CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -3 03
`
`CHEMISTRY REVIEW! S)
`
`KVK-TECH EXHIBIT 1049
`KVK-TECH EXHIBIT 1049
`
`

`

`SLI 381, loss of appetite and nausea were more common in boys, and dyspepsia was
`more common in girls; however, the sponsor did not compare the relative risks for these
`events between boys and girls. Similarly, among subjects receiving SLI 381, insomnia
`was more common among Caucasians, while abdominal pain, loss of appetite, anxiety,
`emotional lability, and nervousness were more frequent among non-Caucasians, but
`here again the Sponsor did not analyze these data in terms of differences in relative risk
`by ethnic origin.
`
`8.6 Adequacy of safety assessment: The safety methodology was generally adequate.
`An analysis of weight and height, especially in the long term trial, would have been
`helpful. Also, the analysis of laboratory abnormalities could have been improved by
`selecting criterion values for significant abnormalities, and then determining the number
`of such abnormalities that were treatment emergent. The same comment applies to the
`vital sign analysis. Finally, more discussion could have been provided regarding the
`qualitatively abnormal ECG readings. which were simply listed in the report; presumably
`none were considered particularly concerning from a clinical standpoint.
`
`8.7 Overall conclusions about safety
`
`This is the first large clinical trial dataset available in some time for an amphetamine
`drug product. Overall the safety profile appears consistent with what would be
`expected for a sympathomimetic psychostimulant. Weight 'loss and anorexia were two
`of the the most frequent adverse reactions, which is not surprising for a drug product
`that was originally marketed for weight loss. The psychostimulant effects of
`amphetamine were reflected in the incidence of emotional lability, insomnia and
`nervousness. Although the findings were not entirely consistent aoross trials, it is
`evident that the drug can raise heart rate and blood pressure. There did not appear to
`be any findings of concern with respect to laboratory or ECG parameters.
`The sponsor should provide clarification regarding the abnormalities'In serum calcium
`that were reportedIn study 301. The sponsor should also provide more information on
`the two subjects in study 301 who developed premature atrial systoles during treatment
`with SLI 381.
`
`‘
`
`9.0 Overall Conclusions and Recommendations
`This drug product'Is approvable'In my opinion. My suggestions for labeling are
`attached to this review.
`
`Andrew D. Mosholder, MD.
`Medical Officer, HFD—120
`
`Cc: Laughren, Wheelous, Mosholder
`
`17
`
`

`

`
`
`/3 page(s) of
`revised draft labeling
`has been redacted I
`
`from this portion of
`the review.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`
`this page IS the manifestation of the electronic signature.
`
`
`
`
`Andy Moshol‘der
`7/24/01 02:21:23 PM
`MEDICAL OFFICER
`
`Thomas Laughren
`7/28/01 12:16:17 PM
`MEDICAL OFFICER
`
`I agree that this NBA is approvable; see memo to file for more detaile
`d cornments.——TPL
`
`

`

`NDA 21-303
`Single-Entity Amphetamine Product) Shire Laboratories Inc.
`
`51.1481 (Extmded—release capsule of Mixed Salts of a
`
`1
`
`DIVISION OF NEU'ROPI-IARMACOLOGICAL DRUG PRODUCTS, RFD-120 I
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`CHEM REVIEW: #1
`NDA 21-303
`SUBMISSION TYPE
`DOCUMENT DATE
`ORIGINAL
`10/3/2000
`18 1110. Stability data
`03/3 0/01
`Response to inquiry
`06/19/01
`
`REVIEW DATE: 10/24/2000 -
`CDER DATE ASSIGNED DATE
`10/3/2000
`10/10/2000
`
`NAME AND ADDRESS OF APPLICANT
`Shire Laboratories Inc.
`
`'
`
`1505 East Gude Drive
`
`Rockville, Maryland 20850
`
`DRUG PRODUCT NAME
`Proprietary:
`Adderall-XR
`Non proprietary/USAN: Amphetamine sulfate USA/USN, amphetamine aspartate, dextroamphetamine sulfate
`USP/USAN, dextroamphetamine saccharate
`Code Name/Number:
`
`SL1 381
`
`Chem. Type/Then Class:
`
`35
`
`PHARMACOLOGICAL CATEGORY/INDICATION:
`narcolepsey
`-
`DOSAGE FORM:
`' STRENGTHS:
`ROUTE OF ADMINISTRATION:
`
`Capsules
`10 mg, 20 mg, and 30 mg
`Oral
`,
`
`1) Treatment of ADI-ID 2) Treatment of -
`'
`
`DISPENSED:
`SPECIAL PRODUCTS:
`
`LR): __OTC
`_Yes
`
`x_No
`
`. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Active Pharmaceutical Ingredient
`Chemical Name
`
`CAS Number
`
`Amphetamine sulfate, USP '
`Dextroamphetamine sulfate, USP
`Amphetamine aspartate
`Dextroamphetamine saccharate
`
`(:)-u-Methylphenylan1ine sulfate
`(+)-a-Methylphcnylamine sulfate
`(:)-a-Mcthy1phenylamine aspartatc
`(+)-a—Methylphenylamine saccharate
`
`‘
`
`60-1'3-9
`617-48-8
`51-63-8
`87-73-0
`
`CAS for {ice amphetamine base is 300-62-9
`
`‘
`
`

`

`- 2 _
`
`Dextroamphetamine sulfate USP
`Molecular formula: (C9H13N)2.HZSO4
`Molecular Weight: 368.50
`CAS # 617-48-8
`
`NH3
`
`.
`
`so,2
`
`2 _
`
`Amphetamine sulfate USP
`- Molecular formula: (Cg-I-II3N)2.H2804
`Molecular Weight: 368.50
`‘CAS # 60—13-9
`
`I NH3
`
`.
`
`s04 2
`
`Trade name for immediate release products with this mixed salt combination is ADDERALL.
`
`Chemical Name
`
`Molecular Formula
`
`Molecular Weight
`
`Amphetamine sulfate, USP
`
`_
`
`(C9H13N)2.H2$04
`
`,
`
`368.50
`
`Dextroamphetamine sulfate, USP
`
`(C9H13N)2.H2804
`
`-
`
`368.50
`
`

`

`f—H
`
`Amphetamine aspartate
`
`(C9H13N)2.C4H7N04.H20
`
`Dextroamphetamiuesaccharate
`
`(caning-cams
`
`.
`
`_ 3 _
`
`.
`
`'
`
`286.33
`
`480.56
`
`Comments and Qcommendation:
`
`This NDA describes a modified-release formulation of previously approved Adderall immediate
`release dosage form. The sponsor has satisfactorily addressed CMC concerns raised by chemistry
`
`reviewer. However, CGMP violations were found at the manufacturing site__ ______ _‘_______
`
`'
`Until the time compliance issues (CGMP) are resolved, this NDA is non-
`'approvable.
`
`APPEARS THlS WAY
`0N ORIGINAL
`
`APPEARS THlS-WAY
`0N ORIGINAL
`
`APPEARS THIS IIIAv
`0N ORIGINAL.
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS, RFD-120
`REVIEW OF CHEMISTRY,MANUFACTURING, AND CONTROLS
`
`.
`NDA 21-303 CHEM REVIEW: #1
`SUBMISSION TYPE
`DOCUMENT DATE ‘
`ORIGINAL
`10/3/2000
`
`REVIEW DATE: 10/24/2000
`CDER DATE
`ASSIGNEDDATE/ACTION
`10/3/2000
`10/10/2000
`
`0
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`
`Proprietary:
`
`'
`
`Non proprietary/USAN :
`Code Name/Number:
`
`Chem. Type/Ther. Class:
`
`SLI 3 81
`
`38
`
`Shire Laboratories Inc.
`
`1505 East Gude Drive
`
`Rockville, Maryland 20850
`
`Amphetamine sulfate USA/USN, amphetamine
`aSpartate, dextroamphetamine sulfate
`USP/USAN, dextroamphetamine saccharate
`
`PHARMACOLOGICAL CATEGORY/INDICATION:
`narcolepsey
`DOSAGE FORM:
`STRENGTHS:
`ROUTE OF ADMINISTRATION:
`
`Capsules
`10 mg, 20 mg, 30 mg
`Oral
`
`1) Treatment of ADI-ID 2) Treatment of
`
`DISPENSED:
`' SPECIAL PRODUCTS:
`
`x_Rx ___OTC
`__Yes
`
`x_No -
`
`.CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Active Pharmaceutical Ingradient
`Chemical Name
`
`CAS Number
`
`Amphetamine sulfate, USP
`Dextroamphetamine sulfate, USP
`Amphetamine aspartate
`Dextroamphetamine saccharate
`
`(:)—a-Methylphenylamine sulfate
`(+)-a-Methylphenylamine sulfate
`(i)-a-Methylphenylamine aspartate
`'(+)-a-Methylphenylamine saccharate
`
`60-13-9
`617—48—8
`51-63-8
`87-73-0
`
`CAS for free amphetamine base is 300-62-9
`
`Trade Name for immediate release products with this mixed salt combination is ADDERALL
`Chemical Name
`Molecular Formula
`Molecular Weight
`
`Amphetamine sulfate, USP
`
`'
`
`(C9H13N)2.H2804
`
`-
`
`368.50
`
`Dextroamphetamine sulfate, USP
`
`(C9H13N)2.H2804
`
`Amphetamine aspartate
`
`C9H13N.C4H7NO4.H20
`
`'
`
`_
`
`Dextroamphetamine saccharate
`
`(C9H13N2)2.C6H1003
`
`368.50
`
`286.33
`
`480.56
`
`

`

`NDA 21-303
`Amphetamine Product)
`
`ADDERALL XRTM CII (Extended Release Capsule- Mixed Salts of a Single-Entity
`'
`
`2
`
`SPECIFICATIONS
`
`Method
`
`_
`
`.. SPFCificatiOns
`
`Identification A
`
`Identification B
`
`'
`
`'
`
`
`
`
`
`__
`
`Loss on Drying
`Specific Rotation
`(USP Test Dextroamphetamine)
`
`Residue on Ignition
`Organic Volatile Impurities
`Residual Solvents
`
`
`
`Chromatographic Purity
`-
`_....... _
`
`
`
`-
`
`
`
`STABILITY STUDIES: The sponsor has conducted stability studies for the '
`_____________ conditions for
`the first 12 months for the three primary stability batches of each finished product strength. The results
`showed that the drug product appearance, average content, and dissolution properties were virtually
`_ unchanged over this period. There were no apparent trends1n these results. There were no degradant
`peaks. Moisture results showed no_significant change over time. Microbial limit results showed no
`significant microorganism growth for the product;
`
`The stability studies were also conducted at ---_-:-=_—.._ condition through six months period The
`results demonstrate that the product appearance, average content, and dissolution were essentially
`unchanged over the test period. There were no degradant peaks. Moisture results showed no significant
`change over time. Microbial limit results showed no significant microorganism growth for the product.
`
`Preposed Expiration Period: Sponsor is requesting the assignment of a 24-month expiration date period
`for.the product. In supportof the requested 24—month expiry period Shire has provided a 12- mo of
`
`approximately six months after submission of this NDA.
`
`

`

`NDA 21-303
`Amphetamine Product)
`
`ADDERALL )(RTM Cll (Extended Release Capsule-Mixed Salts ofa Single-Entity
`
`3
`
`Quantitative Composition:
`
`The theoretical composition in weight percent of each component in SLI 38-1 Immediate-Release and
`Delayed-Release Tablets is given in the table below. The actual percentages ofeach component in the
`formulation differ slightly from the theoretical percentages due to losses ofthe diSpersion components
`during the fluidized bed drug layering, enteric coating and final coating procedures.
`
`
`
`_
`
`
`Amphetamine Aspartate
`
`
`Amphetamine Sulfate, USP
`Dextroamphetamine Saccharate
`
`Dextroamphetamine Sulfate,
`USP
`_
`
`Hydroxypropylmethyl Cellulose,
`
`
`USP (Methocel E% Premium
`
`LV)
`
`
`
`Sugar Sphere 30/35 Mesh, NF
`
`
`Methacrylic Acid Copolymer
`
`
`Dispersion, NF
`(Eudragit L30D-55)
`
`Triethylcitrate, NF
`____._______
`
`_ Opadry Beige, (YS-1-17274-A)
`
`
`
`
`__ IR Pellets Weight Percent
`DR Pellets Weight Percent
`————_...
`-—---——-.
`
`-"""—""—"'-5
`'--—---
`.._._.__..,
`
`
`
`"
`-=-"—"""
`
`.
`
`—-—-—.
`
`' """"
`*
`__.______
`
`
`
`' "'
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`NDA 21-303
`Amphetamine Product)
`
`ADDERALL XRTM ClI (Extended Release Capsule- Mixed Salts of a Single-Entity
`
`4
`
`”Theoretical Milligram/Capsule ofComponents in SLI 381 Capsules, 10 mg, 20 mg, and 30 mg
`
`Component
`
`
`
`Amphetamine Aspartate
`Amphetamine Sulfate,
`
`.
`
`10 mg
`(mg/capsule)
`.-—
`
`Dextroamphetamine
`
`Dexttoamphetamine
`
`Hydroxypropylmethyl
`Cellulose, USP
`(Methocel E% Premium
`
`
`
`
`
`20 mg
`30 mg
`
`(mg/capsule)
`(mg/capsule)
`.—-—...‘
`
`
`
`
`
`
`
`
`LV)
`-
`
` Methacrylic Acid
`
`C0polymer Dispersion,
`
`NF
`
`(Eudragit L3 OD-SS)
`
`Triethylcitrate, NF
`__ Talc, USP
`Opadry Beige, (YS-l-
`17274-A)
`
`
`
`Hard Gelatin Capsule
`
`COMMENTS: This NDA is fileable for CMC.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`