CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202155Orig1s002
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`Clinical Pharmacology/Biopharmaceutics Review
`Labeling Supplement
`
`PRODUCT (Generic Name):
`NDA:
`PRODUCT (Brand Name):
`DOSAGE FORM:
`
`DOSAGE STRENGTHS:
`INDICATION:
`
`SUBMISSION DATE:
`
`SPONSOR:
`REVIEWERS:
`TEAM LEADER:
`OCP DIVISION:
`
`0ND DIVISION:
`
`Apixaban
`202-155
`ELIQUIS®
`Tablets
`
`2.5 mg and 5 mg
`(m4) of stroke, systemic embolism,
`in patients with non-valvular atrial fibrillation
`4/29/2013
`
`(but)
`
`Bristol-Myers Squibb and Pfizer
`Ju-Ping Lai, Ph.D.
`Raj anikanth Madabushi, Ph.D.
`DCP 1
`
`HFD 120
`
`TABLE OF CONTENTS
`
`1 EXECUTIVE SUMNIARY
`
`1.1 RECOMMENDATIONS
`
`2 CLINICAL PHARMACOLOGY SUMNIERY
`
`3 DRAFT LABELING RECONflVfENDA'IIONS
`
`4 APPENDIX— INDIVIDUAL LITERATURE REVIEWS
`
`2
`
`3
`
`3
`
`5
`
`9
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`1. EXECUTIVE SUMMARY
`
`In this submission, the applicant proposes
`
`the results of a dedicated study in ESRD
`subjects maintained on hemodialysis. In addition, the applicant also proposes to include the
`PK/PD information based on the results of a dedicated PK/PD drug interaction study of apixaban
`with prasugrel.
`
`(I!)(4)
`
`Apixaban was approved in December 2012 as a factor Xa inhibitor anticoagulant indicated to
`reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In
`the original submissions, an activated charcoal study showed that half-life of apixaban decreased
`from ~l3h to ~ 5h when charcoal is administered 2 hours post apixaban. Since no clear
`hypothesis explaining the effect of charcoal (not systemically absorbed), Agency felt the need to
`explain this finding in the US package insert. With available information at the time, we
`reflected our thoughts in the approved label. The rationale is summarized below.
`
`Apixaban has an absolute bioavailability (BA) of 50%. ~ 50 % of apixaban was recovered in the
`feces after an oral dose. Distal small bowel and ascending colon have absorption capacity up to
`~50 % of that absorbed fiom oral administration. Activated charcoal administered 2 h after
`
`apixaban resulting in ~50% decrease in exposure of apixaban. The biliary excretion of apixaban
`is minimal (2.4%). Our understanding was that activated charcoal binds/adsorbs apixaban in the
`gastrointestinal (GI) preventing additional absorption from the remaining drugs in the GI tract. In
`this sense, elimination of apixaban from systemic circulation was not expected to change by
`activated charcoal therefore half-life change was not expected. However, half-life of apixaban
`decreased from ~l3h to ~ 5h with charcoal. When looking into IV data, the half-life is apparently
`shorter (~6 h) suggesting a possibility of prolonged absorption causing a longer apparent half-life
`after oral administration.
`
`The applicant believes that direct intestinal excretion (IE) and entero—enteric recirculation (EER)
`play a significant role on apixaban excretion/disposition. It is noted that this is a new proposal
`and is contrary to the applicant’s understanding of the pharmacokinetics of apixaban in the
`original submission, i.e., there is insignificant intestinal and biliary excretion for apixaban. Based
`on this information, the applicant claims that the half-life reduction of apixaban when charcoal is
`administered is justified.
`
`Based on the findings from the two dedicated studies i.e., impact of ESRD and the interaction
`between apixaban and prasugrel, the applicant is seeking to update sections 12.2 and 12.3 of the
`US package insert.
`
`We have reviewed the submitted information and conducted additional literature search. We
`
`conclude that neither mechanisms proposed by the applicant can be confirmed without additional
`clinical studies. We find the results of the dedicated study in ESRD subjects maintained on
`hemodialysis and the interaction study with prasugrel acceptable.
`
`(11/03/2008)
`
`Reference ID: 3396823
`
`2
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`1.1 Recommendations
`
`The Office of Clinical Pharmacology has reviewed this submission and has the following
`recommendations:
`0
`
`o The impact of charcoal administration on the AUC but not the half-life findings will be
`included in the label.
`
`0 Dosing instructions for patients with ESRD maintained on hemodialysis will be provided
`in the label. The recommended dose of apixaban in ESRD patients is 5 mg b.i.d.
`In
`ESRD patients either age280 years or body weights 60 kg, the recommended dose is 2.5
`mg b.i.d.
`
`Detailed labeling recommendations are presented in Section 3.
`
`2. CLINICAL PHARMACOLOGY SUNINIARY
`
`
`
`(11/03/2008)
`
`Reference ID: 3396823
`
`3
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`2.2 Impact of ESRD and Hemodialysis on the Pharmacokinetics of Apixaban
`
`
`
`Compared to healthy subjects, apixaban AUC was 36% greater in ESRD subjects after
`hemodialysis. This increase is slightly lower than that previously reported in subjects with severe
`impairment in renal function (CrCl of 15 - 30 mL/min - exposure 50% greater compared to
`normal renal flmction). It should be noted, currently there is no dose adjustment recommended in
`patients with severe impairment of renal function.
`
`In subjects with end-stage renal disease (ESRD), a 4-hour hemodialysis session with a dialysate
`flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min started 2 hours
`
`(1 1/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`after administration of a single 5 mg dose of apixaban, the AUC of apixaban was 17% greater
`compared to those with normal renal fimction. As expected the dialysis clearance of apixaban is
`approximately 18 mL/min resulting in a 14% decrease in exposure due to hemodialysis.
`
`Protein binding was similar between healthy controls and the two periods: 93.2%, 91.5% and
`94.1%. So the impact of protein binding is not significant.
`
`The concentration-anti-Xa activity relationship in the ESRD subjects is reasonably similar
`compared to healthy subjects with normal renal fimction.
`
`3. DRAFT LABELING RECOMMENDATIONS
`
`Only Sections contain clinical pharmacology related changes are provided. Sponsor’s new
`proposal is marked in Blue. Sponsor proposed deletions are shown as—striket-h-Foughs. The
`OCP’s recommendations are shown as track changes in Red. The rationale supporting the
`reviewer’s edits are provided below the specific edits as Rew'ewer’s Comments.
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dose
`
`The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily
`
`M4)
`
`Reviewer ’s Comments:
`
`(no)
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`| 8.6
`
`ESRD Patients Maintained with hemodialysis
`
`Ihe recommended dose [or ESRD patients maintained with hemodialysis is 5 mg orally twice
`dail . For the ESRD atients maintained with hemodial sis havin either one o the risk actors
`
`at age >80 years or body weight < 60kg the recommended dose should be reduced to 2.5 mg
`twice dail . Ihere is no clinical er erience or this dosin re "men in this atient o ulation.
`
`Reviewer ’s Comments: As ESRD patients were not enrolled in the pivotal trial, there is no
`clinical experiencefor this patientpopulation. The dose recommendation is based on the similar
`apixaban exposure and similar anti-FXa activity observed in the new PK/PD study report in this
`submission when compared to the datafrom severe renal impairedpatients.
`
`1 0
`
`OVERDOSAGE
`
`There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding [see
`Warnings and Precautions (5.2)].
`
`(11/03/2008)
`
`Reference ID: 3396823
`
`5
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg
`daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no
`clinically relevant adverse effects.
`
`
`
`In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-m
`dose of a ixaban reduced mean a ixaban AUC b 50% and 27%, res ectivel
`.
`
`|
`
`e manaiement o aiixa an overdose or accidental iniestion#
`
`, administration of activated charcoal ma be usefiil in
`
`Reviewer ’s Comments:
`
`
`
`
`1 2
`
`CLINICAL PHARMACOLOGY
`
`1 2.2
`
`Phannacodynamics
`
`Reviewer’s Comments:
`
`Pharmacodynamic Drug Interaction Studies
`
`Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel,
`enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were
`observed with aspirin .clopidogrel,
`- 50% to 60% increase in anti-FXa
`activity was observed when apixaban was coadministered with enoxaparin or naproxen.
`
`Reviewer ’s Comments: Addition ofPD interaction information with prasugrel is acceptable. As
`the bleeding related AEs were significantly more flequent in the co-administered group,
`additional language to describe thefindings will be provided by the medical oflicer.
`
`(11/03/2008)
`
`Reference ID: 3396823
`
`6
`
`

`

`NDA# 202155
`
`Drug Name: Apixaban
`
`12.3
`
`Phannacoklnetics
`
`
`
`Absorption
`
`
`
`The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of
`
`ELIQUIS. Food does not aflect the bioavailability of apixaban. Maximum concentrations C
`
`3 to 4 hours after oral administration of ELI UIS
`
`Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for
`oral doses up to 10 mg. At doses 225 mg, apixaban displays dissolution-limited absorption with
`decreased bioavailability.
`
`Elimination
`
`Apixaban is eliminated in bofll urine and feces. Renal excretion accounts for about 27% of total
`clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in file
`feces.
`
`
`
`Apixaban has a total clearance of approximately 3.3 L/hour and an a
`
`aren
`
`half-life of airoximateli 12 hours followin oral administratio
`
`Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.
`
`Reviewer ’s Comments:
`
`Drug Interaction Studies
`
`famotidine, atenolol, prasugrel, and
`In dedicated studies conducted in healthy subjects,
`enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.
`
`In studies conducted in healthy subjects, apixaban did not meaningfully alter
`pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid.
`
`the
`
`(11/03/2008)
`
`Reference ID: 3396823
`
`7
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`Reviewer ’s Comments: Addition ofPK interaction information with prasugrel is acceptable.
`
`Specific Populations
`
`The efl'ects of level of renal impairment, age, body weight, and level of hepatic impairment;
`”(4’ on the pharmacokinetics of apixaban are summarized in Figure 3.
`
`Population Description
`
`End-Stage Renal
`Disease‘lNormal
`.
`Renal Impairment:
`Severe'lNonnal
`
`Renal Impairment:
`Moderate/Manna]
`
`Renal Impairment:
`Mild/Normal
`
`Age:
`265 years/18-40 years
`
`Body Weight:
`2120 kg/65-85 kg
`
`Body Weight:
`550 kg/65-85 kg
`
`Hepatic Impairment
`Moderate/Manna]
`
`Hepatic Impairment
`Mild/Normal
`
`PK
`
`cw
`AUC
`
`c"m
`AUC
`
`cm
`AUC
`
`Cm
`AUC
`
`AUC
`
`CmI
`AUC
`
`cw
`AUC
`
`Cw
`AUC
`
`Cm
`AUC
`
`Cm
`
`Fold Change and 90% Cl
`
`Recommendation
`
`'
`
`'
`
`om
`
`.
`No dose adjustment
`No dose adjustment
`
`No dose adjustment
`
`N0 dose adjustment
`
`No dose adjustment
`
`No dose adjustment
`
`No dose adjustment
`
`Dosing recommendation
`cannot be provided
`
`No dose adjustment
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`Change Relative to Reference‘
`
`* ESRD subjects maintained with chronic and stable hemodialysis; Reponed PK findings are following sin le
`dose of apixaban p_ost hemodialysis
`0' (0
`
`Creatinine clearance 15 to 29 mL/min.
`
`it Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations.
`
`A study in healthy subjects comparing the pharmacokinetics in males and females showed no
`meaningful difference.
`
`The results across pharmacokinetic studies in normal subjects showed no difl'erences in apixaban
`pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No
`dose adjustment is required based on race/ethnicity.
`(b
`”(”ESRDg a 4-hour hemodialysis session with a dialysate
`In subjects with
`flow rate of 500 mL/min and a blood flow rate 1n the range of 350 to 500 mL/min started 2 hours
`I after administration of a single 5 mg dose of apixaban,
`«0(4)
`
`(11/03/2008)
`
`Reference ID: 3396823
`
`8
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`a”) the AUC of apixaban was 17%
`greater compared to those with normal renal function. The dialysis clearance of apixaban
`IS a
`roximatel 18 mL min resultin in a 14° decrease in e osure due to hemodial sis
`
`compared to off-dialysis period.
`
`Protein binding was similar between healthy controls and the on-dialysis and off-dialysis
`periods reported as 93.2 %. 94.1 (’[q and 91.5 019. respectively.
`
`Reviewer ’3 Comments: Addition ofPK information in ESRD patients with dialysis is acceptable.
`As new information become availablefrom the study, keyfindings are to be provided in the label
`and to support the labelfor ESRD patients on hemodialysis. Currently there is no dose
`adjustment recommended in patients with severe impairment ofrenalfimction. The proposed
`action is no different than what we currently have ofpatients with severe impairment ofrenal
`firnction (CrCI 15 - 30 mL/min). Details regarding the study are included in the individual study
`review in Section 4 in this review.
`
`4. APPENDIX— INDIVIDUAL STUDY REVIEWS
`
`Renal Impairment — ESRD maintained with hemodialysis
`
`Study Period 06/28/1 1-09/ 12/ 1 1
`Report#CV185087
`I Title
`Single-Dose Study To Evaluate the Pharmacokinetics, pharmacodynamics, and
`Safe of A ixaban in Sub'ects on Hemodial sis
`
`EDR Link \\cdsesubl\evsprod\nda202155\0086\m5\53-clin—stud—rep\533-rep—human—pk-stud\5333-inuin-factor-
`pk-stud—rep\cvl85087\study—cv185087—csr-final.pdf
`
`Non-Randomized Open-Label
`INormal (A)
`
`ElMild 7 ElModerate
`
`Single-Center
`ElSever
`IESRD (B)
`
`
`
`7
`No. of Grou u s
`No. of Subject
`/Com O leted
`
`Males/Females
`
`A ye, Mean ran - e
`Body Weight, kg,
`Mean rano e
`
`47.0(34_59)
`87.4
`(66.3—114.7)
`
`f
`.
`
`V
`
`j
`.
`
`46.9(36-63)
`92.5
`(62.2-126)
`
`Enrollment and pre—classification of subjects was based upon the estimated CLcr value
`determined using Cockcroft—Gault formula at the time of screening and baseline. Estimation of
`GFR was also erformed on da -1 usin MDRD euation.
`
`All subjects received apixaban after at least a 10-hr fast.
`Group A: Subjects received a single oral dose of 5 mg apixaban
`Group B: Subjects requiring dialysis followed a thrice-weekly dialysis schedule. Apixaban was
`dosed twice in hemodialysis subjects may 1 of Periods l and 2) separated by a washout of at
`least 7 days.
`On Da 1 of Period 1, a 4-hour hemodial sis session was started 2 hours after a ixaban
`
`(11/03/2008)
`
`Reference ID: 3396823
`
`9
`
`

`

`
`
`
`
`NDA # 202155
`
`Drug Name: Apixaban
`
`administration.
`On Day 1 of Period 2, apixaban was dosed immediately after completion of a 4-hour
`hemodialysis session.
`Sampling Times:
`PK, plasma: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 60 and 72 hours
`post dose.
`PK, urine: Pre-dose and 0-12, 12-24, 24-48 and 48-72 hours post dose.
`PD, plasma: Pre-dose and 0.5, 1.5, 3, 6, 12, 24, 48 and 72 hours post dose.
`Dialysate: 2, 2-3, 3-4, 4-5 and 5-6 hours post dose.
`
`
` 
`
` Classification of renal function is consistent with the FDA Guidance Recommendations:
` Yes  No
`
` Renal function was determined via  C-G formula for healthy subjects at screening and Day -1
`  MDRD formula on Day -1
` Renal function was determined at:  Screening Baseline
` The control group is adequate  Yes  No
` The groups are matched by Age  Sex  Body Weight  Smoking Status  Race
` The selected dose is acceptable  Yes  No
` Protein Binding: All Limited (in all subjects)
`
`Sampling Times: 4 hours after apixaban dose
`
`Method: Equilibrium dialysis
` Dosing is long enough to obtain steady state  Yes  No Not Applicable
` Sample size was determined based on statistical analysis  Yes  No
` The overall study design acceptable:  Yes  No
`
`Analytical Method (Study Samples Analysis)
`
` 
`
` Study samples were analyzed within the established stability period:
` Quality control samples range is acceptable
`
`Internal standard was used
` Method was validated prior to use
` Chromatograms were provided
` Overall performance is acceptable
`
` Yes  No
` Yes  No
` Yes  No
` Yes  No
` Yes  No
` Yes  No
`
`10
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
` Yes  No
`
`LC-API/MS/MS methods were utilized for determination of apixaban and its metabolite, BMS-
`730823 (M1). Assay performances are provided below:
`
`
`
`
`
`
`Pharmacokinetics of Apixaban
`
`1. Is there a relationship between creatinine clearance and AUC? Yes No NA, if yes
`explain
`2. Is there a relationship between creatinine clearance and Cmax? Yes No NA, if yes
`explain
`
`
`
`
`11
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`12
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`
`
`
` Compared to healthy subjects, apixaban AUC(INF) and AUC(0-T) were 36% and 39%
`higher in ESRD subjects, respectively, after hemodialysis; whereas apixaban Cmax was
`10% lower in these subjects but the 90% CI includes 1, when apixaban was administered
`immediately after completion of hemodialysis (Group B, Period 2).
` Hemodialysis appears to reduce apixaban Cmax, AUC(INF) and AUC0-T by 13%, 14%
`and 14%, respectively, in ESRD subjects, respectively, when apixaban was administered
`2 hr before the start of the dialysis session (Group B, Period 1) compared to when
`apixaban was administered immediately after completion of hemodialysis. Thus,
`compared to healthy subjects,apixaban AUC(INF) and AUC(0-T) appeared to be only
`17% and 19% higher, respectively, in ESRD subjects when hemodialysis was started 2 hr
`after apixaban administration; apixaban Cmax appeared to be 21% lower than that
`observed in healthy subjects.
`
`
`Pharmacokinetics of Metabolite (M1, BMS-730823)
`
`
`13
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`14
` (11/03/2008)
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`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
` Exposure to BMS-730823 was low, with geometric means of maximum plasma
`concentrations ≤ 20 ng/mL across the 3 groups.
` BMS-730823 geometric mean Cmax and AUC(0-T) was approximately 1.85- and 4.6-
`fold higher in ESRD subjects with apixaban administered immediately after completion
`of hemodialysis than that observed in subjects with normal renal function.
` BMS-730823 geometric mean Cmax and AUC(0-T) were approximately 1.47- and 3.6-
`fold higher in ESRD subjects when hemodialysis was started 2 hr after apixaban
`administration than that observed in subjects with normal renal function.
` BMS-730823 Tmax was also increased in ESRD subjects.
` Metabolite exposure was lower in ESRD subjects when hemodialysis was started 2 hr
`after apixaban administration; BMS-730823 concentration in dialysate was negligible
`(i.e. below the lower limit of quantitation, LLOQ).
`
`
`Protein binding
`
`
`
`
`
`
`
`
`15
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`
`
`
` Unbound apixaban PK parameters followed similar trends to those observed for total
`drug concentration. Unbound apixaban Cmax, AUC(0-T), and AUC(INF) were 13%,
`73%, and 69% higher, respectively, in ESRD subjects when apixaban was administered
`immediately after completion of hemodialysis, than that observed in healthy subjects.
`In ESRD subjects, unbound apixaban Cmax, AUC(0-T) and AUC(INF) were
`approximately 40% lower when hemodialysis started 2 hr after apixaban administration,
`resulting in unbound apixaban AUC comparable to that observed in healthy subjects and
`a 32% lower Cmax than that observed in healthy subjects.
`
`
`
`
`Pharmacodynamics
`
`
`
`
`16
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`
`
`
`
`
`
` Baselines of INR and PT in ESRD subjects appear to be higher than those in
`healthy subjects.
` Following administration of apixaban, INR and PT increased initially then
`returned to baseline in each group. The percent change from baseline appeared
`comparable across the three treatment groups.
` For aPTT, following administration of apixaban, aPTT increased initially then
`returned to baseline. Percent change from baseline varied slightly between Groups
`A and B, and between Periods for subjects in Group B. The largest mean
`increases (± SD) relative to baseline, were 19.85% (± 20.398) at 3 hr, 6.96% (±
`9.624 ) at 2 hr, and 23.04%( ± 14.811 ) at 3 hr for Group A, Group B Period 1,
`and Group B Period 2, respectively.
`
`
`
`Anti-Factor Xa Activity
`
`
`17
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
` A direct linear relationship between anti-FXa activity values and apixaban plasma
`concentrations in all three groups
`
`
`Safety
`
`Was there any death or serious adverse events?  Yes  No  NA
`
`Conclusions
`
`Is there is a need to adjust the dose in patients with renal impairment? Yes No NA
`Exposure and anti-FXa activity of apixaban in ESRD patients maintained with
`hemodialysis appeared to be similar to those with moderate to severe renal impaired
`patients. Dose adjustment based solely on this study may not be warranted; however,
`combination of additional risk factors might lead to dose adjustment.
`
`
` ESRD subjects had 36% higher apixaban exposure (AUC) than that observed in
`healthy subjects with normal renal function.
` Hemodialysis decreased apixaban exposure in ESRD subjects by ~14% resulting
`in an AUC that was approximately 17% higher than that in subjects with normal
`renal function.
` Apixaban Cmax was lower in ESRD subjects than that observed in subjects with
`normal renal function, with the greatest difference (21% lower Cmax) being
`observed when hemodialysis was started 2 hr after apixaban administration.
` Apixaban dialysis clearance was 17.7 mL/min.
` Apixaban protein binding was generally comparable between ESRD subjects with
`hemodialysis started 2 hr after apixaban administration (94.1% bound) and
`subjects with normal renal function (93.2% bound). Protein binding appears to be
`
`18
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`slightly lower in ESRD subjects when apixaban administered immediately after
`completion of hemodialysis (91.5% bound).
` The metabolite, BMS-730823, Cmax and AUC(0-T) were approximately 1.9- and
`4.6-fold higher in ESRD subjects than that observed in subjects with normal renal
`function, respectively. When hemodialysis was started 2 hr after apixaban
`administration, BMS-730823 Cmax and AUC(0-T) was approximately 20% and
`22% lower, respectively, than when apixaban was administered immediately after
`hemodialysis.
` Anti-FXa activity demonstrated a linear relationship with apixaban plasma
`concentration within both healthy and ESRD subjects.
` The effect of apixaban on INR, PT, and aPTT appeared to be consistent between
`healthy subjects with normal renal function and ESRD subjects, however with
`large variability observed in these results.
` A single 5-mg oral dose of apixaban was safe and well tolerated in healthy
`subjects with normal renal function and subjects with ESRD maintained with
`hemodialysis in this study.
`
`
`Reviewer’s Comments:
`
`
` The higher exposure of the metabolite, M1, is consistent with previous results
`from renal impairment study. Similarly, as M1 is inactive and the level of M1
`observed in this study is lower than that observed in the toxicological study in
`animals, the PK changes is not expected to have clinically meaningful impact.
` Apixaban was administered during the dialysis as well as during off-dialysis
`period. The exposure and anti-FXa activity of apixaban in ESRD patients
`maintained with hemodialysis appeared to be similar to those with moderate to
`severe renal impaired patients. As previously approved, no dose adjustment is
`required for patients with moderate to severe renal impairment. Hence, dose
`adjustment based solely on renal impairment or ESRD disease state is not
`warranted.
`In addition, given the available data in this report, we thought there is enough
`information to label ESRD patients on hemodialysys.
`-
`The recommended dose for ESRD patients maintained with hemodialysis
`is 5 mg orally twice daily.
`For the ESRD patients maintained with hemodialysis having either one
`of the risk factors of age ≥80 years or body weight ≤ 60kg, the
`recommended dose should be reduced by half to 2.5 mg twice daily.
`
`
`
`-
`
`
`
`19
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`DDI- Apixaban VS Prasugrel
`
`CV] 8 5073
`
`EDR Link \\cdsesubl\evsprod\nda202155\0086\m5\53-
`Study Period
`clin-stud-rep\532-rep-stud-pk-human-biomat\5322-rep-hep-
`5/21/10
`9/21/10
`— metab-interact-stud\cvl85073\stu -cv185073-csr-final.
`
`DRUG INTERACTION STUDY IN HEALTHY SUBJECTS
`
`Objectives
`
`Primary: To assess the effect of prasugrel on the PK of apixaban and the
`effect of apixaban on the PK of the active metabolite of prasugrel, R-
`138727, when co-administered.
`
`Rationale: Prasugrel (Effient®) is a P2Y platelet inhibitor indicated for the reduction of
`thrombotic cardiovascular events (including stent thrombosis) in patients with acute
`coronary syndrome (ACS) who are to be managed with primary percutaneous coron
`intervention (PCI).
`
`)(4)
`
`this study was conducted to provided assurance
`that these two medications did not influence the harmacokinetics of each other.
`
`Study Design Multiple-Dose Randomized Open-labelled Crossover Single-Center
`Three-Period Healthy Vonuteers
`
`Subjects were randomized to 1 of the 6 treatment sequences as detailed in the table below.
`
`\V/CF Period 2 W'ICF Period 3
`
`Sequence 1
`
`3 days
`
`
`
`
`
`
`
`
`
`
`Sequence 3
`
`Sequence 4
`
`Sequence 5
`
`Treatments: (2 8 hr fast before morning doses, evening doses of apixaban were given
`regardless of evening meal time)
`A: 5 mg Apixaban orally, BID on Days 1-4
`B: 60 mg Prasugrel orally on Day 1 followed by 10 mg Prasugrel orally, QD on Days 2-4
`C: 5 mg Apixaban orally, BID on Days 1-4 and 60 mg Prasugrel orally on Day 1 followed
`
`Study medication
`
`Active Substance
`
`Apixaban (BMS-
`562247)
`
`Prasugrel (Effienlg)
`
`.
`
`-
`
`.'
`
`
`
`Dosage Form
`
`Film-coated tablets
`
`Film-coated [ablels
`
`Expiration Date: Jan 2011
`
`Expiration Date: Aug
`201 l
`
`
`
`
`
`SFS 7006
`
`A657074A
`
`1 730401(‘
`
`(11/03/2008)
`
`20
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`PK Sampling (Blood):
`Apixaban and R-138727 (active metabolite of prasugrel):
` Pre-dose on days 2, 3 and 4 for each period
` Day 4: 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9 and 12 hours post dose and one last
`sampling for R138727 at 24 hours post dose
`PD Sampling (Blood) for Platelet Aggregation:
` Pre-dose on days 1, 2 and 4
` Day 1: 2, 4, 6, 9 hours post dose
` Day 4: post dose 4, 6, 9 and 12 hours
`PD Sampling (Blood) for Anti-FXa Activity:
` Pre-dose on days 1 and day 4
` Day 4: 1, 2, 4, 6, 9 and 12 hours post dose
`Analytical Method
`The performance of the assay method during study sample analysis is acceptable and is
`summarized in the table below.
`Analyte
`Method
`Matrix
`LOQ
`Range
`QCs
`
`R-138727
`Apixaban
`LC/MS/MS
`LC/MS/MS
`Plasma
`Plasma
`0.250 (ng/mL)
`1.00 (ng/mL)
`1.00 to 1000 (ng/mL) 0.250 to 250 (ng/mL)
`3.00, 35.0, 400, 800
`0.750, 2.00, 7.50, 30.0,
`(ng/mL)
`190 (ng/mL)
`4.51%
`4.86%
`Accuracy/Bias
`Precision (CV%) 5.46%
`4.99%
`
`Statistical Method:
`PK: To assess the effect of prasugrel on apixaban Cmax and AUC(TAU), a general linear
`model analysis was performed on log(Cmax) and log[AUC(TAU)] of apixaban. Point
`estimates and 90% CIs for differences on the log scale were exponentiated to obtain
`estimates for ratios of geometric means on the original scale. Similar analyses were
`conducted on log(Cmax) and log[AUC(TAU)] of R-138727.
`PD: Summary statistics were tabulated by treatment and time for platelet aggregation and
`anti-FXa activity, along with corresponding changes from baseline for platelet
`aggregation. Linear and semi-logarithmic plots of the mean and individual platelet
`aggregation and anti-Factor Xa activity were plotted versus time by treatment,
`respectively.
`Study Population :
`36/53#/35/1*
`Planned/Dosed/Completed/ Discontinued Due to AE
`18-45 yr
`Age [range]
`34/19
`Male/Female
`53
`Race (White)
`# 17 subjects for whom multiple PK samples were not collected were discontinued and
`replaced as stated by the sponsor.
`* 1 subject was discontinued due to a moderate AE (haematochezia).
`
`21
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`Results
`Pharmacokinetics of Apixaban
` Apixaban exposure was not altered by co-administration with prasugrel when
`compared with apixaban alone; the 90% CIs for apixaban Cmax and AUC(TAU)
`geometric least squares (LS) mean ratios were contained within the predefined no
`effect interval of 0.8 - 1.25.
`
`
`Apixaban mean plasma concentration-time profile on Day 4
`
`
`Summary statistics of Apixaban PK
`
`
`
`
`
`
`Pharmacokinetics of R-138727
`
` 
`
` The 90% CI for R-138727 AUC(TAU) geometric least squares (LS) mean ratios were
`contained within the predefined no effect interval of 0.8 - 1.25.
` For Cmax, geometric LS mean ratio was 0.885, with the upper bound of the 90% CI as
`0.991 and the lower bound of the 90% CI as 0.789.
`
`
`R-138727 mean plasma concentration-time profile on Day 4
`
`22
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`Summary statistics of R-138727 PK
`
`
`
`
`
`
`Pharmacodynamics
`ADP-induced platelet aggregation
` Apixaban generally had no effect on ADP-induced platelet aggregation. However, it is
`noted that there was an apparent decrease in the ADP-induced platelet aggregation at
`the 9-hour time point following apixaban administration on Day 4. There are no clear
`reasons to explain this finding. It should be noted that platelet aggregation returned to
`baseline by the 24-hour time point.
` Prasugrel alone decreased ADP-induced platelet aggregation on Day 1 and maintained
`through Day 4 which was consistent with prasugrel’s mechanism of action.
` Co-administration of apixaban with prasugrel did not alter ADP-induced platelet
`aggregation when compared with that of prasugrel alone.
`
`
`
`23
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`
`
`Anti-FXa Activity
` The anti-FXa activity was not altered by co-administration of prasugrel when
`compared with apixaban alone.
` All subjects receiving prasugrel alone had anti-FXa activity values under the
`detectable limit (<0.1 IU/mL).
`
`
`
`
`
`
`
`24
` (11/03/2008)
`
`Reference ID: 3396823
`
`

`

`NDA # 202155
`
`Drug Name: Apixaban
`
`
`Relationship between apixaban concentration and anti-FXa activity
` A direct linear relationship was observed between the individual subject anti-Xa
`activity and apixaban plasma concentrations. This linear relationship was not impacted
`by co-administration of prasugrel.
`
`
`
`
`
`Safety
` Was there any death or serious adverse events?  Yes No  NA
`
`19 subjects (35.8%) experienced adverse bleeding-related AEs which were considered to
`be related to study drug and mild in intensity with the exception of 1 event
`(haematochezia). The majority of the bleeding-related events were reported more
`frequently when apixaban was co-administered with prasugrel than when either agent was
`administered alone.
`
`25
` (11/03/2008)
`
`Reference ID: 3396