CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202155Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`Tertiary Pharmacology Review
`
`By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`NDA: 202155
`Submission date: 9/28/2011
`Drug: apixaban
`Sponsor: Bristol-Myers Squibb Company and Pfizer
`Indication: Prevention of stroke and systemic embolism in patients with non-
`valvular atrial fibrillation
`
`Reviewing Division: Division of Cardiovascular and Renal Products
`
`
`Comments: The pharm/tox reviewer and supervisor found the nonclinical
`information submitted for apixaban to be sufficient to support the proposed use.
`
`The applicant and reviewer proposed pregnancy category B for the labeling. This
`appears appropriate as no fetal toxicity or malformations were observed in rats,
`mice and rabbits.
`
`Apixaban was evaluated for carcinogenicity in 2-year rat and mouse studies. The
`Executive Carcinogenicity Assessment Committee concluded that these studies
`were adequate and there were no clearly drug-related tumors in either study.
`
`Testicular degeneration was noted in male rats treated with apixaban for 3
`months beginning on postnatal day 4. The incidence was 33% at the highest
`dose of 600 mg/kg, which was higher than concurrent and historical controls. The
`severity at this dose was moderate to marked. The findings appeared reversible
`after a recovery period of 35 days and no impairment of mating or reproductive
`parameters was noted. Based on levels of unbound drug, there appears to be no
`margin between the NOAEL and the human exposure for this finding. The
`pharm/tox reviewer recommended that an additional juvenile animal study be
`conducted to determine if there is a critical period for toxicity before any pediatric
`trials are conducted.
`
`Conclusions:
`I concur with the Division pharm/tox conclusion that the nonclinical data support
`approval of this NDA. No additional nonclinical studies are recommended at this
`time. The proposed Established Pharmacologic Class for apixaban is "factor Xa
`inhibitor". This is appropriate because it is consistent with other moieties of this
`class. I agree with the division pharm/tox recommendations on labeling.
`
`
`Reference ID: 3148881
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PAUL C BROWN
`06/21/2012
`
`Reference ID: 3148881
`
`

`

`
`
`
`
`
`
`
`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:
`
`202,155
`Electronic Document Room (EDR)
`09/28/11, 09/29/10 (Nonclinical)
`09/28/11, 09/19/10 (Nonclinical)
`Apixaban
`Prevention of stroke and systemic embolism in
`patients with non-valvular atrial fibrillation.
`Bristol-Myers Squibb Company and Pfizer
`Applicant:
`Division of Cardiovascular and Renal Products
`Review Division:
`Patricia P. Harlow, Ph.D.
`Reviewer:
`Thomas Papoian, Ph.D., D.A.B.T.
`Supervisor/Team Leader:
`Norman Stockbridge, M.D., Ph.D.
`Division Director:
`Alison Blaus
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202,155 are owned by Bristol-Myers Squibb Company
`and Pfizer or are data for which Bristol-Myers Squibb Company and Pfizer has obtained
`a written right of reference. Any information or data necessary for approval of NDA
`202,155 that Bristol-Myers Squibb Company and Pfizer do 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 202,155.
`
`Reference ID: 3131634
`
`1
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
`
`
` EXECUTIVE SUMMARY ......................................................................................... 5
`1.1
`INTRODUCTION.................................................................................................... 5
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 5
`1.3 RECOMMENDATIONS............................................................................................ 5
`2 DRUG INFORMATION ............................................................................................ 9
`2.1 DRUG................................................................................................................. 9
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 9
`2.3 DRUG FORMULATION ........................................................................................... 9
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 10
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 10
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 10
`2.7 REGULATORY BACKGROUND .............................................................................. 10
`3 STUDIES SUBMITTED.......................................................................................... 10
`3.1
`STUDIES REVIEWED........................................................................................... 10
`3.2
`STUDIES NOT REVIEWED ................................................................................... 11
`3.3 PREVIOUS REVIEWS REFERENCED ....................................................................... 11
`
`Reference ID: 3131634
`
`2
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Table of Tables
`
`Table 1: Apixaban Regulatory Submissions.................................................................. 10
`
`
`Reference ID: 3131634
`
`3
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Table of Figures
`
`Figure 1: Structure of Apixaban....................................................................................... 9
`
`
`Reference ID: 3131634
`
`4
`
`

`

`NDA 202,155
`
`
`1
`
`Executive Summary
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Introduction
`1.1
`Apixaban, an inhibitor of the coagulation Factor Xa (FXa), is being developed as an
`antithrombotic/anticoagulant agent
`. Under NDA 202,155,
`apixaban is proposed for the prevention of stroke and systemic embolism in patients
`with nonvalvular atrial fibrillation. The dosing regimen in the Phase 3 trial was 5 mg of
`apixaban twice a day in patients with normal renal function.
`1.2 Brief Discussion of Nonclinical Findings
`This addendum to the previous nonclinical review filed on 2/21/12 is limited to
`documenting recommendations for the nonclinical portions of the label.
`
`1.3 Recommendations
`
`1.3.1 Approvability
`NDA 202,155 for apixaban is approvable from a pharmacology and toxicology
`perspective for the prevention of stroke and systemic embolism in patients with
`nonvalvular atrial fibrillation.
`
`1.3.2 Additional Non Clinical Recommendations
`The nonclinical addendum dated 4/13/2012 recommended that the label should indicate
`that apixaban is dialyzable.
`
`1.3.3 Labeling
`
`Sponsor’s proposal:
`
`8.1 Pregnancy
`Pregnancy Category B
`
`
`Reviewer’s recommendation:
`
`8.1 Pregnancy
`
`Reference ID: 3131634
`
`5
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Pregnancy Category B
`There are no adequate and well-controlled studies in pregnant women. Treatment
`during pregnancy may induce pregnancy-related hemorrhage and/or emergent delivery
`for which a reversal agent is not available.
`Demonstrated fetal exposure to apixaban during treatment of pregnant rats, rabbits and
`mice after implantation until the end of gestation did not induce fetal malformations or
`fetal toxicity. No maternal or fetal deaths were attributed to bleeding. Increased
`incidence of maternal bleeding was observed in rats, rabbits and mice at maternal
`exposures that were 4, 1, and 19 times, respectively, the human exposure of unbound
`drug, based on AUC comparisons at the maximum recommended human dose (MRHD)
`of 10 mg (5 mg twice daily). ELIQUIS should be used during pregnancy only if the
`potential benefit justifies the potential risk to mother and fetus.
`
`
`The sponsor did not propose wording for Section 8.2
`
`Reviewer’s recommendation:
`
`8.2 Labor and Delivery
`Safety and effectiveness of apixaban during labor and delivery have not been studied in
`clinical trials. Consider the risks of bleeding and of stroke in using apixaban in this
`setting [see Warnings and Precautions (5.2)].
`Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation
`Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure) did
`not result in death of offspring or mother rats during labor in association with uterine
`bleeding. However, increased incidences of bleeding signs, primarily during gestation,
`occurred at apixaban doses of ≥25 mg/kg, a dose corresponding to ≥1.3 times the
`human exposure.
`
`
`Sponsor’s proposal:
`
`8.3 Nursing Mothers
`
`Reviewer’s recommendation:
`
`8.3 Nursing Mothers
`
`Reference ID: 3131634
`
`6
`
`(b) (4)
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`It is unknown whether apixaban or its metabolites are excreted in human milk. Data in
`rats indicate a high excretion of apixaban in milk (12% of the maternal dose). A risk to
`newborns and infants cannot be excluded.
`A decision must be made either to discontinue breastfeeding or to discontinue/abstain
`from ELIQUIS therapy.
`
`
`Sponsor’s proposal:
`
`12
`Clinical Pharmacology
`12.1 Mechanism of Action
`
`Reviewer’s recommendation:
`
`Apixaban is an oral, reversible, and selective active site inhibitor of FXa. It does not
`require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound
`FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation,
`but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa,
`apixaban decreases thrombin generation and thrombus development. Preclinical
`studies of apixaban in animal models have demonstrated antithrombotic efficacy in the
`prevention of arterial and venous thrombosis.
`
`
`Sponsor’s proposal:
`
`13
`Nonclinical Toxicology
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Reference ID: 3131634
`
`7
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Reviewer’s recommendation:
`
`Apixaban was not carcinogenic when administered to mice and rats for up to 2 years.
`The systemic exposures (AUCs) of unbound apixaban in male and female mice at the
`highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20-times, respectively, the
`human exposure of unbound drug at the MRHD of 10 mg/day. Systemic exposures of
`unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day)
`were 2- and 4-times, respectively, the human exposure.
`Apixaban was not mutagenic in the bacterial reverse mutation (Ames) assay, and not
`clastogenic in Chinese hamster ovary cells in vitro, in a 1-month in vivo/in vitro
`cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in
`vivo.
`Apixaban had no effect on fertility in male or female rats when given at doses up to 600
`mg/kg/day, a dose resulting in exposure levels that are 2 and 4-times, respectively, the
`human exposure.
`Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation
`through the end of lactation produced no adverse findings in male offspring (F1
`generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5-times
`the human exposure. Adverse effects in the F1-generation female offspring were limited
`to decreased mating and fertility indices at 1000 mg/kg/day, a dose resulting in
`exposure that is 5-times the human exposure.
`
`Sponsor’s proposal:
`
`Reviewer’s recommendation:
`
`Section 13.2 was omitted in the dabigatran and rivaroxaban labels and should be
`omitted from the apixaban label.
`
`
`
`Reference ID: 3131634
`
`8
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202,155
`
`2 Drug Information
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Apixaban
`
`2.1 Drug
`CAS Registry Number: 503612-47-3
`
`Generic Name:
`
`Code Names:
`
`Chemical Name: 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-
`
`
`
`
`4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
`
`Molecular Formula/Molecular Weight: C25H25N5O4/459.50
`
`Structure:
`
`BMS-562247, DPC-AG0023
`
`Figure 1: Structure of Apixaban
`
`
`
`Pharmacologic Class: Factor Xa inhibitor
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`IND 68598, DCRP (11/09/2006)
`2.3 Drug Formulation
`Apixaban is formulated for oral administration as immediate release, film-coated tablets
`containing either 2.5 or 5 mg of active compound. The tablets also contain anhydrous
`lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and
`magnesium stearate. The film coating for the 2.5 mg tablet is
`
` which contains hypromellose
` lactose monohydrate, titanium dioxide,
`triacetin, and iron oxide yellow. The film coating for the 5 mg tablet is
`
`
`Reference ID: 3131634
`
`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202,155
`
`Patricia P. Harlow, PhD.
`
`“M", which contains hypromellose
`triacetin, and iron oxide red.
`
`2.4 Comments on Novel Excipients
`
`“m" lactose monohydrate, titanium dioxide,
`
`No novel excipients are used in the manufacture of apixaban tablets.
`
`2.5 Comments on lmpurities/Degradants of Concern
`
`A detailed review of the apixaban impurities was filed in DARRTS on October 31, 2011.
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`Apixaban is being developed for the prevention and treatment of multiple thrombosis-
`mediated conditions. Under NDA 202,155, apixaban is proposed for the prevention of
`stroke or systemic embolism associated with atrial fibrillation. The dosing regimen in the
`Phase 3 trial was 5 mg of apixaban once a day in atrial fibrillation patients with normal
`renal function.
`
`2.7
`
`Regulatory Background
`
`Apixaban submissions have been reviewed
`
`"m"
`
`Documents originally submitted to NDA 202,155 on 09/29/2010 included nonclinical
`study reports. Additional submissions were made to NDA 202,155 on 11/03/2010 and
`08/18/2011 prior to the PDUFA submission on 09l28l2011.
`
`Table 1: Apixaban Regulatory Submissions
`
`Application
`
`Division
`
`Initial date
`
`Indication
`
`(m4)
`
`IND 68598
`
`I DCRP
`
`I 11/09/2006
`
`Prevention of thromboembolic events in atrial
`fibrillation patients
`
`(m4)
`
`NDA 202,155
`
`DCRP
`
`09l28l2011
`
`(m4)
`
`
`DCRP U wsron ot Cardiovascular and Renal Products
`
`
`
`
`Prevention of stroke or systemic associated with
`atrial fibrillation
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`None.
`
`Reference ID: 3131634
`
`10
`
`

`

`
`
`Patricia P. Harlow, Ph.D.
`
`NDA 202,155
`
`3.2 Studies Not Reviewed
`None.
`
`3.3 Previous Reviews Referenced
`Please refer to the nonclinical review of NDA 202,155 by P. Harlow filed on 02/21/2012.
`
`
`Reference ID: 3131634
`
`11
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PATRICIA P HARLOW
`05/16/2012
`
`THOMAS PAPOIAN
`05/16/2012
`I concur.
`
`Reference ID: 3131634
`
`

`

`
`
`
`
`
`
`
`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:
`
`202,155
`Electronic Document Room (EDR)
`09/28/11, 09/29/10 (Nonclinical)
`09/28/11, 09/19/10 (Nonclinical)
`Apixaban
`Prevention of stroke and systemic embolism in
`patients with non-valvular atrial fibrillation.
`Bristol-Myers Squibb Company and Pfizer
`Applicant:
`Division of Cardiovascular and Renal Products
`Review Division:
`Patricia P. Harlow, Ph.D.
`Reviewer:
`Thomas Papoian, Ph.D., D.A.B.T.
`Supervisor/Team Leader:
`Norman Stockbridge, M.D., Ph.D.
`Division Director:
`Alison Blaus
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202,155 are owned by Bristol-Myers Squibb Company
`and Pfizer or are data for which Bristol-Myers Squibb Company and Pfizer has obtained
`a written right of reference. Any information or data necessary for approval of NDA
`202,155 that Bristol-Myers Squibb Company and Pfizer do 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 202,155.
`
`Reference ID: 3115968
`
`1
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 5
`1.1
`INTRODUCTION.................................................................................................... 5
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 5
`1.3 RECOMMENDATIONS............................................................................................ 6
`2 DRUG INFORMATION ............................................................................................ 6
`2.1 DRUG................................................................................................................. 6
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 7
`2.3 DRUG FORMULATION ........................................................................................... 7
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 7
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 7
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 7
`2.7 REGULATORY BACKGROUND ................................................................................ 8
`3 STUDIES SUBMITTED............................................................................................ 8
`3.1
`STUDIES REVIEWED............................................................................................. 8
`3.2
`STUDIES NOT REVIEWED ..................................................................................... 9
`3.3 PREVIOUS REVIEWS REFERENCED ......................................................................... 9
`4 PHARMACOLOGY.................................................................................................. 9
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS ................................................ 9
`5.1
`PK/ADME.......................................................................................................... 9
`TOXICOKINETICS ............................................................................................... 13
`5.2
`6 GENERAL TOXICOLOGY..................................................................................... 13
`
`7 GENETIC TOXICOLOGY ...................................................................................... 13
`
`8 CARCINOGENICITY ............................................................................................. 13
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 13
`
`SPECIAL TOXICOLOGY STUDIES................................................................... 13
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 13
`
`APPENDIX/ATTACHMENTS............................................................................. 13
`
`10
`
`11
`
`12
`
`
`Reference ID: 3115968
`
`2
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Table of Tables
`
`Table 1: Apixaban Regulatory Submissions.................................................................... 8
`Table 2: List of Studies Reviewed ................................................................................... 8
`Table 3: Reviewer’s Summary - Results from Study 930039361 .................................... 9
`Table 4: Reviewer's Summary – Results from Study 930046725 – Effect of Activated
`Charcoal on Apixaban Exposure................................................................................... 11
`Table 5: Sponsor’s Tables from Study 930046779 ....................................................... 12
`
`
`Reference ID: 3115968
`
`3
`
`

`

`NDA 202,155
`
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Table of Figures
`
`Figure 1: Structure of Apixaban....................................................................................... 7
`Figure 2: Sponsor's Figure from Study 930046779 ....................................................... 12
`
`
`Reference ID: 3115968
`
`4
`
`

`

`NDA 202,155
`
`
`1
`
`Executive Summary
`
`
`
`Patricia P. Harlow, Ph.D.
`
`Introduction
`1.1
`Apixaban, an inhibitor of the coagulation Factor Xa (FXa), is being developed as an
`antithrombotic/anticoagulant agent
`. Under NDA 202,155,
`apixaban is proposed for the prevention of stroke and systemic embolism in patients
`with nonvalvular atrial fibrillation. The dosing regimen in the Phase 3 trial was 5 mg of
`apixaban twice a day in patients with normal renal function.
`1.2 Brief Discussion of Nonclinical Findings
`This document is an addendum to the previous nonclinical review filed on 2/21/12. The
`two studies reviewed in this document
`
`could not be located in the NDA 202,155 submission.
`As a follow-on study to the previous pharmacokinetic interaction study using activated
`charcoal, dogs received five treatments in a Latin-square design. The treatments were
`apixaban (5 mg/kg) alone, apixaban followed by oral administration of a low dose of
`activated charcoal (250 mg/kg) at 3 hours after the apixaban dose, apixaban followed
`by oral administration of a low dose of activated charcoal at 5 hours after the apixaban
`dose, apixaban followed by oral administration of a low dose of activated charcoal at 3
`and 5 hours after the apixaban dose, or apixaban followed by oral administration of a
`high dose of activated charcoal (2500 mg/kg) at 3 hours after the apixaban dose. The
`greatest reduction of apixaban AUC(0-24) was 45.7% for the high dose charcoal
`treatment at 3 h post apixaban dose. Neither the low dose nor the high dose treatment
`significantly decreased Cmax values. However, the high dose charcoal treatment
`significantly increased the clearance as well as decreased the plasma trough
`concentration and mean residual time. This additional study in dogs provides further
`support that activated charcoal may be useful in cases of apixaban overdose.
`The second study examined the effect of hemodialysis on circulating concentrations of
`apixaban after oral or intravenous administration to four fasted male beagle dogs. The
`dogs received the following four sequential treatments separated by at least 48 hours:
`oral apixaban (5 mg/kg) without hemodialysis, intravenous apixaban (1 mg/kg) without
`hemodialysis, intravenous apixaban (1 mg/kg) with hemodiaIysis, and oral apixaban (5
`mg/kg) with hemodialysis. Over the total 4 hour dialysis period, approximately 19% and
`5.5% of the apixaban dose was recovered in the dialysate after intravenous and oral
`dosing, respectively. Although the overall AUC(0-24hr) of apixaban was not reduced, the
`AUC(0-4hr) was reduced 19.8% and 6.5% during dialysis following intravenous and oral
`apixaban administration, respectively. The mean plasma apixaban Cmax concentrations
`for the four dogs were reduced 24% and 12% during dialysis after intravenous and oral
`administration, respectively. These results indicate that apixaban is dialyzable and
`dosage adjustments may be necessary for patients taking apixaban while undergoing
`dialysis treatments.
`
`Reference ID: 3115968
`
`5
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202,155
`
`Patricia P. Harlow, Ph.D.
`
`1.3
`
`Recommendations
`
`1.3.1 Approvability
`
`NDA 202,155 for apixaban is approvable from a pharmacology and toxicology
`perspective for the prevention of stroke and systemic embolism in patients with
`nonvalvular atrial fibrillation.
`
`1.3.2 Additional Non Clinical Recommendations
`
`The sponsor should be encouraged to conduct a study in patients undergoing dialysis.
`The label should indicate that apixaban is dialyzable.
`
`1 .3.3 Labeling
`
`Section 2.2 indicates that
`
`(him
`
`The sponsor should be encouraged to
`conduct a study with rivaroxaban in patients undergoing dialysis. The label should
`indicate that “A preclinical study in dogs demonstrated that apixaban was found in the
`dialysate after oral and intravenous administration of apixaban administration.
`
`Section 10 already indicates that
`
`0”“)
`
`No change is necessary.
`
`2
`
`Drug Information
`
`2-1
`
`Drug
`
`CAS Registry Number: 503612-47-3
`
`Generic Name:
`
`Apixaban
`
`Code Names:
`
`EMS—562247, DPC-AGOOZ3
`
`Chemical Name:
`
`1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-
`4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3—carboxamide
`
`Molecular Formula/Molecular Weight: Cz5H25N5O4/459.50
`
`Reference ID: 31 15968
`
`

`

`NDA 202,155
`
`
`Structure:
`
`Figure 1: Structure of Apixaban
`
`
`
`Patricia P. Harlow, Ph.D.
`
`
`
`Pharmacologic Class: Factor Xa inhibitor
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`IND 68598, DCRP (11/09/2006)
`2.3 Drug Formulation
`Apixaban is formulated for oral administration as immediate release, film-coated tablets
`containing either 2.5 or 5 mg of active compound. The tablets also contain anhydrous
`lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and
`magnesium stearate. The film coating for the 2.5 mg tablet is
`
`, which contains hypromellose
`, lactose monohydrate, titanium dioxide,
`triacetin, and iron oxide yellow. The film coating for the 5 mg tablet is
`
` which contains hypromellose
` lactose monohydrate, titanium dioxide,
`triacetin, and iron oxide red.
`2.4 Comments on Novel Excipients
`No novel excipients are used in the manufacture of apixaban tablets.
`
`2.5 Comments on Impurities/Degradants of Concern
`A detailed review of the apixaban impurities was filed in DARRTS on October 31, 2011.
`
`
`
`2.6 Proposed Clinical Population and Dosing Regimen
`Apixaban is being developed for the prevention and treatment of multiple thrombosis-
`mediated conditions. Under NDA 202,155, apixaban is proposed for the prevention of
`
`Reference ID: 3115968
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202,155
`
`Patricia P. Harlow, PhD.
`
`stroke or systemic embolism associated with atrial fibrillation. The dosing regimen in the
`Phase 3 trial was 5 mg of apixaban once a day in atrial fibrillation patients with normal
`renal function.
`
`2.7
`
`Regulatory Background
`
`Apixaban submissions have been reviewed
`
`M“)
`
`. Documents
`
`originally submitted to NDA 202,155 on 09/29/2010 included nonclinical study reports.
`Additional submissions were made to NDA 202,155 on 11/03/2010 and 08/18l2011 prior
`to the PDUFA submission on 09/28/2011.
`
`Table 1: Apixaban Regulatory Submissions
`
`Application
`
`Division
`
`Initial date
`
`Indication
`
`I IND 68598
`
`I DCRP
`
`I 11/09/2006
`
`Prevention of thromboembolic events in atrial
`fibrillation nafienfs
`
`(um)
`
`(m4)
`
`NDA 202,155
`
`DCRP
`
`09/28/2011
`
`lbw)
`DCRP l) VISIon of Cardiovascular and Renal Products
`
`
`
`Prevention of stroke or systemic associated with
`atrial fibrillation
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`The two studies listed in Table 2 are reviewed in this document and were not previously
`reviewed. These studies
`"m"
`
`could not be located in the NDA 202,155 submission.
`However, one other study (930039361) in supporting document 294 had been
`submitted to NDA 202,155 and was reviewed in the previous nonclinical review of NDA
`202,155 (2/21/12).
`
`Table 2: List of Studies Reviewed
`
`Document
`Number
`
`930046725
`
`Study Title
`
`Effects of Activated Charcoal Administration on Phannacokinetics of Apixaban (BMS-
`562247 Followin- Oral Administration in Male Dos follow-on
`
`followinc oral and Intravenous Dosin- in Male Dos
`
`930046779
`
`Effect of Hemodialysis on Circulating Concentrations of Apixaban (EMS-562247)
`
`Reference ID: 31 15968
`
`

`

`NDA 202,155
`
`Patricia P. Harlow, PhD.
`
`3.2
`
`Studies Not Reviewed
`
`None.
`
`3-3
`
`Previous Reviews Referenced
`
`Nonclinical review of NDA 202,155 by P. Harlow filed on 02/21/2012 was referenced.
`
`4
`
`Pharmacology
`
`No additional pharmacology study was submitted.
`
`5
`
`PharmacokineticslADMEIToxicokinetics
`
`5.1
`
`PK/ADME
`
`In the previously reviewed Study 930039361, pharmacokinetics of apixaban were
`determined in four male beagle dogs after oral administration of 5 mg/kg apixaban in
`four sequential treatments that were separated by at least three days. Apixaban alone
`was administered during the first treatment period and apixaban followed by oral
`administration of activated charcoal (250 mg/kg) at 0.25, 1, and 3 hours after the
`apixaban dose was administered in the subsequent three treatment periods. The results
`indicated that all activated charcoal treatments decreased apixaban AUC values;
`however treatment at 3 hours after apixaban administration had the greatest effect of
`37%, 42% and 51% for AUC(M4), AUC(2_24), and AUC(4_24), respectively (Table 3).
`
`Table 3: Reviewer’s Summary - Results from Study 930039361
`
`——-l—
`ParameterlTreatment
`
`——_i—
`
`——-E_
`
`CL/F, mL/h/k m 100-9 i 41*
`
`Reference ID: 31 15968
`
`

`

`
`
`Patricia P. Harlow, Ph.D.
`
`NDA 202,155
`
`Study title: Effects of Activated Charcoal Administration on
`Pharmacokinetics of Apixaban (BMS-562247) Following Oral Administration
`in Male Dogs (follow-on)
`Study no.:
`Conducting laboratory and location:
`
`930046725 (Document 930046725)
`
`Drug, lot #, and % purity:
`
`Apixaban (BMS-562247), lot 7A28071,
`purity 99.6%
`
`
`The pharmacokinetics of apixaban (BMS-562247) was determined in five fasted male
`beagle dogs after oral administration of 5 mg/kg apixaban in 0.5% Tween 80 in Labrafil
`suspension in five sequential treatments that were separated by at least three days. In a
`Latin-square design, the treatments were apixaban alone, apixaban followed by oral
`administration of a low dose of activated charcoal (250 mg/kg) at 3 hours after the
`apixaban dose, apixaban followed by oral administration of a low dose of activated
`charcoal at 5 hours after the apixaban dose, apixaban followed by oral administration of
`a low dose of activated charcoal at 3 and 5 hours after the apixaban dose, or apixaban
`followed by oral administration of a high dose of activated charcoal (2500 mg/kg) at 3
`hours after the apixaban dose. Blood was collected at 0.5, 1, 2, 4, 6, 8, 12, 14, 20, and
`24 hours after apixaban administration. After preparation of plasma, apixaban
`concentrations were determined by a valid LC/MS/MS method. If the animal vomited,
`the vomit was also collected for analysis.
`The low dose activated charcoal treatment decreased plasma apixaban AUC(0-24) values
`by 15.5%, 6.9%, and 21.5% when administered at 3 h, at 5 h, and at both 3 and 5 h,
`respectively, post apixaban dose (Table 4). However, the greatest reduction of apixaban
`AUC(0-24) was 45.7% for the high dose charcoal treatment at 3 h post apixaban dose.
`Neither the low dose nor the high dose treatment significantly decreased Cmax values.
`However, the high dose charcoal treatment significantly increased the clearance (CL/F)
`as well as decreased the plasma trough concentratio