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

`

`Clinical Pharmacology/Biopharmaceutics Review
`(Addendum to Previous Review – DARRTS date: 02/15/2012)
`
`
`
`PRODUCT (Generic Name):
`NDA:
`
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`PRODUCT (Brand Name):
`
`DOSAGE FORM:
`
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`DOSAGE STRENGTHS:
`
`INDICATION:
`
`SUBMISSION DATE:
`SPONSOR:
`
`
`REVIEWERS:
`
`TEAM LEADER:
`
`OCP DIVISION:
`
`OND DIVISION:
`
`
`
`
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`
`
`
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`
`Apixaban
`202-155
`ELIQUIS®
`Tablets
`2.5 mg and 5 mg
`Prevention of stroke, systemic embolism,
` in patients with non-valvular atrial
`fibrillation
`Study report submission on 8/14/2012
`Bristol-Myers Squibb and Pfizer
`
`Ju-Ping Lai, Ph.D.
`
`Rajanikanth Madabushi, Ph.D.
`DCP 1
`HFD 120
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`
` 2
`1.0 EXECUTIVE SUMMARY
` 2
`1.1 RECOMMENDATION
`2.0 DETAILED LABELING RECOMMENDATIONS 3
`3.0 INDIVIDUAL STUDY REVIEW
` 6
`
`
`Reference ID: 3232801
`
`(b) (4)
`
`

`

`1.0 EXECUTIVE SUMMARY
`
`
`The sponsor submitted a study report on August 14, 2012: Effect of Activated Charcoal
`on the Pharmacokinetics of Apixaban in Healthy Subjects, to support NDA 202155
`(NME) for apixaban while the original NDA was submitted on September 30, 2011 as a
`final submission of a series of rolling submissions.
`
`Since there is no antidote for apixaban while high systemic exposure increases bleeding.
`This study evaluated whether activated charcoal could be used to reduce apixaban
`exposure following oral administration of apixaban. The key findings are as follows:
`
` 
`
` Administration of activated charcoal 2 and 6 hours after ingestion of apixaban
`reduced apixaban exposure (AUC) by approximately 50% and 27%, respectively.
` Peak exposure (Cmax) of apixaban was not affected by the administration of
`activated charcoal at 2 hours or 6 hours after apixaban administration.
`
`
`
`
`1.1 RECOMMENDATION
`
`
`The Office of Clinical Pharmacology (OCP/DCP I) has reviewed the study CV185104
`with activated charcoal. The submission is acceptable from a Clinical Pharmacology and
`Biopharmaceutics point of view. Based on the information reviewed in this study,
`labeling recommendations are provided in the sections 5.2, 10 and 12.3 of the label.
`
`
`
`
`Reference ID: 3232801
`
`2
`
`

`

`2.0 DETAILED LABELING RECOMMENDATIONS
`
`
`The text in Blue colored font represents the labeling statements proposed in this review.
`
`
`5.2 Bleeding
`
`There is no established way to reverse the anticoagulant effect of apixaban, which can be
`expected to persist for about 24 hours after the last dose, i.e., for about two half-lives. A
`specific antidote for ELIQUIS is not available. Because of high plasma protein binding,
`apixaban is not expected to be dialyzable [see Clinical Pharmacology (12.3)]. Protamine
`sulfate and vitamin K would not be expected to affect the anticoagulant activity of
`apixaban. There is no experience with antifibrinolytic agents (tranexamic acid,
`aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale
`for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in
`individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin
`complex concentrate, activated prothrombin complex concentrate, or recombinant factor
`VIIa may be considered but has not been evaluated in clinical studies. Activated oral
`charcoal
`reduces absorption of apixaban
`thereby
`lowering apixaban plasma
`concentrations [see Overdose (10)].
`10
`OVERDOSAGE
`
`There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding
`[see Warnings and Precautions (5.2)].
`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-mg dose of apixaban reduced mean apixaban area under plasma-concentration time
`curve (AUC) by 50% and 27%, respectively. Mean apparent half-life of apixaban
`decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9
`hours, respectively, when activated charcoal was administered 2 and 6 hours after
`apixaban indicating that charcoal reduced the extent of absorption of apixaban from the
`gut. [see Clinical Pharmacology (12.3)]. Thus, administration of activated charcoal may
`be useful in the management of apixaban overdose or accidental ingestion, and may also
`facilitate discontinuation of drug in the event of bleeding [see Warnings and Precautions
`(5.2)].
`
`
`
`Reference ID: 3232801
`
`3
`
`

`

`
`
`Reviewer’s Note: Above labeling recommendations were provided based on the
`information obtained from activated charcoal study. Detail review of the study is
`provided in the individual study review in section 3.0 of this review.
`
`
`12.3 Pharmacokinetics
`The pharmacokinetics of apixaban are complicated by prolonged absorption. Thus,
`despite a short clearance half-life of about 6 hours, the apparent half-life during repeat
`dosing is about 12 hours, which allows BID dosing to provide effective anticoagulation,
`but also means that when the drug is stopped for surgery, anticoagulation persists for at
`least a day.
`Absorption
`
`Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration
`of ELIQUIS. Apixaban is absorbed throughout the gastrointestinal tract. The distal small
`bowel and ascending colon contribute to ~55% of apixaban absorbed via oral route.
`Elimination
`
`Following intravenous administration, ~98% of apixaban is eliminated within 24 hours,
`with a dominant half-life of ~ 5 hours.
`
`Following oral administration, the apparent half-life is ~12 hours because of prolonged
`absorption.
`
`Reviewer’s Note:
` This information is provided to clarify the prolonged absorption of apixaban which
`facilitate the effect of activated charcoal to prevent additional absorption of
`apixaban from later part of the GI tract.
` The second point is to clarify that the apparent half-life of ~12 hours is because of
`prolonged absorption. When the continued absorption is stopped, the elimination
`half-life from systemic is ~ 5 hours.
`
`
`
`
`
`Reference ID: 3232801
`
`4
`
`(b) (4)
`
`

`

`
`
`Other Labeling Changes:
`
`During the labeling communication, the sponsor proposed to
` in order to be consistent with the labeling
`recommendations of apixaban and enoxaparin. While a dedicated DDI study with
`enoxaparin was conducted and revealed no PK interaction and expected PD
`interaction of ~50 % increase in anti-FXa activity, the results didn’t lead to
`recommend
`. The sponsor’s proposal is
`based solely on clinical considerations. The sponsor’s proposal is considered
`acceptable.
`
`
`
`
`
`Reference ID: 3232801
`
`5
`
`(b) (4)
`
`(b) (4)
`
`

`

`3 INDIVIDUAL STUDY REVIEW
`
`Report #
`CV185104
`
`Title
`
`Objectives
`
`Apixaban VS Activated Charcoal
`Study Period
`EDR Link
`\\cdsesub1\EVSPROD\NDA202155\\0070\m5\53-clin-stud-
`05/06/11
`05/17/11
`
`rep\533-rep-human-pk-stud\5331-healthy-subj-pk-init-tol-
`stud-rep\cv185104\cv185104.pdf
`Effect of Activated Charcoal on the Pharmacokinetics of Apixaban in
`Healthy Subjects
`To assess the effect of activated charcoal on the pharmacokinetics of
`apixaban, when administered 2 hours or 6 hours following the dose of
`apixaban in healthy subjects.
`Rationale: There is no antidote for apixaban while high systemic exposure could increase
`bleeding. Activated charcoal has been used in the routine management of oral drug
`overdose including digoxin, phenytoin. This study hence evaluated whether activated
`charcoal could be used to reduce apixaban exposure following oral administration of
`apixaban.
`Study Design Single-Dose Randomized Open-Label Crossover Single-Center
`3-Treatment 3-Period Healthy Vonuteers
`
`Subjects were admitted to the clinical facility on Day -1. Subjects were randomized on
`Day 1 of Period 1 to 1 of 6 treatment sequences. Each subject received all 3 treatments
`(showed below) with 1 treatment given on Day 1 of Periods 1, 2, and 3.
`
`
`
`Washout: at least 4 days
`Screening: -21days
`Sequence
`Showed in the table above
`Treatments: (Fasted)
`A: single oral dose of 20-mg apixaban (4 × 5 mg tablets)
`B: single oral dose of 20-mg apixaban followed by administration of an aqueous
`suspension of activated charcoal (50 g of activated charcoal and 96 g of sorbitol in 240
`mL water) 2 hours after dosing with apixaban.
`C: single oral dose of 20-mg apixaban followed by administration of an aqueous
`suspension of activated charcoal (50 g of activated charcoal and 96 g of sorbitol in 240
`mL water) 6 hours after dosing with apixaban.
`Study medication
`Apixaban (BMS-562247) 20 mg (4 x 5 mg tablets), single dose administered orally, batch
`number 0E56753.
`
`
`
`Reference ID: 3232801
`
`6
`
`

`

`Actidose® (activated charcoal) with sorbitol suspension, 50 g activated charcoal and 96 g
`sorbitol, single dose administered orally, lot number 0372802.
`
`PK Sampling (Blood) for Apixaban:
`Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 8, 10, 12, 18, 24, 36, 48, and 72 hours post-dose
`on Day 1 through 4 of each treatment period
`Analytical Method
`The performance of the assay method during study sample analysis is acceptable and is
`summarized in the table below.
`Apixaban
`Analyte
`LC-API/MS/MS
`Method
`Plasma
`Matrix
`1.00
`LOQ (ng/mL)
`1.00 to 1000
`Range (ng/mL)
`3.00, 35.0, 400, 800
`QCs (ng/mL)
`7.14%
`Accuracy/Bias
`5.58%
`Precision (CV%)
`
`Statistical Method: Geometric means were included for AUC(INF), AUC(0-T), and
`Cmax. Point estimates and 90% CIs for the differences on the log scale were
`exponentiated to obtain estimates for ratios of geometric means and 90% CIs on the
`original scale. Treatment comparisons included Treatment B compared with Treatment A
`(B/A) and Treatment C compared with Treatment A (C/A).
`Study Population :
`Enrolled/Dosed/Completed/ Discontinued Due to AE
`Age [Median (range)]
`Male/Female
`Race (White/Black or African American)
`
`Results
`Pharmacokinetics of apixaban
`
`18/18/18/0
`30.5 (18-45) yr
`10/8
`14/4
`
`
`
`
`
`Reference ID: 3232801
`
`
`
`7
`
`

`

`
`
` 
`
` Similar apixaban Cmax and median Tmax were observed across the 3 treatments.
` Apixaban mean apparent T-HALF was 5.3 hours, 4.9 hours, and 13.4 hours,
`respectively, when activated charcoal was administered 2 and 6 hours after dosing
`with apixaban, and after apixaban administration alone.
`
`
`Reviewer’s Note:
` The half-lives observed were apparent half-lives and not elimination half-lives. While
`activated charcoal should act on direct contact with drugs in GI, administration of
`activated charcoal should only prevent additional absorption and should not be
`expected to change the elimination half-life. The apparent half-life after apixaban
`alone (13.4 hrs) represents a combination of elimination and continuous absorption
`while the apparent half-lives after charcoal treatment (~5 hrs) represent real
`elimination phase.
` From the intravenous study (Study CV185020) where there is no absorption phase, the
`half-life of apixaban 5 mg dose is 8 hrs. However it should be noted that by 24 hrs,
`~98 % is eliminated with a dominant half-life of ~5 hrs. This is consistent with the
`finding in the activated charcoal study when continuous absorption is prevented. The
`apparent half-life of apixaban is prolonged after oral dosing due to continuous
`absorption of apixaban throughout the GI tract.
`It should be also noted that from a dedicated regional gastrointestinal absorption
`study (Study CV185007), apixaban is shown to be absorbed throughout the GI tract.
`The distal small bowel and ascending colon contribute to ~55% of apixaban absorbed
`via oral route. This further confirms that the decreased exposure of apixaban by
`avtivated charcoal is by preventing further absorption of apixaban from the GI.
`
`
`
`
`Statistic summary
`
`
`
`Reference ID: 3232801
`
`8
`
`

`

`
`
` 
`
` Following activated charcoal administration 2 hours after apixaban administration, the
`ratio of the geometric least squares (LS) means (90% CI) for AUC(0-T) and
`AUC(INF) of apixaban was 0.503 (0.456 – 0.554) and 0.496 (0.450 – 0.547),
`respectively.
` Following activated charcoal administration 6 hours after apixaban administration, the
`ratio of the geometric LS means (90% CI) of AUC(0-T) and AUC(INF) of apixaban
`was 0.737 (0.674 – 0.806) and 0.723 (0.661 – 0.792), respectively.
` Peak exposure (Cmax) of apixaban was not affected by the administration of activated
`charcoal at 2 hours or 6 hours after apixaban administration as the ratio of the
`geometric LS means for Cmax was 0.999 (0.903 – 1.105) and 1.030 (0.939 – 1.130),
`respectively.
`
`
`Safety
` Was there any death or serious adverse events?  Yes No  NA
`
` Higher percentages of subjects reported AEs after receiving apixaban and activated
`
`
`
`
`
`Reference ID: 3232801
`
`9
`
`

`

`charcoal administered 2 hours or 6 hours after dosing with apixaban (72.2% and
`77.8%, respectively) compared with apixaban alone (16.7%).
` The highest percentages of subjects reported AEs classified as gastrointestinal
`disorders (83.3%) and nervous system disorders (33.3%) (diarrhea: 11 subjects
`(61.1%) each, nausea: 9 and 8 subjects (50.0% and 44.4%, respectively), abdominal
`pain: 6 subjects each (33.3%), vomiting: 4 and 3 subjects (22.2% and 16.7%,
`respectively), and headache: 4 subjects each (22.2%)).
`
`
`Reviewer’s note: Based on the sponsor, the majority of AEs were largely consistent with
`the known tolerability profile of activated charcoal.
`Conclusion
` Administration of activated charcoal 2 and 6 hours after ingestion of apixaban reduced
`apixaban exposure (AUC) by approximately 50% and 27%, respectively.
` Peak exposure (Cmax) of apixaban was not affected by the administration of activated
`charcoal at 2 hours or 6 hours after apixaban administration.
`
`
`
`
`
`
`Reference ID: 3232801
`
`10
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JU PING LAI
`12/17/2012
`
`RAJANIKANTH MADABUSHI
`12/17/2012
`
`Reference ID: 3232801
`
`

`

`BIOPHARMACEUTICS REVIEW
`
`Office of New Dru_ 0 uali
`
`' Assessment
`
`Application No.:
`Division:
`
`NDA 202-155 (000)
`DPARDP
`
`Reviewer:
`Sandra Suarez Sharp. Ph.D.
`
`Applicant:
`
`Bristol Myers Squibb
`
`Acting Biopharmaceutics Supervisory Lead:
`Angelica Dorantes. PhD
`
`Trade Name:
`
`Eliquis
`
`Generic Name:
`
`Indication:
`
`Formulation/strength
`
`Route of Administration
`
`Apixaban (BMS-562247) film-
`Coated IR Tablets
`
`Antithrombotic/anticoagulant
`a . ent
`
`Immediate Release Tablet/2.5 mg
`and 5 mg
`
`SUBMISSIONS REVIEWED IN THIS DOCUMENT
`
`Date Assi -_ ned:
`
`Rolling NDA- Oct . 2011
`
`Date of Review:
`
`Feb 19' 2012
`
`Submission Dates
`
`Date of informal/Formal
`
`PDUFA
`
`Rolling NDA Sep 29. 2011
`Original NDA Nov 3. 2011
`Dec 9. 2011
`Dec 29. 2011
`Feb 14. 2012
`
`Type of Submission:
`
`Rolling NDA
`
`Consult
`Oct 2011
`
`DA
`March 28. 2012
`
`Dissolution method and acceptance criterion
`Acceptability of
`
`Type of Consult:
`
`. Acceptability of the lower strength
`Acceptability of data supporting the bridging throughout the apixaban
`development
`Role of dissolution on O bD
`
`SUMNIARY 0F BIOPHARMACEUTICS FINDINGS:
`
`Apixaban (BMS-562247) is a novel. orally active. selective. direct. reversible inhibitor of the coagulation
`factor Xa (FXa). It was developed as an antithrombotic/anticoagulant agent. Apixaban immediate release
`film coated tablets. 2.5 mg and 5 mg are intended to be given
`(mm
`
`"" “" for the proposed drug product.
`
`The product and process development of apixaban was conducted under a Quality by Design (QbD)
`paradigm to ensure desired product performance in terms of quality. safety. and efficacy. Dissolution was
`identified as one of the Critical Quality Attributes (CQAs) for the drug product.
`
`This review focuses on the evaluation of: 1) The acceptability of the dissolution method and acceptance
`criterion; 2) Data supporting the acceptability of the 2.5 mg strength, 3) The acceptability of data
`supporting the bridging throughout the apixaban clinical development. 4) The acceptability of the proposed
`use of
`(am); and 5) The
`role of dissolution on the
`
`Reference ID: 3092004
`
`

`

`1) Dissolution Method and Acceptance Criterion:
`The following dissolution method and acceptance criterion for apixabn IR tablets, 2.5 mg and 5 mg are
`being proposed by the Applicant:
`
`pH 6.8
`phosphate
`bufifl. 0.05%
`SLS
`
`The proposed dissolution method and acceptance criterion are deemed acceptable. The Applicant
`submitted sufficient information to support the discriminating ability of the dissolution method. The
`dissolution acceptance criterion was based on the mean dissolution profiles of clinical and stability batches
`and on the ability of the specification to reject batches that were shown not to be bioequivalent.
`
`2) Data Supporting the Acceptability of the 2.5 mg strength
`Two tablet strengths, 2.5 mg and 5 mg. as immediate-release film-coated tablets have been developed for
`commercialization. The two tablet strengths are
`M"
`The acceptability of the lower strength is based on the following information included in the
`present submission:
`0 The 2.5 mg strength and the 5 mg strength have the same dosage form;
`0 The 2.5 mg strength is
`W" in its active and inactive ingredients to the 5 mg strength
`product;
`Dissolution profile comparisons in three different media between the 5 mg and 2.5 mg strengths were
`close to super irnposable suggesting similar in vitro dissolution performance despite the act that the 12
`similarity factor could not be calculated due to existence of rapid dissolution profiles;
`Apixaban
`(m4) was assessed in an intra-subject dose escalation study (CV185013)
`using single doses of 2.5. 10. 25. and 50 m 7 in a double-blinded. randomized trial. According to the
`Applicant, apixaban showed
`a" 4’ exposure up to doses of S 10 mg
`
`
`
`3) Acceptability of data supporting the bridging throughout the apixaban development
`There were some major process and formulation changes implemented to the Phase 3 clinical trial
`formulation. These changes are supported by the result of two BA/BE study linking the phase 2 and phase
`3 formulation. These studies are being reviewed by OCP.
`
`The definitive food effect study was conducted with the Phase 2 formulation. The Applicant included
`dissolution profiles comparisons between the Phase 2 formulation and the Phase 3 formulation. The f2
`similarity testing values were > 50 indicating no difference in the in vitro performance between the Phase 2
`and Phase 3 formulations. In addition, according to the Applicant. the results from relative BE study
`CV185024 conducted under fasting conditions indicate that the phase 2 formulation and the phase 3
`formulation were BE. These data indicate that the conclusions made under the food effect study conducted
`with the phase 2 formulation can be extrapolated to the Phase 3 and commercial formulations.
`
`The Phase 3 clinical trial and commercial tablets are IR film coated tablets that differ only in the shape or
`tablet dimensions and film coat color/composition. Specifically, the differences between the commercial
`vs. clinical film coats are in their color, weight of fihn coat
`m4) % w/w) and lactose/HPMC
`(Hydroxypropyl methylcellulose) ratio
`”(4’). It was established through dissolution testing in
`three difi'erent media that these changes are minor and do not affect the release of apixaban from the drug
`.roduct.
`
`Reference ID: 3092004
`
`

`

`
`
`Reference ID: 3092004
`
`

`

`
`lb) (4)
`
`The Applicant stated on submission dated Feb 14. 2012,
`that changes to the manufacturing process that may have the potential to impact the quality of the drug
`product will be assessed within BMS internal quality control system.
`
`RECOMMENDATION:
`
`The ONDQA-Biophannaceutics team has reviewed NDA 202-155 for Apixaban IR tablets. 2.5 mg and 5
`mg. The following dissolution method and dissolution acceptance cn'terion have been found acceptable.
`
`From the Biopharmaceutics perspective, NDA 202-155 for Apixaban Tablets is recommended for approval.
`
`pH 6.8
`phosphate
`bufl'er. 0.05%
`SLS
`
`Office of New Drug Quality Assessment
`
`Additionally, the Applicant agreed to perform dissolution testing for release and stability as recommended
`by the Agency. The Applicant may
`(m4)
`
`. In addition, the Applicant stated that changes to the manufacturing process
`that may have the potential to impact the quality of the drug product will be assessed within BMS internal
`quality control system.
`
`Sandra Suarez Sharp, Ph. D.
`Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`
`Angelica Dorantes, Ph.D.
`Acting Biopharmaceutics Supervisory Lead
`
`Reference ID: 3092004
`
`

`

`BIOPHARMACEUTICS ASSESSNIENT
`
`INTRODUCTION
`
`Apixaban (EMS-562247) is a novel, orally active, selective, direct, reversible inhibitor of
`the coagulation factor Xa (FXa). It is being developed as an antithrombotic/anticoagulant
`agent. Apixaban is intended to be given
`M“)
`
`The dose used in Phase 3 studies in adults for prevention of stroke and systemic
`embolism in subjects with AF was 5 mg administered orally twice daily (BID), with an
`option to use 2.5 mg BID in select subjects at increased risk of bleeding.
`
`The Clinical Pharmacology and Biopharmaceutics program of this NDA is based
`primarily on three key apixaban Clinical Pharmacology/Biopharmaceutics studies, a
`bioequivalence study (CV185019), a relative bioavailability study (CV185024), and a
`food effect study (CV185008). These studies provide the data that bridge findings from
`tablets utilized in early clinical development (Phase 1 and Phase 2) with those used in
`later clinical development (Phase 1 and Phase 3) and their application to understanding
`the expected pharmacokinetics G’K), safety and efficacy profile of the proposed
`commercial (hereafter “commercial”) tablet formulation.
`
`This review focuses on the evaluation of: 1) the acceptability of the dissolution method
`and acceptance criterion; 2) Acceptability of the lower strength, 3) Acceptability of data
`supporting the bridging throughout the apixaban development, 4) The acceptability of the
`proposed use of
`M“)
`mm for
`
`; and 5) the role of dissolution on the
`the proposed drug product.
`
`Drug Substance
`Apixaban drug substance is a white to yellow, nonhygroscopic, crystalline powder.
`Apixaban is a non-ionizable compormd; thus, the aqueous solubility is not affected by
`changes in pH. The aqueous solubility of apixaban is 0.04 mg/mL at 37°C over a pH
`range 1.2 to 6.8.
`
`The Applicant classified Apixaban as a Biopharmaceutics Classification System (BCS)
`Class 1]] compound (high solubility/low permeability). The proposed dose of apixaban
`M“). According to BCS classification criteria,
`apixaban is classified as highly soluble at doses 3 10 mg, since the dose/solubility ratio is
`E 250 mL (10 mg/0.04 mg/mL = 250 mL).
`
`Drug Product
`Two tablet strengths, 2.5 mg and 5 mg, as immediate-release film-coated tablets have
`been developed for commercialization. The two tablet strengths are
`m“)
`The components and composition of apixaban
`
`are summarized in Table 1.
`
`Reference ID: 3092004
`
`

`

`Table 1. Composition of apixaban Tablets, 2.5 mg and 5 mg
`Function
`2.5mg
`mg/tablet
`2.50
`
`
`
`Active
`
`5mg
`mg/tablet
`5.00
`
`Component
`
`Apixaban (BMS-562247-01),
`Lactose Anhydrous
`Microcrystalline Cellulose
`Croscarmellose Sodium
`Sodium Lauryl Sulfate
`Magnesium Stearate
`
`
`
`
`
`
`
`
`
`
`Croscarmellose Sodium
` Magnesium Stearate
`Core Tablet Weight
`Film Coat
`
`208.00
`
`104.00
`
`Total Tablet Weight
`
`Formulation Development
`Nine oral formulations (five tablets and four oral solutions) and a solution formulation for
`intravenous (IV) administration were developed to support the apixaban clinical
`development program.
`
`Four immediate-release tablet formulations were developed for clinical studies as
`follows:
`• The apixaban
` tablet formulation (Phase 2 tablet, at
`2.5, 5, 10 and 20 mg strengths): This formulation was developed and used in
`Clinical Pharmacology studies conducted early in the development program
`and in most of the Phase 2 safety/efficacy clinical studies of apixaban.
`• Two Phase 3 prototype tablets (20 mg): These formulations were developed to
`support formulation development. The
` Phase 3 prototype
`tablet (20 mg) was similar in composition to the Phase 3 tablets (2.5 and 5
`mg) except for the percent active in the tablets. These two prototype tablets
`were used only in the bioequivalence study (CV185019). The
`
`tablet was selected for further development based on the results of this study.
`• The apixaban film-coated
` tablet formulation (Phase 3 tablet, at
`2.5 and 5 mg strengths): This formulation was developed and used in all Phase
`3 and additional Clinical Pharmacology studies including the relative BA
`assessment, CV185024.
`• An immediate-release,
`, film-coated tablet formulation (at 2.5
`and 5-mg strength): This formulation was identical to the Phase 3 tablet
`
`
`
`Reference ID: 3092004
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(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)
`
`

`

`formulation with the exception of the tablet shape (2.5 mg tablet) or
`dimensions (5 mg tablet) and fihn coat, was developed for commercialization.
`
`The commercial tablet formulation had minor modifications when compared to the Phase
`3 tablet. The Phase 3 and commercial tablets are immediate release film coated tablets
`
`that differ only in the shape or tablet dimensions and film coat color/composition. These
`changes are considered minor difl‘erences that will not affect
`tablet performance.
`Therefore, pivotal bioequivalence or dose strength equivalence studies were not needed
`to qualify the commercial formulation from the Phase 3 tablet. Figure 1 shows the main
`BE studies conducted to bridge changes implemented to the Phase 3 clinical trial
`formulations. These BE studies are being reviewed by OCP.
`
`2.5, 5, 10, 20 mg
`9“"
`
`(um) (20 mg)
`Film—coated Tablet
`Phase 3 prototype
`
`IBE Study (5019) Dis
`
`ution
`
`Phase 2 Tablets
`
`5 mg
`
`Commercial
`FC Tablet
`
`2-5 mg
`Commercial
`FC Tablet
`
`I
`I
`
`BA Study (5024)
`
`“(4) 2.5, 5, 20 mg
`FC Tablets
`Phase 3 Tablets
`
`Figure 1. Schematic Overview of the apixaban oral formulation development and studies
`supporting the changes implemented.
`
`1) DISSOLUTION METHOD AND DISSOLUTION ACCEPTANCE CRITERION
`Dissolution Method
`
`The dissolution method proposed as a quality control tool for apixaban film—coated IR
`tablets, 2.5 and 5 mg is summarized below:
`
`(wfv) SLS
`
`Phosphate
`Bufl'er pH 6.8
`0.05%
`
`50 nm
`
`Dissolution Method Development
`a. Dissolution Medium Selection
`
`According to the Applicant, at the proposed dosage strengths of 2.5 mg and 5 mg,
`apixaban has high aqueous solubility (Dose Strength/Solubility S 250 mL) as defined by
`
`Reference ID: 3092004
`
`

`

`the BCS. It is a non-ionizable compound and its aqueous solubility is independent of pH
`as shown in Table 2. The aqueous solubility of apixaban (0.04 mg/mL) indicated flat the
`three difl'erent bufl'er media (pH 1.2, 4.5 and 6.8) provide sink conditions (of greater than
`five times) with a medium volume of 900 mL. In addition, Figure 2 shows that the
`dissolution profiles are independent ofpH.
`
`Table 2. Aqueous Solubility of Apixaban as a Function ofpH at 37°C
`
`pH
`
`Butler/Media
`
`Solubllty
`
`(III/IL)
`
`Dosestrelgtll Solubility of
`
`Avila“- (IIL)
`
`2.5-mg
`
`s-ng
`
`1.2
`
`4.5
`
`6.8
`
`0.1N HCl
`
`0.05M SodiumCitnte
`
`0.05 M SodiumMy:
`
`100
`
`8
`
`
`
`
`
` ‘588Drugdissolved(%)
`
`0
`
`1o
`
`20
`
`30
`
`4o
`
`50
`
`so
`
`Tlme (nin)
`
`Figure 2. Efi'cct of pH/media on Dissohltion of Apixaban FC Tablets, 2.5 g (50 rpm).
`Generated using Applicant provided data.
`
`Although, the equilibrium solubility of apixaban indicates sink condition in USP media,
`the tablets of both 2.5-mg and 5-mg strengths showed incomplete dissolution at 50 rpm
`dining the paddle speed study. Therefore, a low level of surfactant (0.05% SLS) was
`added to the dissolution medium to ensure the complete dissolution of 5-mg tablets
`
`Reference ID: 3092004
`
`

`

`(Table 3). A buffered dissolution medium of pH 6.8 was selected to avoid low pH
`instability of SLS.
`
`Table 3. Dissolution of Apixaban 5-mg Proposed Commercial Tablets and Phase 3 Tablets at 75
`rpm in 50 mM Phosphate Buffer with 0.05% SLS, pH 6.8
`
`
`
`b. Effect of Surfactant
`
`The solubility of apixaban was studied in the pH 6.8 phosphate bufl'er containing SLS at
`various concentrations. Figure 3 shows that
`the solubility of apixaban was not
`significantly enhanced when the SLS concentration is S 0.05%.
`
`
`
`“III!OdlfllflyML)
`
`I).
`
`II.
`
`95s
`
`asm hm nun-u. plum
`
`E
`p8
`
`nos
`
`mo
`
`(115
`
`no
`
`as
`
`nan
`
`Figure 3. Effect of SLS Concentration on Solubility of apixaban
`
`c. Selection on Apparatus
`The effect of different dissolution apparatus on the drug release for both 2.5-mg and 5-
`mg tablets was also evaluated The Basket method (Apparatus I) at 100 rpm yielded
`similar dissolution profiles to the Paddle method at 75 rpm for 2.5 mg tablets
`mufactured using drug substance of- particle size I um). However, 5-mg tablets
`
`Reference ID: 3092004
`
`

`

`manufactured using drug substance of - um particle size exhibited incomplete
`dissolution (< - dissolved in 60 minutes) when the basket method was used (Figure
`4).
`III)
`
`i“wind
`
`
`
` Cl
`0
`10
`N
`I)
`40
`50
`60
`10
`mm
`
`10
`
`Figure 4. Dissohltion Profiles of Commercial Apixaban Film- Coated Tablets (2.5 mg and 5 mg)
`in Phosphate Buffer with 0.05% SLS, pH 6.8 Using Paddle at 75 1pm and Basket at 100 rpm
`
`d. Selection of paddle rotation speed
`Dissolution of 2.5-mg and 5-mg proposed commercial tablets at 50 rpm paddle speed
`using three dissolution media at different pH (pH 1.2: 0.1 N HCl; pH 4.5: 50 mM acetate
`bufl'er; and pH 6.8: 50 mM phosphate buffer) was studied (Table 4). The data provided
`showed incomplete dissolution profiles (< 95% dissolved at 60 min) using a 50 rpm
`paddle speed for both dosage strengths. Although, 60 rpm provided complete dissolution
`at 60 min for the 2.5—mg tablets; the 5—mg tablets showed incomplete dissolution at 60
`rpm. These tablets showed incomplete dissolution even at 75 1pm using the above
`dissolution media. The paddle speed of 75 rpm was selected to avoid possible tablet
`momding at lower paddle speeds. In order to obtain a complete dissolution profile for 5-
`mg tablets, dissolution medium with surfactant was evaluated.
`
`Table 4. Dissolution of Apixaban Commercial Film-Coated Tablets (5-mg) at 50 rpm
`Paddle Speed in Three Media
`
`
`
`Reference ID: 3092004
`
`10
`
`

`

`e. Discriminating Power of the Dissolution Method
`The discriminating power of the dissolution method was tested against material attributes
`and tablet properties that could affect product performance, namely drug substance
`particle size and disintegrant level.
`
`In order to evaluate the dissolution method for its discriminating ability, 2.5-mg and 5-
`mg tablets were made using various drug substance particle size and disintegrant level.
`Table 5 shows that, when the drug substance of
`mm particle size M") = (gum) is
`used to produce the 2.5-mg tablets, the dissolution rate is significantly slower compared
`to that of the tablets made using drug substance with a particle size within the
`specification limit M“’=M«)um). The F2 value is 37 comparing the two dissolution
`profiles, indicating the method is discriminating for particle size of the drug substance
`used to manufacture the tablets. In addition, when the disintegrant is absent from the 2.5
`mg and 5 mg tablets but other formulation/process parameters are within the proposed
`specifications, the dissolution rate is significantly slower compared to that of the tablets
`within the formulation/process
`(mo
`
`Table 5. Dissolution Profiles of Commercial Apixaban Tablets (2.5-mg) Using Drug Substance
`of Different Particle Size
`
`Time“
`
`(min)
`
`5
`
`10
`
`15
`
`20
`
`30
`
`60
`
`9'6 Dissolved
`
`77507-044-2.5mg—C
`Drug substance M(4): Mmum
`Average
`_
`
`
`
`‘ Additional timepoints were added for investigatioml purpose
`
`F2=3 7. calculated using first three timepoints. n=6.
`
`77507-046-I5Ing—C
`Drug substance 0’)(4)=M”rm
`Average
`9‘6RSD
`48
`4.8
`
`63
`
`71
`
`76
`
`82
`
`91
`
`2.3
`
`1.1
`
`0.8
`
`0.9
`
`0.6
`
`In addition the method is considered bio-relevant, because it is able to re