I CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER:
`
`NDA 20-717/S-009
`
`Name:
`
`Provigil Tablets
`
`Generic Name:
`
`modafinil
`
`Sponsor:
`
`Cephalon, Inc.
`
`Approval Date:
`
`07/29/2003
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 20-717/S-009
`
`CONTENTS
`
`
`
`Reviews / Information Included in this Review W‘
`
`
`
`X
`
`A roval Letter
`
`A 7. rovable Letter s
`Final Printed Labelin
`Medical Review s
`
`'
`
`Chemist Review s
`
`Pharmacolo Review s
`
`Statistical Review s)
`
`Microbiolo_ Review s
`Clinical Pharmacolo [Bio harmaceutics Review s .
`Administrative and Corresvn ondence Document s)
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TION NUMBER:
`NDA 20-717/S-009
`
`APPROVAL LETTER
`
`

`

`é DEPARTMENTOFHEALTH&HUMANSERVICES
`
`'
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 20-717/S-009
`
`Cephalon, Inc.
`Attention: Paul Kirsch
`
`Senior Director, Regulatory Affairs
`145 Brandywine Parkway
`West Chester, PA 19380-4245
`
`Dear Mr. Kirsch:
`
`Please refer to your Supplemental New Drug Application submitted on March 28, 2003, under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for Provigil® (modafinil) Tablets.
`
`This supplement provides for a new formulation of the drug product, manufacturing changes,
`and the addition of a new site, E
`Jfor manufacturing, testing, packaging and labeling of
`the reformulated drug product.
`
`We acknowledge receipt of your amendments dated June 13, 17 and 18, 2003.
`
`We have completed our review of this supplement and the application is approved.
`
`We also wish to forward the following additional advice for future submissions:
`
`1. Please note that the dissolution test should only use one tablet per vessel rather than
`two, to allow for the evaluation of the quality of each tablet.
`
`2.
`
`In the future, the highest tablet strength, rather than the highest dose, should be used
`in bioequivalence studies.
`
`Ifyou should have any questions, please call Ms. Anna Marie H. Weikel, Senior Regulatory
`Health Project Manager, at (301) 594-5535.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, MD.
`Director
`
`Division ofNeuropharmacological Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Thomas Laughren
`7/29/03 07:54:02 AM
`Signed for Russell Katz, M.D.
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TION NUMBER:
`NDA ‘20-717/S-009
`
`CHEMISTRY REVIEW! S!
`
`

`

`NDA 20—717, SCF 009, Provigil fluodaflnil) Tablets
`
`CHEMIST'S REVIEW
`
`1. ORGANIZATION
`HFD-120 DNDP
`
`3. NAME AND ADDRESS OF APPLICANT
`
`(City and SEECE)
`
`Inc.
`Cephalon,
`145 Brandywine Parkway
`West Chester, PA 19380—4245
`
`6. NAMEOF DRUG
`PROVIGIL®
`
`7. NONPROPRIEI'ARY NAME
`Modafinil
`
`5. SUPPLEMENT (S)
`NUMBERS) DATES(S)
`
`SCF-009
`
`3/31/2003
`
`including drug
`a. mmmsmmw nouns mm: multiple changes
`product
`formulation
`change, manufacturing
`process
`change, a new DP manufacturing site, and corresponding
`labeling changes.
`
`9.AM'ENDMENTSDATES
`
`Facsimile of 7/10/03
`(updated stability data)
`
`10 . PHARMACOLDGICAL CATEGORY
`
`Narcolepsy
`
`11 . HOW DISPENs-RX
`
`12 . Rm'I'ED IND/NDA/DMF
`
`13. DOSAGE FORM(S)
`
`l4. POTENCY
`
`Tablets
`
`100 and 200 mg/tablet
`
`15. CHEMICAL NAME AND STRUCTURE
`
`16. RECORDS ‘AND REPORTS
`
`2-[(Diphenylmethyl)sulfinyl]acetamide
`
`O
`
`0
`
`S
`
`NH2
`
`17. COW‘EENTS
`
`See review notes.
`
`13. CONCLUSIONS AND mwmnmmus
`
`.
`
`APPROVABLE for chemistry provided the sponsor submits the multi—point dissolution
`
`
`
`L:(iata for the reformulated product manufactured at
`
`:3 (refer to comments in the OCPB review of S— 009).
`
`the new site,[:
`
`:1
`
`Chengyi Liang, Ph. D.
`
`SIGNATURE
`
`DATE COMPLETED
`
`7— 17- 2003
`
`DISTRIBUTION
`
`ORIGINAL NDA
`
`DIVISION FILE
`
`-
`
`Reviewer:
`C'Y' Liang
`(RFD-150)
`Revised by M.
`Guzewska
`
`:
`
`I
`
`-
`
`‘
`
`Chemistry Team Leader
`M. Guzewska
`V
`(RFD-120)
`
`

`

`Redacted
`
`H
`
`page(s)
`
`_
`
`T of trade secret and/or
`
`confidential commercial
`
`information from
`
`
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Maryla Guzewska
`7/17/03 01:50:00 PM
`CHEMIST
`‘
`
`

`

`CHEMIST'S REVIEW
`
`1'mmmmmum
`HFD—120 DNDP
`
`3. NAME AND ADDRESS OF APPLICANT
`
`(City and State)
`
`Cephalon, Inc.
`145 Brandywine Parkway
`West Chester, PA 19380—4245
`
`6. NAME OF DRUG
`PROVIGIL®
`
`7. NONPROPRIEI‘ARY NAME
`Modafinil
`
`including drug
`smmfimmT pmwnms Rm: multiple changes
`a.
`product
`formulation
`change, manufacturing
`process
`change, a new DP manufacturing site, and corresponding
`labeling changes.
`
`5.smmmmfl(m
`ummm$)1mmum
`
`SCF-009
`
`3/28/2003
`
`10 . mmIDGICAL CATEGORY
`
`Narcolepsy
`
`11. HOW DISPENS- RX
`are
`
`12. RELATED IND/NDA/DMF
`IND 42 , 873
`
`13 . DOSAGE FORM (3)
`
`14 . POTENCY
`
`Tablets
`
`100 and 200 mg/tablet
`
`15. CHEMICAL NAME AND STRUCTURE
`
`16. RECORDS AND REPORTS
`
`2—[(Diphenylmethyl)sulfinleacetamide
`
`YES_\/ NO
`
`YES-1 NO
`
`NH2
`
`o
`
`o
`
`Hs
`
`1
`
`17. COMMENTS
`
`C
`(Case
`in multiple media
`Dissolution results
`S—009.
`review #2 of
`is a
`This
`:1 were submitted on July 17, 2003, and reviewed
`for the DP made inc:
`dissolution)
`by the OCPB reviewer on July 18, 2003. The similarity of
`the dissolution profiles
`supports the SUPAC level II equipment change and level III site change for the E;
`:3
`site. The OCPB found the additional data for the E_
`2] site acceptable.
`
`18. CONCLUSIONS AND RECOMMENDATIONS
`
`APPROVAL of S-009 is recommended
`
`I
`'
`NAME
`Maryla Guzewska, Ph.D.
`
`51mm
`
`DISTRIBUTION
`
`ORIGINAL NBA
`
`DIVISION FILE
`
`Reviewer:
`M" Guzewska
`
`,
`
`:
`
`DATE COMPLETED
`‘7—28—2003
`
`Chemistry Team Leader
`M. Guzewska
`(
`
`

`

`Appears This Way
`0n Original
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the'electronic signature.
`
`Maryla Guzewska
`7/28/03 10:29:23 AM
`CHEMIST
`
`Maryla Guzewska
`7/28/03 10:30:18 AM
`CHEMIST
`
`

`

`CHEM IST REVIEW
`
`1. ORGANIZATION:
`
`OF SUPPLEMENT
`
`7
`
`7. APPLICANT NAME AND ADDRESS:
`
`2. NDA NUMBER:
`4. SUPPLEMENT NUMBERS/DATES:
`letterdate:
`stampdate:
`5. AMMENDMENTS/REPORTS/DATES:
`6. - RECEIVED BY CHEMIST:
`
`Cephalon, Inc.
`145 Brandywine Parkway
`West Chester, PA 19380.
`
`HFD-120
`
`20-717
`SCF-009(FA)
`8-JAN-2004
`9-JAN-2004
`.
`17-MAR—2004
`
`8. NAME OF DRUG:
`.9. NONPROPRIETARY NAME:
`10. CHEMICAL NAME/STRUCTURE:
`
`'
`
`Provigil®
`modafinil
`2-[(diphenylmethyl)suIfinyllacetamide
`
`CASregistry#[68693-11-8]
`
`11. DOSAGE FORM(S):
`
`Tablets
`
`© 3
`
`l
`0
`
`"“2
`
`0
`
`12. POTENCY:
`13. PHARMACOLOGICAL CATEGORY:
`
`100, 200 mg
`Treatment of narcolepsy and hypersomnia
`
`-
`14. HOW DISPENSED:
`15. RECORDS & REPORTS CURRENT:
`SPECIAL PRODUCTS
`16. RELATED IND/NDA/DMF:
`
`(OTC)
`XXX (RX)
`(NO)
`XXX (YES)
`(YES) XXX (NO)
`
`17. SUPPLEMENT PROVIDES FOR: Final Printed Labeling for the commercial labels for 100-count, 100 mg;
`100-count, 200 mg, and the package insert.
`
`18. COMMENTS: A reformulation of Provigil drug product was approved in July 2003 (SCF-OOQ). The package insert
`ingredients list was updated to reflect this. The barcode and NBC numbers in the package insert and on the bottle
`labels for the two dosage forms were similarly updated.
`
`19. CONCLUSIONS AND RECOMENDATIONS: The final printed labeling is acceptable.
`
`20. REVIEWER NAME
`
`SIGNATURE
`
`DATE COMPLETED
`
`David J. Claffey, PhD.
`
`14-APR-2004
`
`cc: Orig. NDA 20—717
`HFD—120/DivFiIe
`HFD—120/MMille
`HFD-120/DCIaffey
`INT: MG
`
`.
`
`filename: N 20—717(SCF-009-FA) Provigil modafinil.doc
`
`

`

`
`
`Redacted 1,;2 _ page(s)
`
`
`
`of trade Secret and/or
`
`confidential Commercial
`
`information from
`
`
`
`_
`
`_
`
`.ew@w#
`
`.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`David Claffey
`4/15/04 02:59:43 PM
`CHEMIST
`
`Mary1a_Guzewska
`4/15/04 03:02:37 PM
`CHEMIST
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 20-717/S-009
`
`CLINICAL PHARMACOLOGY/
`
`BIOPHARMACEUTIC S REVIEW; S 2
`
`

`

`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS REVIEW
`
`
`NDA:
`Brand Name:
`Generic Name:
`
`20-717 tSCF-009)
`Provigil
`Modafinil
`
`Type of Dosage Form: Oral Tablets
`Strengths:
`100 mg, 200 mg
`Indications:
`Narcolepsy
`Type of Submission:
`CMC Supplement
`Sponsor:
`Cephalon Inc.
`Submission Dates:
`March 28, 2003
`June 13, 2003
`
`OCPB Division:
`0ND Division:
`OCPB Reviewer:
`OCPB Team Leader:
`
`_
`DPE—I
`Division of Neuropharmacological Drug Products HFD-120
`Sally Usdin Yasuda, MS, PharmD
`Ramana Uppoor, PhD
`
`1 Executive Summary
`
`This NDA review evaluates in vivo and in 'vitro data regarding PROVIGIL tablets (100
`mg and 200 mg). The Sponsor has submitted data to support a SUPAC level III
`formulation change at E.
`:1 will not continue
`to manufacture the drug product. Therefore, the Sponsor has submitted documentation to
`link the E.
`:1 site and the l: 3 site, supporting the manufacture of the reformulated
`drug product at the current I; 3 site. Addition of a new site E
`3 also involves a
`SUPAC level 11 equipment change, for which supporting data has not been submitted.
`
`The pivotal bioequivalence study demonstrated bioequivalence between the proposed
`formulation and the current formulation of the 200 mg strength tablets of PROVIGIL
`E
`' j r. Dissolution studies demonstrated similar dissolution profiles between the
`proposed formulation of the 100 mg and 200 mg strength tablets L”;
`:1 that are
`compositionally proportional. Therefore the Office of Clinical Pharmacology and
`Biopharmaceutics recommends a biowaiver for the 100 mg strength tablets of the
`proposed formulation.
`
`Dissolution studies conducted in the approved medium and using the approved methods
`met the regulatory specification for PROVIGIL tablets for all lots tested. Similarity of
`the dissolution profiles of specific lots of the current and proposed formulations supports
`the change in formulation (E, j and I:
`:1).
`
`There are no proposed labeling changes related to the Clinical Pharmacology section of
`the label.
`
`

`

`1.] Recommendations
`
`The Office of Clinical Pharmacology and Biopharmaceutics (OCPB) finds the submitted
`data in NDA 20-717/S—009 for PROVIGIL acceptable for the I:
`:1 andC :1 products.
`However, there is insufficient data to support the equipment change associated with the
`E’.
`3 product. Therefore the OCPB does not find the data submitted for the l:
`3
`product acceptable.
`
`Please forward the Comments to Sponsor (found in section 3.2) to the Sponsor.
`
`Sally Usdin Yasuda, MS, PharmD
`Reviewer, Neuropharmacological Drug Section, DPE I
`Office of Clinical Pharmacology and Biopharmaceutics
`
`Concurrence:
`
`Ramana Uppoor, PhD
`Team Leader, Neuropharmacological Drug Section, DPE I
`Office of Clinical Pharmacology and Biopharmaceutics
`
`cc:
`
`HFD-120
`
`HFD—860
`
`NDA 20—717 (8009)
`' CSO/ A. Homonnay
`/Biopharm/S. Yasuda
`/TL Biopharm/R. Uppoor
`/DD DPEI/M. Mehta, C. Sahajwalla
`
`

`

`2 Table of Contents
`
`1
`
`2
`
`3
`
`EXECUTIVE SUMMARY .................................................................................................................. 1
`
`1.1 RECOMMENDATIONS ............................................................... 2
`
`TABLE OF CONTENTS ..................................................................................................................... 3
`
`SUMMARY OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS FINDINGS.. 4
`
`3.1 BACKGROUND ........................... 4
`
`3.2
`
`CURRENT SUBMISSION..................................................................................................................... 4
`
`4 APPENDICES ....................................................................................................................................... 8
`
`4.1
`
`4.2
`4.3
`
`BIOANALYTICAL METHODOLOGY .................................................................................................... 8
`
`BIOEQUIVALENCE STUDY .............................................................................................................. 10
`DISSOLUTION STUDIES .................................................................................................................. 16
`
`

`

`3 Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`3.1 Background
`
`PROVIGIL (modafinil) is indicated to improve wakefulness in patients with excessive
`daytime sleepiness associated with narcolepsy (NDA 20717).
`It is available as
`immediate release tablets (100 mg and 200 mg) and is given once daily. The usual dose
`is 200 mg/day. The labeling states that doses of 400 mg/day have been well tolerated but
`that there is no consistent evidence of additional benefit beyond that of the 200 mg dose.
`
`According to the PROVIGIL label, modafinil (a racemic mixture) has an elimination
`half-life of approximately 15 hours after multiple doses, with steady state reached after 2-
`4 days of dosing. The enantiomers of modafinil demonstrate linear kinetics after multiple
`dosing of 200-600 mg once daily in healthy volunteers. The major route of elimination is
`via hepatic metabolism. Two metabolites, modafinil acid and modafinil sulfone, reach
`appreciable plasma concentrations, although they do not appear to be involved in the
`pharmacologic activity of modafmil. Modafmil is metabolized in part via CYP3A4 that
`appears to be a primary pathway, for formation of modafmil sulfone according to the
`OCPB review of NBA 20-717 (November 1997). According to that review, the
`formation of modafinil acid does not appear to involve a P450. Modafmil induces
`CYP3A4. Modafmil inhibits CYP2C19, and in hepatocytes has resulted in
`concentration—related suppression of CYP2C9.
`
`The Office of Clinical Pharmacology and Biopharmaceutics previously reviewed the
`proposed documentation that was submitted 7/19/99 and recommended that the
`formulation changes fall under Level 3 in the Components and Composition section
`identified under SUPAC (due to adding or deleting an eXcipient), requiring dissolution
`documentation and in vivo bioequivalence documentation. It was suggested that the
`Sponsor could perform a biostudy with the 200 mg strength tablets, and request the
`approval of the reformulated 100 mg tablets on the basis of dissolution profile testing, as
`the two strengths appear to be compositionally proportional.
`
`3.2 Current Submission
`
`The purpose of the present submission is to support a new formulation of the drug
`product for Provigil tablets (100 mg and 200 mg). This formulation change has been
`made at thel:
`:1. site and at the C 3 site (both are approved sites for current
`formulation). The supporting documentation includes a bioequivalence study at the
`I:
`:[site and Case B dissolution profile comparison for the proposed and current
`formulations at the [;
`:11 site, as well as a Case B dissolution profile linking the new
`formulation at the I: :1 site and at the E 3 site. Finally the Sponsor has requested
`addition of an additional site, 1:.
`_
`'3 for which there is an
`equipment change in addition to a site change.
`
`

`

`The following table summarizes the changes that have been submitted in the present
`supplement and the documentation that is required. The E.
`I] and E
`3 sites
`manufacture the new formulation.
`'
`
`Change
`
`SUPAC Change
`
`Required Dissolution/BE
`Documentation
`
`New Formulation for 100 mg and
`200 mg tablets (E.
`3 Site)
`
`Level III change in
`Components and
`Composition
`
`0 Case B dissolution profile
`Comparison for proposed
`and current formulation
`(Multipoint dissolution
`profile in compendial
`medium)
`Full BE study (based on
`compositional
`proportionality, the 100 mg
`strength could be evaluated
`on the basis of dissolution
`. rofile testin
`
`0
`
`0
`0
`
`Case B dissolution profile
`BE documentation not
`re- uired
`
`Case C dissolution profile
`(multipoint dissolution
`profiles in multiple media
`for proposed and current
`formulations)
`BE documentation not
`
`
`
`Same Formulation Change as
`Above (C lsite)
`
`Site Change and Equipment
`Change (1:: me E.
`:1)
`
`Linked new formulation at
`E:
`:i to I: 1(falls under
`level 111 site change)
`Level 111 site change
`Level II equipment change
`Minor in process change
`
`required
`
`The following clinical pharmacology studies have been submitted and reviewed:
`
`0 C1538c/41 1/BE/US — Pivotal bioequivalence study of the highest strength tablets
`o Dissolution Documentation
`
`The bioanalytical methods were validated and documented appropriately.
`
`The key findings with respect to the clinical pharmacology and biopharmaceutics of the
`new formulation of PROVIGIL tablets are as follows:
`
`0 Bioequivalence was demonstrated for the proposed aqueous formulation relative to
`Il formulation of PROVIGIL 200 mg strength tablets afier
`the current 21;
`administration of a single oral dose of 400 mg (2 x 200 mg tablets). The new
`formulation was the same lot as used in the dissolution studies. The Sponsor has not
`stated the rationale for using a 400 mg dose, although the reviewer notes that the
`Sponsor collected samples for analysis of the metabolites as well as for the parent
`
`

`

`compound, and the present analytical assay is limited with regard to the sensitivity for
`measuring the sulfone metabolite.
`-
`
`o Dissolution studies were conducted in the approved medium using the approved
`methods. The dissolution performance for all lots tested met the regulatory
`specification for PROVIGIL tablets.
`'
`
`1; full
`o Dissolution profiles comparing the current commercial formulation ( E;
`scale commercial lot) and the proposed formulation ( I: 3; same lot as used in the
`bioequivalence study) of the 200 mg strengths were similar using the approved
`method, as were the dissolution profiles comparing the current commercial
`formulation (1:
`3; full scale commercial lot) and the proposed formulation
`C E J.) of the 100 mg strengths. This supports the change in formulation.
`
`0 Comparison of the dissolution profiles of the proposed formulation of the 200 mg'
`strength (‘LL
`3.; same lot as used in the bioequivalence study) and the proposed 100
`mg tablets (‘1:
`3) were similar (as calculated by the reviewer). This supports a
`biowaiver of the lower strength 'E :1 tablets.
`
`o Dissolution profiles comparing either strength of the proposed formulation at 'E j
`and L" 3 were similar. This, along with the in vivo bioequivalence study for the
`formulation change at the 'C 3 site, supports the new formulation to be
`manufactured at E. J
`
`0 There are no proposed labeling changes related to the Clinical Pharmacology section- >
`of the label.
`
`II site is a SUPAC Level 11
`j. to the E.
`0 The equipment change from the E,
`change for which the Sponsor has not provided the required dissolution
`documentation. The product from the L I]. site is therefore not acceptable.
`
`The Office of Clinical Pharmacology and Biopharmaceutics finds that the submitted data
`in NDA 20-717/S-009 are acceptable only for the C II. and C 3 sites. The submitted
`data for the E
`‘_'| site are not acceptable.
`.
`
`Please forward the comments below to the Sponsor.
`
`Comments to Sponsor:
`
`'3 also involves a SUPAC Level II equipment
`Jto L:
`1. The change from ‘E
`change. This change requires Case C dissolution documentation involving multi-
`point dissolution profiles in water, 0.1 N HCl, and USP buffer media at pH 4.5,
`6.5, and 7.5 (five separate profiles) for the proposed and currently accepted
`.
`formulations. The dissolution profiles of. the proposed and currently used
`formulations should be similar. Please refer to the Guidance for Industry entitled '
`
`

`

`“Irnmediate Release Solid Oral Dosage Forms. Scale-Up and Postapproval
`Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing,
`and In Vivo Bioequivalence Documentation” that can be found at
`http://www.i‘da.gov/cder/ggidance/cmcS.pdf.
`
`.
`
`.
`
`In the future, to link different strength tablets in an in vitro dissolution study, the
`Sponsor should note that the dissolution test should use only 1 tablet per vessel,
`rather than dissolving 2 tablets per vessel. This allows for evaluation of the
`quality of each individual tablet.
`
`In the future, the Sponsor should note that the highest strength tablet (rather than
`the highest dose) should be used in bioequivalence studies.
`
`

`

`4 Appendices
`4.1 Bioanalytical Methodology _
`
`Bioanalytical Method for Modafinil and Metabolites in NBA 20-717
`
`A high performance liquid chromatographic (HPLC) assay was developed and validated
`for determination of modafmil and its metabolites, modafmil acid and modafmil sulfone,
`in human plasma. E
`j
`w—h—fl
`
`

`

`In conclusion, the bioanalytical method used for analysis of plasma samples in the
`clinical studies in this NDA 20-717 supplement is considered adequately documented and
`validated.
`
`

`

`4.2 Bioequivalence Study
`
`AN OPEN-LABEL, RANDOMIZED, TWO-WAY CROSSOVER STUDY TO
`
`COMPARE THE RELATIVE BIOAVAILABILITY AND BIOEQUIVALENCE
`OF TWO ORAL TABLET FORMULATIONS OF PROVIGIL
`
`Study Investigators and Site:
`
`L:
`
`:1
`
`Protocol Number: C1538c/41 1/BE/US
`
`OBJECTIVES:
`
`To evaluate the bioavailability of a new aqueous formulati0n (Formulation B, test)
`relative to the current f:
`j formulation (Formulation A, reference) of
`PROVIGIL (modafinil) 200 mg strength tablets after administration of a single 400 mg
`oral dose.
`
`FORMULATIONS:
`
`Table 1. Products used in C1538c/411/BE/US
`
`‘
`
`Test Product (T)
`Modafmil 200 mg tablets
`C
`’3
`Reference Product (R)
`Modafinil 200 mg tablets
`C
`j
`
`'
`
`Package Lot
`Number
`823203
`
`Dose Form
`Lot Number
`1538-FL19-2
`
`729501
`
`087645
`
`-
`
`Date of Manufacture
`(Dates of Study)
`3/10/98
`(1/99-7/20/99)
`
`10/8/97
`(1/99-7/20/99)
`Expiry Date: / months
`
`3. into
`:lwas L:
`jand the l;
`The batch size for the test product was I:
`:1 tablets for the 200 mg strength. The
`multiple tablet strengths that included};
`proposed commercial batch size isIE
`3. Stability data for the test product suggests
`stability (by I-IPLC assay and dissolution testing) at E 3 months.
`
`STUDY DESIGN:
`
`This study was an open—label, randomized, 2-period, 2-treatment, 2-sequence crossover
`study, as shown in Table 1, below. For Treatment A, subjects received modafinil
`Formulation A 400 mg (2x200 mg) as a single dose (reference, R). For Treatment B,
`subjects received modafinil Formulation B 400 mg (2x200 mg) as a single dose (test, T).
`There was a minimum interval of 7 days and no more than 21 days between
`
`10
`
`

`

`administration of each formulation. The 200 mg strength is the highest marketed strength
`of PROVIGIL. The 400 mg dose is the highest dose in the labeled dose range.
`
`Table 2. Treatment Seguence in C1538c/411/BE/US
`Seguence Number
`Treatment Period 1
`l
`A )
`2
`B (T)
`
`Treatment Period 2
`B T
`A (R)
`
`'
`
`Inclusion criteria included healthy nonsmoking males, 18 to 45 years of age (inclusive).
`Exclusion criteria included prior experience with modafmil, use of prescribed systemic or
`topical medication within 4 weeks of the start of dosing or any systemic or topical
`nonprescription medications within 2 weeks of the start of dosing, treatment agents such
`as barbiturates, phenothiazines, or cimetidine known to alter major organs or systems
`within 4 weeks of the start of dosing, history of alcohol, narcotic, or drug abuse, had
`clinically significantexcessive consumption of coffee, tea, or other caffeine-containing
`beverages or food within 14 days prior to the first dose.
`
`After overnight fast, subjects were administered a single 400 mg (2x200 mg tablets) oral
`dose of modafmil with 180 m1 of water on each of two dosing occasions. Subjects
`continued to fast until 4 hours following the dose, except for 200 ml water at 1 hour
`before and 2 and 4 hours after dosing. Caffeine intake was restricted to 1 cup of tea or
`coffee with meals while subjects were in the clinic. Subjects remained in the clinic for at
`least 24 hours after dosing, and returned to the clinic for the last three assessments.
`Blood samples were collected for drug assay at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12,
`16, 24, 36, 48, and 60 hours of dosing.
`
`ASSAY:
`
`The study included determination of plasma concentrations of the parent and metabolites
`modafinil acid and modafinil sulfone. However, since these metabolites are not
`considered to contribute to the pharrnacologic activity of modafinil, their concentrations
`have not been evaluated in the present review, since measurement of only parent drug is
`generally recommended in this case (Draft Guidance for Industry: “Bioavailability and
`Bioequivalence
`Studies
`for Orally Administered Drug Products — General
`Considerations”, July 2002).
`
`ll
`
`

`

`RESULTS:
`
`Demographics
`
`Twenty-four male subjects were enrolled in the study. Twenty-two subjects completed
`the entire study and were eligible for pharrnacokinetic analysis. One subject was
`discontinued due to death from accidental injury and a second subject was discontinued
`due to a protocol violation. Demographics of the subjects completing the study are
`shown below.
`
`Table 4. Demographics of Subjects Completing the Study
`Mean Age (Range)
`Weight gmean :l: SD!
`Race
`1
`31(2245)
`76.8: 11.1 kg
`Asian
`2
`Black
`Caucasian 17
`
`.
`
`1
`
`Hispanic 2
`
`Pharmacokinetics
`
`Pharmacokinetic parameters were determined using noncompartmental analysis. The
`plasma concentration time course and the pertinent pharmacokinetic parameters for
`modafmil are shown in Figure 1 and Tables 5 and 6, below.
`
`12
`
`

`

`Figure 1. Mean Plasma Concentration Time Course for Modafinil after Administration of Test
`(open circles) or Reference (solid squares) Formulations (as provided by Sponsor).
`
`.__.0:2
`
`4" Formulation A (Reference Product)
`‘0‘ hmmeanhflhwmo
`
`
`
`PlasmaModafinilConcentration(pg/mL) S
`
`
`
`
`
`0.1
`
`081624324048566472
`
`Time (hours)
`
`Table 5. Pharmacokinetic Parameters (Arithmetic Mean) for Modalinil (Stud! C1538c/411/BE/US)
`Test (Formulation B)
`Reference (Formulation A)
`(% CV)
`(% CV)
`n=22
`n=22
`
`Modafinil
`,
`tmax (11)”
`Cm (Hg/mL)
`W...
`*
`$31122?“ mm”
`
`3.0 (1.00-5.00)
`9.2 (22)
`122-382;
`.
`0.05 (17)
`
`7
`
`13.6 (15)
`13.6 (16)
`fl____—________-
`“ median (range)
`bcalculated by reviewer
`
`2.0 (1.00-6.00)
`9.2 (22)
`32:52:;
`.
`0.05 (15)
`
`13
`
`

`

`Table 6. Bioeguivalence Assessment for Study C1538c/411/BE/US
`
`Geometric Mean
`Ratio of
`Test
`Geometric
`ormulation B
`Means“
`
`Reference
`emulation A
`
`90% CI for the
`Ratio of Geometric
`Means
`
`Modafinil
`
`(0.90, 1.09)
`0.99
`9.0
`9.0
`Cm,x (pg/ml)
`(0.96, 1.05)
`1.00
`129.5
`130.0
`AUC (H (”gm/mm
`AUC o...(ug*h/mL)
`133.8
`133.4
`1.00
`(0.96,1.04)
`
`
`3calculated by reviewer
`
`Reanalysis of the data by the reviewer was in agreement with that provided by the
`sponsor regarding the pharmacokinetic parameters for modafinil as well as the
`bioequivalence of the test and reference compounds.
`
`The 90% confidence intervals on the geometric means of the Cmax, AUC (H, and AUC0_24
`ratios are within: the bioequivalence interval of 0.8 to 1.25 for modafinil.
`
`Safefl
`
`Treatment-emergent adverse events were reported in 54% of subjects following
`administration of Formulation A (reference) and in 45% following administration of
`Formulation B (test). The adverse effect profiles for the test and reference products were
`similar, except that a larger percentage of subjects reported nervousness afler
`Formulation A (reference, 13%) than alter Formulation B (test, 0%). The most common
`adverse events that were considered possibly or probably related to study medication
`were headache, asthenia, nausea, nervousness, dizziness, insomnia, confusion, and
`paresthesia.
`
`CONCLUSIONS:
`
`This study demonstrated bioequivalence between the new aqueous formulation
`(Formulation B, test) relative to the current 1;
`J formulation (Formulation A,
`reference) of PROVIGIL (modafinil) 200 mg strength tablets manufactured at the C
`site after administration of a single 400 mg oral dose.
`
`:1
`
`The 400 mg dose of modafinil used in the present study utilized 2 x 200 mg tablets (the
`highest strength tablet). The dose of 400 mg is within the labeled dose range, although
`the label states that there is no consistent evidence that this dose confers additional
`benefit beyond that of the 200 mg dose. The Sponsor has not identified the reason for
`using the 400 mg dose, although this dose would have allowed for greater
`characterization of the pharmacokinetics of the sulfone metabolite than would a lower
`dose, using the present analytical assay. In the future, the Sponsor should note that the
`highest strength tablet should be used in bioequivalence studies.
`-
`
`Since modafinil is neither a substrate nor an inhibitor of CYP1A2, the inclusion of
`caffeine in the present study is unlikely to have had an impact on the pharmacokinetic
`results. However, xanthine or caffeine-containing foods and beverages are generally
`
`14
`
`

`

`restricted in these types of studies from prior to the study period until after the last blood
`sample is collected. In addition, the sponsor should note that in BA and BE studies study
`drug is generally administered with 240 ml of water. The Sponsor should take this into
`consideration in fiJture studies.
`
`Appears Thls Way
`0n Original
`
`15
`
`

`

`4.3 Dissolution Studies
`
`PROVIGIL DISSOLUTION - IN VITRO CONIPARATIVE RESULTS
`
`Rationale for Evaluation Methodology
`
`The Sponsor has submitted in vitro dissolution studies to support a new formulation
`(proposed aqueous formulation compared to current E '
`II formulation) of the
`100 mg and 200 mg strengths of the drug product for PROVIGIL Tablets. In addition,
`the site for manufacturing, testing, packaging, and labeling of the reformulated product
`has changed such that L
`:1 will be removed as a site, the new
`formulation will be made at the E 2! site (a current site), and I:
`jwill be added as a
`new site (a level 1]] site change). The Sponsor has submitted in vitro dissolution studies
`as documentation that link the new formulation at the C7
`:I site and the E J site, as
`well as dissolution studies to support a level III site change for the I:
`:1 site.
`
`’ 3 step during manufacturing has been changed. This involves an equipment
`The];
`change to allow for either E
`:1 and E 21‘) or the
`_j(L'_
`E
`7
`7
`V
`7
`j). TheTable
`below (as provided by Sponsor) compares the equipment used in the manufacturing
`process at each site. The accompanying Figure below (as provided by Sponsor) outlines-
`the manufacturing process, comparing the I:
`J
`I:
`I
`:1 Based on these comparisons, the Office
`of Clinical Pharmacology and Biopharmaceutics, after consultation Withithe Office of
`New Drug Chemistry, has determined that this change involves a SUPAC Level II
`equipment change and a minor process change (since the same E;
`J
`r:
`_
`:1
`'
`
`16
`
`

`

`Proposed changes in formulation were previously reviewed by the Office of Clinical
`Pharmacology and Biopharmaceutics (September 1999) that concluded that the changes
`corresponded to SUPAC Level 111 changes in Components and Composition due to
`deleting or adding an excipient. Therefore it was recommended that dissolution
`documentation would require a multi-point dissolution profile on at least 12 individual
`dosage units in the NDA approved medium at 15, 30, 45, 60, and 120 minutes, with
`dissolution profiles being similar between the biobatches of reformulated and current
`products.
`
`17
`
`

`

`The following table summarizes the proposed changes and the documentation that is
`required to support those changes.
`
`Change
`
`SUPAC Change
`
`
`
`
`
`Required Dissolution/BE
`Documentation
`
`0
`
`
`
`Level IH change in
`New Formulation for 100 mg and
`Case B dissolution profile
`
`
`Components and
`200 mg tablets (‘E
`3 site)
`Comparison for proposed
`
`
`
`Composition
`and current formulation
`
`
`
`
`(Multipoint dissolution
`
`profile in compendial
`
`medium)
`Full BE study (based on
`0
`
`compositional
`
`proportionality, the 100 mg
`
`strength could be evaluated
`
`on the basis of dissolution
`. rofile testin ;
`
`Same Formulation Change as
`Above (lE :1 site)
`»
`
`Linked new formulation at
`f.
`:1 to E 3 (falls under
`level III site change)
`
`0
`0
`
`1
`
`Case B dissolution profile
`BE documentation not
`re uired
`
`Level III site change
`Site Change and Equipment
`Level II equipment change
`Change (1: j to C J)
`Case C dissolution profile
`
`
`Minor in process change
`(multipoint dissolution
`
`profiles in multiple media
`for proposed and current
`formulations)
`BE documentation not
`
`0
`
`0
`
`
`
`
`
`
`Lot Summag
`
`required
`
`Current Commercial
`Formulation; Full Scale
`
`Commercial Lot
`
`Current Commercial
`
`
`Formulation; Full Scale
`
`
`
`Commercial Lot
`
`
`809001
`[IM- 1': “3- (3/10/98
`
`
`823203
`200 mg
`[L :1 (3/10/98)
`
`
`
`
`
`
`*
`
`
`
`—IIM-
`
`
`
`Lot #
`
`
`
`
`730003
`
`Strength
`
`100 mg
`
`Manufacturer (Date of
`Manufacture)
`E
`3 (10/6/97)
`
`806902
`
`200 mg
`
`-
`
`C.
`
`:1 (2/10/98)
`
`'
`
`
`
`
`
`
`
`
`
`
`.
`
`(not the same as used in
`the bioavailability
`swab»)
`Pro nosed Formulation
`Proposed Formulation
`(same as used in the
`bioavailabili stu
`
`l8
`
`

`

`Composition of Current and Proposed Formulations
`
`The tablet below shows the composition of the current and proposed formulations of both
`the 100 mg and 200 mg strength tablets. The changes in formulation involve addition or
`deletion of excipients. In addition, it can be seen that the 100 mg and 200 mg strength
`ta