CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-303/S-001
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`Page 1 of 8
`
`KVK-TECH EXHIBIT 1020
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`sNDA:
`Name ofDrug:
`
`Indication of Drug:
`Type of Document:
`
`Sponsor:
`Reviewer:
`
`Date of Document: 10/26/01, 11116/01, 1129/02
`
`21-303/S001
`Adderall XR (Mixed Amphetamine and Dextroamphetamine Salts)
`10 mg, 20 mg and 30 mg Capsules
`Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)
`New Supplement for the Addition of New Strengths,
`5, 15 and 25 mg Capsules
`Shire Laboratories Inc., Rockville, MD
`Hong Zhao, Ph.D.
`
`Overall Summary
`
`Adderall XR is a modified-release capsule formulation based on the existing immediate(cid:173)
`release (IR) tablet of Adderall® (mixed salts of a single-entity amphetamine product).
`Both Adderall XR and Adderall IR contain d-amphetamine and /-amphetamine salts in
`the ratio of 3: 1. The Adderall XR formulation consists of two types of pellets in the ratio
`of ::.,...... in a gelatin capsule: an IR pellet and a delayed-release (DR) pellet with the
`pulsatile delivery scheme mimicking the effects of taking two doses of IR medication 4
`hours apart. The mechanism of drug release from the DR (enteric-coated) pellets is based
`on the higher pH values found in the small intestine compared with the stomach.
`
`Adderall XR capsules in strengths of 10, 20 and 30 mg have recently been approved for
`the treatment of attention-deficit/hyperactivity disorder (ADHD). Adderall XR capsules
`in strengths of 5, 15 and 25 mg have been developed to extend the available dosing
`options. The 15 mg and 25 mg capsules contain the same IR and DR pellets in the same
`proportions as the approved strengths and have similar dissolution profiles. Therefore, the
`in vivo bioequivalence study of these two strengths are not conducted. The 5 mg capsule,
`however, uses the same DR pellet and a
`-
`
`An in vivo study has
`.. ,_,.~-~~-~.:;-'f.""-~__, .. ~oj.'S".:k_····•:l'l-"i<<.:.~"'.\1·"~:::?<~·-t=-;~,'l-_.._., .... _~,..<, ... ""'~-'-~~~-~~;.-,.;..;_~( ... ~:".'~~~">:-'~,;:e·~~;:.:.:;:.r.:.--."'
`been conducted to assess its bioequivalence to the 20 mg Adderall XR capsule following
`a single dose of 20 mg (4x5 mg vs. 1x20 mg). The bioequivalence between the two
`strengths at the same dose has been established for both d- and /-amphetamine
`determined in this study.
`
`Major Findings:
`1. Bioequivalence (single dose, 4x5 mg vs. 1x20 mg): Bioequivalence was demonstrated
`between Adderall XR 4x5 mg capsules and Adderall XR 1x20 mg capsule in terms of
`rate and extent of absorption.
`
`2. Dissolution: Taking the 20 mg biobatch as, the reference and using the approved
`dissolution method, the value of the similarity factor for each of the new strengths
`was greater than 50, indicating thatthe dissolution profiles are similar.
`
`1
`
`Page 2 of 8
`
`

`

`Comment to the Sponsor
`
`The sponsor is requested to adopt the following dissolution method and specifications for
`all six strengths (5, 10, 15, 20,25 and 30 mg) of Adderall XR capsules:
`
`Media: -----
`
`Apparatus: USP Apparatus IT (paddle) at
`
`_;~~
`
`Specifications:
`
`Recommendation
`
`This submission (NDA 21-303/S001) has been reviewed by the Office of Clinical
`Pharmacology and Biopharmaceutics (OCPB) and has been found to be acceptable for
`allowing the approval ofthe three new strengths (5 mg, 15 mg and 25 mg). The sponsor
`is requested to adopt the dissolution methodology and specifications for all six strengths
`of Adderall XR capsules, as outlined in Comment to the Sponsor.
`
`Hong Zhao, Ph.D. __ __ _______ _
`
`RD/FT Initialed by Raman Baweja, Ph.D. ____________ _
`
`cc: NDA 21-303/S001 (Adderall XR) HFD-120, HFD-860 (Zhao, Baweja, Mehta),
`Central Documents Room (Biopharm-CDR)
`
`2
`
`Page 3 of 8
`
`

`

`Study Review
`
`In support of the addition of the new strength of Adderall XR capsule ( 5 mg) which uses
`the same delayed-release (DR) pellet and a .
`~ the sponsor has conducted a bioequivalence study comparing this new 5 mg
`strength to the approved 20 mg strength (4x5 mg to lx20 mg capsule). Comparable
`dissolution profiles are provided to support the approval of the other two new strengths
`(15 mg and 25 mg) which contain the same IR and DR pellets in the same proportions as
`the approved strengths.
`
`.. , ... -, · r-
`
`The following questions have been raised and answered through the review of this
`supplement NDA:
`
`Question 1: Are the new strengths compositionally proportional to the approved
`strengths?
`Yes. The two new strengths ( 15 mg and 25 mg) contain the same IR and DR pellets in the
`same proportions as the approved strengths. Comparable dissolution performance using
`the approved dissolution method should be sufficient to support the approval for these
`two strengths.
`
`No. The 5 mg capsule, however, uses the same DR pellets. -~~~~··=~=-
`--
`-
`~, .... ..,.........-~...,_-_,.,;,;_, .• ..,.,...,~-'l'-"·':0<;;.,..;--.~ ... 7<;..-."·"""·,;.':>-::''-"''''"'",,:!"..;:~!"·,~·-"=-....:.:: .. •·.;.o.o..;s;~,. .. -"-"'~'I.--'O;l;~.,.:.--:.-.>">';f;.r._~,,-:-.,..~,;r-""'.""""~~~-~""'-.Z!3i:IO~;;!!:; ... 'Y.~~--~~ ... n::-;-v..:..
`-
`-
`-
`-
`-
`_,.....~fll'·;..>:~~--;,.."'::.';?.~-,-·;~-;-i,~1'-<"'.i'S·;:;,....,.,.---;:~:}.;-Jjj."j!ls;:<;.-.":!:"-.':.~:;-~~·.;.!;e:<:1-".s:.;:.-:~ol_;,_~~""-"'·:>.:.;""·t..<'-·:;=";if>-'_;,'1-'.':'1L.W~~;,-L:;;::~-;.;,.-.;:..,-';1:,;>,:ifl:!l:;t':-;~.t.;S~"ci'~~~~
`S'~,,.:~,tlo]~"'~~il.:O-~-ey~A_,f.~;,t>.~~'?,;r;;~otlf~~~~~~.;: • .:.-~-,o.,·~:-::."<'~i~~:.,•.·.-c.:.,!'~~;i:.'U~~~;~c~.~":'C;~.,:.'<'-~~-?=.,._;.'..;1~;;.~9.~~ffd':~- An
`in vivo
`bioequivalence study has been conducted to support the approval of the 5 mg strength.
`
`The compositions of these new strengths are shown in the following tables:
`
`Table 1. Hard Gelatin Capsule Size and Intermediate Pellet Active Dose Amounts Used in the New
`Strengths of Adderall XR Capsules
`Adderall XR Capsules
`. Hard Gelatin
`Capsule Size
`Capsugel Size # J
`Capsugel Size # I
`Capsugel Size I.._
`
`5-mg Capsules
`15-mg Capsules
`25-mg Capsules
`
`Active Dose Amounts
`from -'IR Pellet
`from DR Pellet
`
`r i
`! - -------------------------------
`
`Table 2. Weight Percentage of Components in the Adderall XR QIR Pellets and IR Pellets
`..___ * Pellets
`IR Pellets
`Component
`Weight Percent(%)
`
`Amphetamine Aspartate
`Amphetamine Sulfate, USP
`Dextroamphetamine Saccharate
`Dextroamphetamine Sulfate, USP
`HydroxYJ>ropylmethyl Cellulose, USP
`
`Sugar Spheres ~~-~- _
`Opadry Beige ( ----~~- ,
`Total
`
`\
`____j
`
`100.00
`
`100.00
`
`3
`
`Page 4 of 8
`
`

`

`Question 2: What was the bioequivalence study design?
`This (Study 381.106) was a randomized, open-label, two-way crossover study. Twenty
`pediatric ADHD patients (17 males and 3 females) with 6 to 12 years of age received a
`single 20 mg dose of each capsule strength (4x5 mg, lot# OH2754A and 1x20 mg, lot#
`OJ2712A) under fasted conditions (an overnight fast before each of the two dosing days
`and standard meals starting 4-h post dose on test days). The two study periods were
`separated by a minimum 7-day washout interval. Blood samples were collected for 48
`hours (pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, and 48 hours post-doing). These
`plasma samples were analyzed for d- and /-amphetamine concentrations using a validated
`LC/MS method.
`
`The race distribution in this study was 14 Caucasians, 2 Blacks and 2 others.
`
`Question 3: Was the analytical method used for determination of amphetamine plasma
`concentrations validated?
`
`r
`
`• This analytical method has been validated with
`quantitation (LOQ) of c.:;,
`,
`acceptable results for linearity, precision and accuracy, recovery, sensitivity and stability.
`Therefore, the plasma concentrations of d-amphetamine and /-amphetamine measured by
`this assay for the bioequivalent study submitted in this supplement NDA are acceptable.
`
`Question 4: What are results of the bioequivalence study?
`Mean plasma d- and /-amphetamine concentration profiles for the two capsule strengths
`were essentially superimposable (see Figure 2-1). The mean pharmacokinetic parameters
`and the 90% confidence intervals for the ratios of the new 5 mg capsules ( 4x5 mg) to the
`approved 20 mg capsule are summarized in the following table:
`
`Table 3. Pharmacokinetic Parameters* from Study 381.106 (Pediatric ADHD Patients)
`AUCo.inr
`AUCo.t
`Cmax
`Tmax
`Single Dose
`(N=20)
`(ng.hr/m1)
`(ng/ml)
`(h)
`d-Amphetamine
`51.9±15.0
`795±179
`815±174
`AdderallXR20mg
`51.9±12.7
`844±188
`873±184
`Adderall XR 4x5 mg
`Point of Estimate (90%CI) 1.06 (1.01-1.10) 1.06 (1.01-1.12) 1.01 (0.92-1.10)
`/-Amphetamine
`15.8±4.5
`247±67
`269±59
`Adderall XR 20 mg
`16.7±4.0
`287±76
`307±69
`Adderall XR 4x5 mg
`Point of Estimate (90%CI) 1.12 (1.07-1.18) 1.16 (1.09-1.24) 1.07 (0.99-1.15)
`*Mean±SD
`
`4.9±1.9
`5.0±2.5
`
`4.5±1.7
`4.7±2.3
`
`t112
`(h)
`
`8.0±1.3
`7.9±1.0
`
`9.1±1.6
`9.0±1.1
`
`The 90% confidence intervals for Cmax, AUCo.t and AUCo.inf ford- and /-amphetamine
`were within the 0.80-1.25 window, demonstrating bioequivalence with respect to both
`compounds between the 5 mg and 20 mg capsules when administered at the same dose.
`
`4
`
`Page 5 of 8
`
`

`

`Figure 2-1 Mean plasma concentrations of d-amphetamine and }-amphetamine
`after oral administration of single 20 mg doses ofthe 5 mg and 20 mg
`ADDERALL XR™ capsules to pediatric patients (Study 381.106).
`
`0-Ampnetamine
`
`-e- 4x5mg
`~~ x20mg
`
`50
`
`40
`
`'"" 30
`~
`g
`8
`
`10
`
`12
`
`24
`
`Time(hJ
`
`36
`
`48
`
`Question 5: What was the dissolution method used to generate dissolution profiles for
`comparison between new strengths and approved strengths?
`The dissolution method used in the dissolution test was the approved dissolution method
`for Adderall XR:
`Apparatus: USP Apparatus IT (paddle) at :------
`Media:
`
`c
`
`Specifications:
`
`Question 6: Did the new strengths have similar dissolution performance as compared
`to the approved strengths?
`As illustrated in Figure 2-2, the dissolution profiles for representative lots of the six
`strengths of Adderall XR were similar. Using the 20 mg capsule as the reference,
`dissolution data and values of the similarity factor (f2) for new strengths are listed in
`Table4:
`
`Table 4. Dissolution Profile Comparison between the 20 mg Biobatch and the Proposed New
`· Strengths
`Strength
`Lot#
`
`20mg
`(OJ2702A)
`Biobatch
`
`20mg
`(9F2702)
`
`25mg
`(OF2725)
`
`5mg
`(OH2754A)
`Biobatch
`
`15mg
`(OF2719A)
`
`0.5-h
`1.0-h
`2.0-h
`2.5-h
`3.0-h
`
`Reference
`
`5
`
`Page 6 of 8
`
`

`

`The value of the similarity factor for each of the new strengths is greater than 50 as
`compared to the 20 mg biobatch, indicating that the dissolution profiles are similar.
`
`Figure 2-2 Mean Dissolution Profiles of5 mg, 10 mg, 15 mg,20 mg, 25 mg, and
`30 mg ADDERALL XR™ Capsules.
`
`100
`
`80
`
`"0
`·~
`~ 60
`
`~ =· §
`
`u
`c..·
`
`40
`
`20
`
`0
`0
`
`--a-,- 5. mg (Lot No. OH2754A)
`-e- 10 mg (Lot No. 9F2797)
`-A- 15 mg (Lot No. OF2719A)
`-'ii'-: 20 mg (Lot No. 9F2702)
`~ 25 mg (Lot No. OF2725)
`--&:- 30 mg (Lot No. 9F2703)
`
`2
`
`3
`
`4
`
`5
`
`Time (h)
`
`6
`
`Page 7 of 8
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Hong Zhao
`2/11/02 10:25:51 AM
`BIOPHARMACEUTICS
`
`Raman Baweja
`2/11/02 01:32:30 PM
`BIOPHARMACEUTICS
`
`Page 8 of 8
`
`