CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-303
`
`CHEMISTRY REVIEW(S)
`
`KVK-TECH EXHIBIT 1049
`KVK-TECH EXHIBIT 1049
`
`

`

`SLI 381, loss of appetite and nausea were more commonin boys, and dyspepsia was
`more commonin girls; however, the sponsor did not comparethe relative risks for these
`events between boys and girls. Similarly, among subjects receiving SLI 381, insomnia
`was more common among Caucasians, while abdominalpain, loss of appetite, anxiety,
`emotionallability, and nervousness were more frequent among non-Caucasians, but
`here again the sponsordid not analyze these data in termsof differencesin 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 commentapplies to the
`vital sign analysis. Finally, more discussion could have been provided regarding the
`qualitatively abnormal ECG readings, which weresimply listed in the report; presumably
`none were considered particularly conceming from a clinical standpoint.
`
`8.7 Overall conclusions about safety
`
`Thisis the first large clinicaltrial 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 emotionallability, insomnia and
`nervousness. Although the findings were not entirely consistent acrosstrials,it is
`evidentthat the drug can raise heart rate and blood pressure. There did not appearto
`be anyfindings of concem with respect to laboratory or ECG parameters.
`The sponsor should provideclarification regarding the abnormalities in serum calcium
`that were reported in 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 iis approvable inmy opinion. My suggestions for labeling are
`attached to this review.
`Andrew D. Mosholder, M.D.
`Medical Officer, HFD-120
`
`Cc: Laughren, Wheelous, Mosholder
`
`17
`
`

`

`_/35_ page(s) of
`revised draft labeling
`has been redacted —
`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 Mosholder
`7/24/01 02:21:23 PM
`MEDICAL OFFICER
`
`Thomas Laughren
`7/28/01 12:16:17 PM
`MEDICAL OFFICER
`I agree that this NDA is approvable; see memo to file for more. detaile
`da comments .--+TPL
`
`

`

`NDA 21-303
`Single-Entity Amphetamine Product) Shire Laboratories Inc.
`
`SLE-381 (Extended-release capsule ofMixed Salts of a
`
`1
`
`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS, HFD-120 |
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`CHEM REVIEW: #1
`NDA 21-303
`SUBMISSION TYPE
`DOCUMENT DATE
`ORIGINAL
`10/3/2000
`18 mo. Stability data
`03/30/01
`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:
`Adderali-XR
`Nonproprietary/JSAN: Amphetamine sulfate USA/USN,amphetamineaspartate, dextroamphetamine sulfate
`USP/USAN,dextroamphetamine saccharate
`Code Name/Number:
`Chem. Type/Ther. Class:
`
`SLI 381
`38
`
`1) Treatment of ADHD 2) Treatmentof |
`’
`
`PHARMACOLOGICAL CATEGORY/INDICATION:
`narcolepsey
`.
`DOSAGE FORM:
`’ STRENGTHS:
`ROUTE OF ADMINISTRATION:
`DISPENSED:
`SPECIAL PRODUCTS:
`
`Capsules
`10 mg, 20 mg, and 30 mg
`Oral
`~
`xRx OTC
`—__Yes
`
`x__No
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Active Pharmaceutical Ingredient
`Chemical Name
`
`CAS Number
`
`Amphetaminesulfate, USP ©
`Dextroamphetamine sulfate, USP
`Amphetamine aspartate
`Dextroamphetamine saccharate
`
`(+)-o-Methylphenylamine sulfate
`(+)-a-Methylphenylamine sulfate
`(+)-a-Methylphenylamine aspartate
`(+)-a-Methylphenylamine saccharate
`
`;
`
`60-13-9
`617-48-8
`51-63-8
`87-73-0
`
`CASfor free amphetamine base is 300-62-9
`
`~
`
`

`

`-2-
`
`Dextroamphetaminesulfate USP
`Molecular formula: (CgH,3N)2-H,SO,4
`Molecular Weight: 368.50
`CAS # 617-48-8
`
`NH3
`
`-
`
`S0,?
`
`2.
`
`Amphetamine sulfate USP
`‘Molecular formula: (CgH,3N)2.H,SO,4
`Molecular Weight: 368.50
`CAS# 60-13-9
`
`_NHg
`
`©
`
`$0,”
`
`Trade name for immediate release products with this mixed salt combination is ADDERALL.
`
`Chemical Name
`
`Molecular Formula
`
`Molecular Weight
`
`Amphetamine sulfate, USP
`
`(CoH)3N)2.H2SO,
`
`.
`
`Dextroamphetamine sulfate, USP
`
`(CoHi3N)2.H2SO,
`
`368.50
`
`368.50
`
`.
`
`

`

`Amphetamine aspartate
`
`3.
`(CoHi3N)2.C4HjNO4H,O
`
`|
`
`Dextroamphetaminesaccharate
`
`(CoH13N)3.CeH90s
`
`286.33
`
`480.56
`
`Comments and Recommendation:
`
`This NDA describes a modified-release formulation ofpreviously approved Adderall immediate
`release dosage form. The sponsorhas satisfactorily addressed CMC concems 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 THIS WAY
`ON ORIGINAL
`
`APPEARS THISWAY
`ON ORIGINAL
`
`APPEARS THIS WAY
`ON ORIGINAL |
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS, HFD-120
`REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROLS
`NDA 21-303 CHEM REVIEW:#1
`REVIEW DATE: 10/24/2000
`SUBMISSION TYPE
`DOCUMENT DATE.
`CDERDATE
`ASSIGNEDDATE/ACTION
`ORIGINAL
`10/3/2000
`10/3/2000
`10/10/2000
`
`On
`
`NAME AND ADDRESS OF APPLICANT
`
`DRUG PRODUCT NAME
`Proprietary:
`
`Nonproprietary/USAN:
`Code Natne/Number:
`Chem. Type/Ther. Class:
`
`SLI 381
`38
`
`Shire Laboratories Inc.
`1505 East Gude Drive
`Rockville, Maryland 20850
`
`Amphetamine sulfate USA/USN, amphetamine
`aspartate, dextroamphetaminesulfate
`USP/USAN,dextroamphetamine saccharate
`
`1) Treatment of ADHD 2) Treatment of
`
`PHARMACOLOGICAL CATEGORY/INDICATION:
`narcolepsey
`DOSAGE FORM:
`STRENGTHS:
`ROUTE OF ADMINISTRATION:
`DISPENSED:
`’ SPECIALPRODUCTS:
`
`Capsules
`10 mg, 20 mg, 30 mg
`Oral
`xRx OTC
`___Yes
`
`x__No-
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA
`Active Pharmaceutical Ingradient
`Chemical Name
`
`CAS Number
`
`Amphetaminesulfate, USP
`Dextroamphetaminesulfate, USP
`Amphetamineaspartate
`Dextroamphetamine saccharate
`
`(+)-a-Methylphenylamine sulfate
`(+)-a-Methylphenylaminesulfate
`(+)-a-Methylphenylamine aspartate
`(+)-a-Methylphenylamine saccharate
`
`60-13-9
`617-48-8
`51-63-8
`87-73-0
`
`CASfor 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
`Amphetaminesulfate, USP
`(CoH3N)7.H)$O4
`-
`368.50
`
`|
`
`Dextroamphetaminesulfate, USP
`Amphetamine aspartate
`
`(CgH13N)2.H2S04
`Co9H13N.C4H7NO4.H20
`
`.
`
`Dextroamphetaminesaccharate
`
`(CoH13N2)2.C6H1 908
`
`368.50
`286.33
`
`480.56
`
`

`

`NDA21-303
`Amphetamine Product)
`
`ADDERALL XR™ Cll (Extended Release Capsule- Mixed Salts of a Single-Entity
`,
`
`2
`
`od
`
`.
`
`oo
`
`Specifications
`| MPS! oS
`
`SPECIFICATIONS
`Test
`Appearance
`Identification A
`
`Identification B
`Loss on Drying
`Specific Rotation
`(USP Test Dextroamphetamine)
`Residue on Ignition
`Organic Volatile Impurities
`Residual Solvents
`
`Chromatographic Purity
`
`-
`
`
`—-—-—_conditions for
`STABILITY STUDIES:The sponsor has conductedstability studies for the
`the first 12 months for the three primary stability batches of each finished product strength. The results
`showedthat the drug product appearance, average content, and dissolution properties were virtually
`_ unchangedoverthis period. There were no apparenttrends in 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 monthsperiod. The
`results demonstratethat the product appearance, average content, and dissolution were essentially
`unchanged overthe test period. There were no degradant peaks, Moisture results showed nosignificant
`change over time. Microbiallimit results showed nosignificant microorganism growthfor the product.
`Proposed Expiration Period: Sponsor is requesting fhe assignment of a 24-month expiration date period
`for the product. In support of the requested 24-month expiry period Shire has provided a 12- mo of
`satisfactory primary stability data at .-—----—-.storage condition. Shire also commits to provide 18
`monthsstability update for the primary stabilitylots at the ——-—=~—-—-_storage condition
`approximately six months after submission of this NDA.
`
`

`

`NDA21-303
`
`Athphetamine Product)
`
`ADDERALL XR™ C]I (Extended Release Capsule-.Mixed Salts ofa Single-Entity
`
`3
`
`Quantitative Composition:
`
`The theoretical composition in weight percent ofeach componentin SLI 38] Immediate-Release and
`Delayed-Release Tabletsis given in the table below. The actual percentages ofeach componentin the
`formulation differ slightly from the theoretical percentages dueto losses ofthe dispersion components
`during the fluidized bed drug layering, enteric coating andfinal coating procedures.
`
`
`
`Component
`—
`IR Pellets Weight Percent
`DRPellets Weight Percent
`Amphetamine Aspartate
`_—_——
`
`
`Amphetamine Sulfate, USP oo,
`
`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)
`
`
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`

`

`NDA 21-303
`Amphetamine Product)
`
`ADDERALL XR™ CII (Extended Release Capsule- Mixed Salts ofa Single-Entity
`
`4
`
`Theoretical Milligram/Capsule ofComponents in SLI 381 Capsules, 10 mg, 20 mg, and 30 mg
`
`
`
`
`
`Component
`10 mg
`20 mg
`30 mg
`
`(mg/capsule)
`(mg/capsule)
`
`(mg/capsule)
`
`
`—,,
`Amphetamine Aspartate|——
`Amphetamine Sulfate,
`
`
`
`Dextroamphetamine
`
`Dextroamphetamine
`
`
`
`
`
`
` Methacrylic Acid
`
`-|Hydroxypropylmethy]
`Cellulose, USP
`(Methocel E% Premium
`LV)
`
`Copolymer Dispersion,
`
`
` (Eudragit L30D-55)
`
`Triethylcitrate, NF
`
`| Talc, USP
`
`Opadry Beige, (YS-1-
`17274-A)
`
`Hard Gelatin Capsule
`
`COMMENTS: This NDAisfileable for CMC.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`