not receiving
`an erythropoietin were waived (NDA 21-135 letter dated June 17, 2005) (too few children with
`disease to study). With the original approval of Venofer for iron deficiency anemia in patients
`with hemodialysis-dependent chronic kidney disease, pediatric studies of Venofer in neonates
`and infants were not required, however, a post-marketing commitment (PMC) #1 requested
`additional information for possible need for and risks involved with Venofer® use in very
`young pediatric patients (approval letter dated November 6, 2000). A letter was sent to the
`sponsor on December 6, 2001 that PMC #1 for Venofer had been fulfilled.
`
`Deferral Request (ages years to 17 years):
`For pediatric patients age
`to 17 years the sponsor proposes to conduct two trials of Injectafer:
`(1)a pharmacokinetic/pharmacodynamic (PK/PD) study to characterize the PK of serum iron
`and determine appropriate dosing of FCM for the pediatric population with iron deficiency
`anemia and (2)a safety and efficacy trial of FCM versus iron sucrose.
`
` I
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` concur with Dr. Lu’s recommendation in the previous Clincal Review (signed 6/8/2012) that
`pediatric studies in this age range may be deferred.
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`Following is suggested wording for the post-marketing requirements (PMR) to address PREA:
`
`
`1. Identify an optimal dose of Injectafer for the pediatric patient population. Conduct one
`or more pharmacokinetic (PK) and pharmacodynamic (PD) trials in pediatric patients
`aged
`to < 17 years with iron deficiency anemia sufficient to justify and to
`
`Reference ID: 3344953
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`(b)
`(4)
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`(b)
`(4)
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`(b)
`(4)
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`(b)
`(4)
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`(b) (4)
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`(b)
`(4)
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`(b)
`(4)
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`(b)
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`NDA 203565
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`Page 5 of 6
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`characterize the dose to be tested in a confirmatory clinical trial of safety and efficacy.
`Identify the most relevant PD endpoints to measure.
`
`2. Determine the safety and efficacy of ferric carboxymaltose in pediatric patients aged I
`to <17 years with iron deficienc anemia b conductin a randomized, active-
`
`
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`controlled clinical trial.
`
`Conclusions and Recommendations:
`
`The sponsor has provided updated safety information in this submission. Overall, from a
`clinical perspective the benefit-risk assessment for approval of ferric carboxymaltose injection
`(Injectafer) with dosing of 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 delivered by
`intravenous infusion or injection remains favorable for the treatment of iron deficiency anemia
`in patients who are intolerant or had unsatisfactory response to oral iron and in patients with
`non-dialysis dependent chronic kidney disease.
`
`Labeling:
`Recommendations for the labeling were included in the CR letter sent to the sponsor on July
`23, 2012. However, it appears that by and large Agency recommendations from that drafi
`labeling were not incorporated in the sponsor’s labeling included in the resubmission.
`
`Recommendations for labeling are as provided in the previous clinical reviews (M. Lu,
`6/8/2012; KM Robie Suh, 7/20/2012) and Dr. Lu’s 7/9/2013 review.
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`Importanfly, it should be noted that in the draft labeling sent to the sponsor with the Complete
`Response letter the Agency recommended wording of the indication to be approved as:
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`Reference ID: 3344953
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`NDA 203565
`Page 6 of 6
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`Thus, the sponsor seeks to include patients with iron deficiency anemia
` without further specification as a labeled population in the
`Indications section of the label. In Study 1VIT0903 in Cohort 2 the sponsor allowed
`enrollment of “Subjects whose physicians feel the subject is inappropriate for a 14 day course
`of oral iron (e.g., baseline Hgb is sufficiently low that the patient requires rapid repletion of
`iron stores to minimize the risk of eventually needing a blood transfusion [e.g., Hgb <8 g/dL
`unless there is evidence of cardiac or respiratory dysfunction in which case IV iron may be
`used without oral run-in if Hgb <9 g/dL]) but who otherwise satisfy the entry criteria”. This
`population of patients (who did not participate in the 14 day oral iron run-in in this study)
`constituted 337 (33.8%) of the 997 patients enrolled in the study. The mean baseline
`hemoglobin in Cohort 2 was 9.1 g/dL (median, 9.1 g/dL) as compared to a mean of 10.6 g/dL
`(median, 10.7 g/dL) among patients in Cohort 1 (who were able to complete the oral iron run-
`in period). For most of these 337 patients the reason given for inclusion in Cohort 2 without
`oral iron run-in was given as “low hemoglobin”. About 130 patients in Cohort 2 had “Other”
`reasons listed for not undergoing run-in. The main “Other” reason given was some history of
`oral iron intolerance (about 77 patients), followed by history of unresponsiveness to oral iron
`in a smaller number (about 15 patients). Several patients had history of gastric bypass or other
`gastrointestinal surgery; several had malabsorption due to other gastrointestinal disorders.
`Thus, it appears that the majority of these “Other” patients who were enrolled in Cohort 2
`without first entering the oral iron run-in period had intolerance or unresponsiveness to oral
`iron based on medical history. About 74% of patients in Cohort 2 were listed as having
`previous iron therapy.
`
`In conclusion, it seems reasonable to conclude that the great majority of patients enrolled in
`Study 1VIT09031 had some exposure or trial of oral iron at some time prior to being
`randomized in the study and were considered for parenteral iron due to intolerance or
`inadequate response. The small group of patients with various gastrointestinal disorders and
`other reasons for receiving parenteral iron in the study (<5% of patients) is not sufficient to
`support a specific claim in the indications statement in the label.
`
`Finally, only patients with non-dialysis dependent chronic kidney disease (CKD) were enrolled
`in the CKD study (1VIT09030) submitted to support this application. Therefore, the labeled
`CKD population should be limited to patients with non-dialysis dependent chronic kidney
`disease.
`
`Post-marketing Studies:
`With regard to clinical post-marketing studies, a waiver for pediatric studies required under
`PREA for the indication should be granted for studies of Injectafer in patients less than years
`of age, because of too few children with the disease to study. A post-marketing requirement to
`study Injectafer in pediatric patients
` years to <17 years should be included with the
`approval. A deferral for these studies should be granted to allow time for the final protocols to
`be developed and the studies to be conducted. Protocols for proposed studies should be
`submitted for review.
`
`Reviews and recommendations from other disciplines should be considered for decision on
`regulatory action, labeling and post-marketing commitments.
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`Reference ID: 3344953
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`(b) (4)
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`(b)
`(4)
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`(b)
`(4)
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATHY M ROBIE SUH
`07/22/2013
`
`Reference ID: 3344953
`
`

`

`_ Ann. T. Farrell, M.D., Division Director
`
`Subject
`NDA/BLA #
`
`203565
`
`Su ilement #
`
`Applicant Name
`Luitpold Pharmaceuticals, Inc.
`Date of Submission
`10/03/11
`
`PDUFA Goal Date
`
`8/03/12
`
`Proprietary Name /
`Established
`S .
`
`Name
`
`Injectafer/Ferrous Carboxymaltose
`
`Dosa _e Forms / Stun- h
`
`Proposed Indication(s)
`For the treatment of iron deficiency anemia
`Action/Recommended Action for
`Complete Response
`NME:
`
`0ND Action Packa - e. includin- :
`
`
`
`David X. Gan, M.D./Leslie Ball. M.D.
`Anthony Orencia. M.D./Janice K. Pohlman. M.D./Susan D.
`Tho .son. M.D.
`
`——
`-——
`——
`—_—
`Other — Matemal Health Team
`Karen Feibus, M.D.l Lisa Mathis. M.D.
`
`Other-
`
`0ND=0ffice ofNew Drugs
`DDMAC=Division ofDrug Marketing, Advatising and Comtmmication
`08E: Ofiice of Sutveillance and Epidemiology
`
`Reference ID: 31 62523
`
`

`

`Signatory Authority Review Template
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`2
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`1. Introduction
`Luitpold submitted this application as a complete response to a non-approval letter
`received for ferrous carboxymaltose (FCM).
`
`An application for ferrous carboxymaltose was originally submitted on July 5, 2006 as
`NDA 022054 and received a non-approval letter on July 9, 2007 due to clinical safety
`concerns. Since that time the applicant has resubmitted the application on September
`18, 2007 and received another non-approval letter on March 11, 2008 due to clinical
`safety concerns.
`
`The applicant responded to the March 11, 2008 complete response letter on October
`3, 2011.
`
`The PDUFA goal date is August 3, 2012.
`
`From Dr. Lu’s review:
`
`FCM has been authorized for use and marketed in other countries by Vifor Pharma or
`a subsidiary company since 2007. It is currently registered under 3 different trade
`names: Ferinject®, Injectafer®, and Iroprem®, varying by country. As of 17 June
`2011, the product is approved for use and marketed in 20 European countries. It has
`been approved but it has not yet been marketed in 15 other countries. The Summary
`of Product Characteristics in U.K. lists that Ferinject is indicated for treatment of iron
`deficiency when oral iron preparations are ineffective or cannot be used.
`2. Background
`Products to treat iron deficiency include oral as well as injectable preparations. The iron
`injection products are available by prescription only. The oral iron products are available
`without a prescription.
`
`The currently marketed products are:
`Iron dextran (InFed and generics): indicated for patients with iron deficiency (any
`cause) who are assessed as not appropriate for oral iron therapy.
`Ferrlecit (ferric gluconate): indicated for patients with iron deficiency who are
`undergoing dialysis and receiving erythropoietin therapy.
`Venofer (iron sucrose): indicated for patients with iron deficiency who are:
`-non-dialysis chronic kidney disease patients (either receiving an erythropoietin
`or not)
`-hemodilaysis patients receiving an erythropoietin
`-peritoneal dialysis patients receiving an erythropoietin
`
`
`
`
`Reference ID: 3162523
`
`

`

`
`
`3
`
`Luitpold originally submitted an application to market Ferrous Carboxymaltose
`(proposed tradename – Ferinject) in 2006 for the following indications:
`
`is an intravenous iron product indicated for the treatment of iron deficiency anemia in:
`• Heavy Uterine Bleeding
`• Postpartum
`•
`Inflammatory Bowel Disease and
`• Hemodialysis patients
`
`The application received a non-approval letter due to safety concerns. Review of the
`controlled studies for the indication showed an imbalance in deaths observed in
`controlled trials. More deaths occurred in the ferrous carboxymaltose treatment arms
`than in the control subjects.
`
`The original database had 8 randomized controlled trials in subjects who were post-
`partum, had uterine bleeding, had inflammatory bowel disease, or were receiving
`hemodialysis. The control treatment was oral iron for the all trials with the exception of
`the hemodialysis trial.
`
`Dr. Rieves’s summary review noted:
`
`Overall, the totality of the efficacy data supports the Ferinject dose regimen's efficacy
`in a pattern indicative of acceptable treatment of iron deficiency anemia, regardless of
`the cause for the iron deficiency…
`
`Overall, the most notable safety findings relate to:
`-mortality among subjects receiving Ferinject
`
`-increased rate of serious adverse events among subjects receiving Ferinject,
`compared to oral iron
`-clinically important hypophosphatemia
`
`
`Dr. Rieves also noted that no clinical data was provided to support the safety of
`repeated “cycles” of ferrous caboxymaltose injections.
`
`Luitpold received a non-approval letter requesting that any resubmission provide the
`following:
`
`Clinical data to resolve the safety risks identified (excess mortality and severe
`hypophosphatemia) and verify the safety of more than one iron replenishment cycle
`
`The following text from Dr. Lu’s review highlights Agency and Applicant interactions
`from the receipt of the Complete Response letter.
`
`
`Reference ID: 3162523
`
`

`

`
`
`4
`
`The Agency issued a Not Approvable action on March 11, 2008. The letter indicated
`that the risk for mortality must be more thoroughly assessed and additional safety
`data should be obtained from clinical studies of Injectafer use among the applicable
`patient population of women who are intolerant to oral iron or who had an
`unsatisfactory response to oral iron. The Agency recommended that these studies
`use appropriate control groups in order to meaningfully interpret the data. The Agency
`stated that the proposed dosage regimen may deliver an excessive iron dose during a
`single administration and recommended that the sponsor consider the development of
`an alternate dosage regimen that delivers a lower (single dose) amount of iron. A
`meeting was held on May 18, 2009 under IND 63,243 between the Agency and the
`sponsor to discuss the proposed further clinical studies (1VIT09031 and 1VIT09030)
`to evaluate the efficacy and safety of a low dose of Injectafer (maximum single dose
`of 750 mg with maximum total dose of 1500 mg) in patients who are intolerant to oral
`iron or who had an unsatisfactory response to oral iron with a oral iron run-in period
`and also in patients with chronic renal disease (CKD). The Agency agreed on the
`proposed studies and the proposed cardiovascular composite safety endpoint to be
`evaluated in these studies. In the proposed studies, other intravenous iron were
`selected as control in patients with CKD and in patients who are intolerant to oral iron.
`The Agency emphasized the double-blind design to assess the safety endpoint.
`3. CMC/Device
`Drs. Lin and Pope-Miksinski and Ms. Brown reviewed this applicaiton. In their reviews
`they state the following:
`
`From the perspective of chemistry, manufacturing, and controls, this NDA may be
`approved, pending an “acceptable” overall recommendation from the Office of
`Compliance for the inspections of the manufacturing and testing facilities for the drug
`substance and drug product.
`
`Based on the provided stability data, a 24-month expiration dating period is granted
`for the drug product when stored at the proposed controlled room temperature.
`
`However, the Office of Compliance has issued a Withhold recommendation; therefore
`the Injectafer application cannot be approved. The initial decision was made in
`February 2012 and revisted in July 2012 and the recommendation stands.
`4. Nonclinical Pharmacology/Toxicology
`The pharmacology and toxicology information was referenced the previous
`submission under NDA 22-054. This application was reviewed and no deficiencies
`were identified for NDA 22-054.
`
`
`
`
`Reference ID: 3162523
`
`

`

`
`
`5
`
`5. Clinical Pharmacology/Biopharmaceutics
`The clinical pharmacology information was referenced the previous submission under
`NDA 22-054. This application was reviewed and no deficiencies precluding approval
`were identified for NDA 22-054.
`
`
`6. Clinical Microbiology
`The Product Quality Microbiology review recommends approval.
`
`
`7. Clinical/Statistical-Efficacy
`I have read NDA 22-054 summary and clinical reviews by Drs. Rieves, Robie-Suh,
`and Lu.
`
`The following text is from Dr. Lu’s review of this submission:
`
`Two randomized controlled pivotal trials (1VIT09031 and 1VIT09030) were conducted
`to support the efficacy of Injectafer with the proposed dose regimen of 15 mg/kg with
`the maximum individual dose of 750 mg and a total dose of 1,500 mg. Study
`1VIT09031 was conducted in patients with iron deficiency anemia who had an
`inadequate response to oral iron treatment, who were intolerant to oral iron during the
`14-day run-in period, or who were deemed unsuitable by the Investigator for the oral
`iron, mainly due to low hemoglobin level with or without co-morbidities. Study
`1VIT09030 was conducted in patients with non-dialysis dependent chronic kidney
`disease (NDD-CKD). Both clinical studies were randomized, open-label, controlled
`studies. In Study 1VIT09031, oral iron was used as control in patients who had an
`inadequate response to oral iron treatment in Cohort 1 and other IV iron products
`(mostly Venofer) were used as control in patients who were intolerant to oral iron in
`Cohort 2. In Study 1VIT09030, Venofer was used as control in patients with CKD. The
`primary efficacy endpoint was the mean change from baseline to the highest
`hemoglobin observed anytime between baseline and Day 35 or time of intervention in
`Study 1VIT09031 and between baseline and Day 56 or time of intervention in Study
`1VIT09030.
`
`In Study 1VIT09031, the results show that the mean increase in hemoglobin from
`baseline to the highest value between baseline and Day 35 or time of intervention in
`the Injectafer group was statistically significantly greater than that in the oral iron
`group in Cohort 1 (1.57 g/dL vs. 0.80 g/dL, p<0.01) and also higher than that in the IV
`standard care group (2.90 g/dL vs. 2.16 g/dL,p<0.01) in Cohort 2. This study
`demonstrated that Injectafer increased hemoglobin level in patients with iron
`deficiency anemia who had an inadequate response to oral iron treatment or
`who were intolerant to oral iron.
`
`In Study 1VIT09031, the mean increase in hemoglobin from baseline to the highest
`value between baseline and Day 56 or time of intervention in the Injectafer group was
`
`Reference ID: 3162523
`
`

`

`
`
`6
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`non-inferior to Venofer (1.13 g/dL vs. 0.92 g/dL, treatment difference 0.21 g/dL [95%
`CI 0.13-0.28 g/dL]). The results from the secondary efficacy endpoints analyses
`including hemoglobin response and iron indices were consistent with the primary
`efficacy analysis results in both studies. The results from subgroup analyses including
`baseline hemoglobin level and etiology of iron deficiency anemia in Study 1VIT09031
`and baseline hemoglobin, EPO use and CKD stage in Study 1VIT09030 were all
`consistent with the results from the primary efficacy endpoint analyses. This
`study demonstrated that Injectafer increased hemoglobin level in patients with iron
`deficiency anemia in NDD-CKD population.
`
` concur with the conclusions of the clinical and statistical review teams regarding the
`demonstration of efficacy for indication.
`8. Safety
`During the original NDA review (22-054), the review team identified excess mortality
`and hypophosphatemia as areas of concern for this product.
`
`Mortality and Cardiovascular Events
`Dr. Lu’s review did a focused analysis of mortality and Cardiovascular Events. The
`following text is from her review:
`
`The mortality rates were similar between Injectafer for the proposed dosing regimen
`and the comparators in pooled analysis of the two pivotal studies (16/1775, 0.9% vs.
`21/1783, 1.2%) and were also similar between Injectafer with the maximum single
`dose of 750 mg with the different total doses and the comparator in pooled analysis of
`the five clinical studies (17/2566, 0.7% vs.22/2590, 0.8%). For all completed studies,
`the overall mortality rate was 0.5% (33/6679) in the Injectafer-treated patients and
`0.6% (30/5394) in comparator-treated patients.
`
`In the two pivotal trials, no significant difference was found for the pre-specified
`primary cardiovascular composite safety endpoint (including death, MI, stroke,
`unstable angina, CHF, hypertension and hypotension) between Injectafer and Venofer
`or pooled comparators (10.8%, 11.1%, and 9.7%, respectively). Hypertensive events
`were found to be significantly higher in the Injectafer group as compared to the
`Venofer group, or the pooled comparator group (6.0%, 4.1%, and 3.5%, respectively).
`
`Treatment-emergent serious adverse events were similar among Injectafer, Venofer,
`and the pooled comparators groups numerically and by organ group. The incidence of
`treatment-emergent serious or severe hypersensitivity/allergic adverse events was
`1.5% for Injectafer and 1.6% for Venofer. Flushing and hypertension were the most
`common adverse events resulting in premature discontinuation from the trial.
`
`Overall assessment of drug-related adverse events
`From Dr. Lu’s review:
`
`
` I
`
`Reference ID: 3162523
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`7
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`The incidence of any drug-related treatment-emergent adverse event was greater in
`the FCM group (23.5%) compared with the Venofer (17.3%) and pooled comparators
`(15.9%) group.
`
`The most common ( ≥1.0%) drug-related treatment-emergent adverse events in the
`FCM group were nausea (7.2%), hypertension (3.8%), flushing (2.7%),
`hypophosphatemia (2.1%),dizziness (2.0%), vomiting (1.7%), injection site
`discoloration (1.4%), headache (1.2%), ALT increased (1.1%), and dysgesusia
`(1.1%). Drug-related treatment-emergent adverse events that occurred more
`frequently (by ≥1%) with Injectafer than with pooled comparator included
`nausea, hypertension, flushing, hypophosphatemia, vomiting, and injection site
`discoloration.
`
`
` concur with the conclusions of the clinical and statistical review teams.
`
`Dr. Lu’s review recommends approval. The following is the text from her review:
`
`From a clinical perspective, Injectafer should be approved for the indication for the
`treatment of iron deficiency anemia in patients who are intolerant to oral iron or have
`had unsatisfactory response to oral iron and in patients with non-dialysis dependent
`chronic kidney disease.
`
`
` I
`
`9. Advisory Committee Meeting
`This product was discussed at a Drug Safety and Risk Management Advisory
`Committee Meeting on February 1, 2008. From Dr. Lu’s review:
`
`The Committee voted that the available clinical data indicated Injectafer® was
`associated with a mortality disadvantage compared to oral iron and recommended an
`unfavorable benefit-risk assessment for the proposed indication. The committee did
`consider the data as providing a favorable benefit-risk assessment for Injectafer in the
`treatment of iron deficiency anemia in post-partum women or women with heavy
`uterine bleeding who have had an unsatisfactory response to oral iron or were
`intolerant of oral iron.
`
`
`
`Pediatrics
`10.
`From Dr. Lu’s review:
`
`The applicant requested a deferral of pediatric studies in and 17 years of age group
`under PMRs and requested a waiver of a pediatric study in the 0- years of age group
`to meet the requirements of Pediatric Research Equity Act (PREA). The proposed
`pediatric studies in and 17 years of age group include one
`pharmacokinetic/pharmacodynamic study and one safety and efficacy study in
`
`Reference ID: 3162523
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
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`8
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`pediatric patients with iron deficiency anemia. The applicant proposed to submit full
`pediatric study protocols within one year of approval and recruitment will begin
`within the first 18 months after the NDA is approved