`
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER: 020717
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`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTIC S REVIEW! S )
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`Nov 19 1997
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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
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`NDA 20-717
`IND-
` .
`
`Submission Date:
`December 27, ‘96, —
`April 10, ‘97, —
`May 13, ‘97.
`June 16, ‘97.
`July 23, ‘97 ~
`Aug. 10, ‘97 ..
`
`PROVIGIL® (Modafinil) (100 mg, 200 mg IR Tablets for Oral Administration)
`
`INDICATION: Narcolepsy
`
`Sponsor: Cephalon Inc., West Chester, PA
`
`Type of submission: NDA (NME),
`
`Reviewer: Rae Yuan, PhD.
`
`— S
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`YNOPSIS:
`
`PROVIGIL® (Modafinil), chemically 2-[(diphenylmethyl)sulfinyl]acetamide
`(MW=273, pKa=lO.4), is claimed to be a centrally acting wakefulness-promoting
`compound that is developed for the treatment ofnarcolepsy. The sponsor is seeking for
`approval on 100 mg and 200 mg uncoated immediate release tablets for oral
`administration. According to the labeling by the sponsor, modafinil will be administered
`at an initial dose of 200 mg/day, and may be increased to a maximum of400 mg/day.
`Because it is believed that all the metabolites ofmodafinil are pharmacologically
`inactive, the focus of this NDA is on the parent drug.
`
`RECOMIVIENDATIONS:
`
`This NDA is acceptable to the OCPB, provided that the sponsor incorporates
`OCPB PK labeling in COMMENT 8 and adopts the dissolution specification in
`COMMENT 9.
`
`Please convey the following COMMENTS to the clinical division and to the
`sponsor.
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`modafinil acid is 40% of AUCM of parent drug, and Cmax is 50% of the parent drug.
`In renal impairment patients, these percentages increased to 340% and 160%,
`respectively (based on single dose study). Had the renal impairment study been
`conducted in multiple dosing regimen, modafinil acid accumulation could be even
`higher. Therefore, the toxicity of modafinil acid needs to be studied.
`3. The sponsor has conducted a drug-drug interaction study between clomipramine and
`modafinil, and concluded no interaction between the two drugs. However, the study
`design, in the reviewer’s opinion, was inadequate in the study to draw such a
`conclusion. A case report submitted as a supplement indicated that PK interaction
`between modafinil and clomipramine is possible. Furthermore, an in vitro study
`conducted by the sponsor demonstrated that modafinil competitively inhibits
`CYP2C19, which may be involved in clomipramine metabolism.
`4. Modafinil was able to induce certain CYP enzymes, as demonstrated in an in vitro
`study. In vivo, modafinil was found to induce self-metabolizing enzyme to result in
`lowered plasma concentration following chronic dosing (>6 weeks). It was also
`demonstrated that modafinil induces enzymes metabolizing antipyrine. Furthermore,
`a case report submitted as supplement indicated that modafinil may induce CYP3A4
`in cyclosporine metabolism.
`
`COMMENTS TO THE SPONSOR:
`
`5. The sponsor is encouraged to provide information regarding the interconversion of
`enantiomers in the future.
`
`6. For the drug-drug interaction stud between clomi ramine and modafinil, the study
` .
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`is inade uate.
`
`
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` .
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`7. Clinical information on modafinil interaction with CYP3A and CYPZCl9 enzyme
`substrates (especially narrow therapeutic drugs as CYP2C19 substrates), as those
`indicated by in vitro studies, should be submitted.
`
`8. The sponsor is requested to incorporate ‘OCPB pharmacokinetic labeling’ as outlined
`in the Labeling section (pg. xiv).
`
`9. Based upon data provided by the sponsor, OCPBis setting the following methodology
`and specification for all strengths ofmodafinil tablets (100 mg and 200 mg):
`
`Apparatus:
`Speed:
`Medium:
`Temperature:
`Specification:
`
`P 2
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`addle)
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`900 ml of 0.1N HCl
`37 °C
`Not less than-in- minutes.
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`TABLE OF CONTENTS
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`CONTENTS
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`PAGE
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`i
`Recommendation..........................................................
`i
`Comments........................................................mmmmm......................................
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`.. iii
`.........................................
`Table of Contents....
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`Summary of the studies
`.......................................www.muviii
`.......................................................xiv
`OCPB PK Labeling........
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`
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`APPENDIX A: REVIEWED INDIVIDUAL STUDIES
`
`Metabolism Studies:
`
`1. A Mass Balance and Metabolism Study of-C-Modafinil (100 uCi) Following
` .
`the Single Dose Administration of a 200 Mg Oral Suspension
`(C1538a/lll/PK/US)............................................................................................ 2
`
`2. Identification and Profiles of Modafinil and Modafinil Metabolites in Urine
`fi'om Human Subjects Administered a Single Oral Dose of ['C] Modafinil
` .
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`3. In Vitro Metabolism of Modafinil by Human Hepatic Microsomes
`(DM-95-025)...................................................................................................... 7
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`Linearity Study:
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`4. Linearity ofthe Kinetics ofModafinil (MOD 018) ....................................... 8
`
`Multiple Dose PK Study:
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`5. Double-Blind, Ascending dose, Seven-Day Administration of Modafinil
`Tablets for Safety, Tolerance, And Pharmacokinetic profile In Normal Male
`Subjects (CEP-2101) .................................................................... 10
`
`Protein Binding Study:
`
`6. Pharmacokinetics ofmultiple doses ofMODAFINIL in healthy humans
`-MOD-019)................................................................................................ 12
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`Food Efl'ect:
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`7. Evaluation of the Eflea of Food on the Pharmacokinetic Profile of Modafinil
`and its Metabolite in a Single Dose Cross-over Study in Healthy Volunteers
`(MOD-022)........................................................................................................... l4
`
`8. Kinetics of the Enantiomers of Modafinil after Oral Administration of the
`Racemate to Humans (MOD-022 Continuation Analysis).................................... 15
`
`9. Evaluation of the Efi‘ect of Alkalind Urine on the Kinetics of Modafinil
`_MOD-023).........................................................................16
` .
`
`Gender Study:
`
`10. A Nine-Week Placebo-Controlled, Double-Blind, Randomized, Parallel-
`Group Study ofthe Safety and Efiicacy of Two Fixed Doses (200 mg, 400 mg) of
`Oral Modafmil in Patients with Narcolepsy Followed By a 40 Week, Open-Label,
`Flexible-Dose continuation Study (C1538a/301/NA/US)..................................... l 8
`
`Age Study:
`
`11. Blood Kinetics Trial of Modafinil (CRL40476) in the Elderly Subject Before
`and After Repeated Administration —MOD-020)..'...................................... 19
` .
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`Special Populations:
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`Liver impairment Study:
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`12. Pharmacokinetics of Multiple Doses of Modafinil in Humans with Severe
`Chronic Hepatic Insuficiency -MOD-02l).................~...........................21
` .
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`Renal Impairment Study:
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`13. Evaluations of The Pharmacokinetics of Modafinil and Its metabolites in
`Severe Chronic Renal Failure _P1595)..................................................23
` .
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`Drug-Drug Interaction Study:
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`14. A Double-Blind Placebo-Controlled 3 Way Crossover Study to Investigate the
`Kinetics and Acute Tolerability ofModafinil and Clomipramine Alone and in
`Combination in Healthy Male Volunteers (C153 8a/107/PK/UK).................25
`
`15. An Open, 3x3 Latin Square, Randomized, Cross-over Study to Investigate the
`Pharmacokinetics of Modafinil And Methylphenidate When Given Alone and in
`Combination in Healthy Male Volunteers (C1 538a/109/PK/UK).......................27
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`16. Evaluation of a New Chemical Entity, Modafinil as an Inhibitor of Human
`P450 Enzymes (DM-96-051 (XT052396))...........................................................29
`
`17. An In Vivo Study of Modafinil Using Primary Human Hepatocyte Cultures:
`Induction of Hepatic Drug Metabolism Activities and Biotransformation
`(DM-96-042)..........................................................................................................3 1
`
`Bioequivalence study:
`
`13. An Open-Label, Randomized, 4x4 Latin Square, Crossover Study to
`Determine the Relative Bioavailability and Bioequivalence of Three Single Oral
`(200 mg) Modafinil Tablet Treatments (C1538a/110/BEIUK).............................32
`
`APPENDIX B: ANALYTICAL ASSAYS
`
`"vs
`
`1. Reports ofAnalytical _methods for Detection ofModafinil, Modafinil
` .
`Acid and Modafinil Sulfone Plasma Levels by Cephalon, Inc. (DM-93-012, DP-
`95-005, DP-95-015)............................................................................................2
`
`2. Reports for Analytical _Methods for Detection of l- and d- Modafinil
` .
`Plasma Levels by Cephalon, Inc. (DP-95-003)........;...........................................3
`
`3. Reports for Analytical _Methods for Detection of Modafinil, Modafinil
` .
`Acid and Modafinil Sulfone Plasma Levels by_(DP-96-023,
` .
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`DPR-96-040).......................................................................................................4
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`. u
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`4. Reports for Analytical-Methods for Detection ofM
` .
`Acid and Modafinil Sulfone Plasma and Urine Levels b
` .
`_(DPR-96-041)....................................................................5
` .
`
`' Modafinil
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`5. Reports for Analytical-methods for Detection of l-and d- Modafinil
` .
`Plasma Levelsby— 93103)..........................6
` .
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`6. Reports for Analytical-Methods for Detection ofModafinil, Modafinil
` .
`Acid and Modafinil Sulfone Urine Levels by Cephalon, Inc.
`(DP-95-017,DP-95-002)......................................................................................7
`
`7. Report for Analytical Radioactivity Quantification Method for Detection of
`plasma RBC, Urine and Feces Radioactivity Levels by Cephalon, Inc.
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`(DP-95-31).............................................................................................................8
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`8. Table of Quantification Methods in All the Studies Conducted.....................§....9
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`APPENDIX C: DISSOLUTION
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` .
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`D
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`APPENDIX D. TABLE OF DRIJG FORMATION AND
`INVESTIGATIONAL BATCHES USED IN BIO-STUDIES
`
`1. Table ofDrug Formulation Development Summary in All the Studies
`Conducted.............................................................................................................. l
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`2. Table of Summary of Modafinil Tablet Batches Used for Bioavailability
`Studies.....................................................................................................................2
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`APPENDIX E. PK LABELING PROPOSED BY THE SPONSOR
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`5— 94068: Evaluation of the Metabolic Profile of Modafinil In Vitro in
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`Human Hepatocytes
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`6. DP-95-005: A Validation of an Internal Standard Assay for Simultaneous
`Determination of Modafinil and Its Acid and Sulfone Metabolites in Human Plasma
`Utilizing—and—
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`7. C1538b/105/BEfUK: Open, Randomized, 2-Way Crossover Study to Compare the
`Bioavailability of a Single Oral dose of 200 mg Modafinil (Formulation A) with 200 mg
`Modafinil (Formulation B) in 20 Healthy Male Volunteers
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`SUMMARY OFSTUDTES
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`Background.
`In the last 40 years, there has not been a novel compound approved for the_
`treatment of narcolepsy. The current therapeutic agents for this disease are
`methylphenidate, d-amphetamine and pemoline, all ofwhoseemcacymem were
`based on uncontrolled case studies, and all ofwhich areconsidered _CNS stimulants -
`'
`_ acting through dopaminergic/noradrenergic mechanisms. Here,thesponsor proposed
`MODAFINIL, chemiCally, 2-[(d1phenylmethyl)sulfinyl]acetamrde,as_acentrallyacting
`wakefirlness-promoting agent for the treatment ofnarcolepsyModafinilascurrently
`availablein France (as Modiodal), and approvalrs pendingin mdstEuropean centuries.
`The sponsor seeks approval of 100 mg and 200 mg 1R uncoated tablets for the
`-
`therapeutic use of200 rug/day as an initial dose and 200-_400 mg/dayas_maintenancedose
`
`in adults.
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`Pharmacokinetics of modafinil and its enantiomers:
`Modafinil is a racemic mixture, with its enantiomers showing different h'netics.
`In the range of 200-600 mg/day once daily, time-independent and dose-independent
`pharmacokinetics were observed for both modafinil and its enantiomers. PK profile of
`~Moda’finil is similar to that of I-(-)-modafinil. Apparent C.I (trough) ofmodafinil and l-(-
`)—modafinil, both ofwhich were much higher than that of d-(+) modafinil (by >10 times)
`'were reached after 3-4 days of dosing. Steady state ofd-(+) modafinil was reached
`within24hrsafierdosing. Fliminationofd-(+)modafinilis3timeaasfastasthatofl—(—
`)-modafinil (Cl=102 ml/min and tm—4hrvs. Cl=34 mllmin and fiBlShr, respectively).
`The enantiomers have similar volume ofdistribution (~40 L).
`.
`.
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`Absorption:
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`Absorption ofmodaiinil tablets'is rapid, with peak plasmaconcentration of~5
`pig/ml or ~10 1.1me being achieved at ~2 hours following daily single dose of 200 or_400
`mg/day, respectively. The relative bioavailability ofmodafinil tabletrs_~1_90%,
`compared to a micronized aqueous suspended solution.
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`Distribution:
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`Metabolism:
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`In vivo metabolism: The metabolism ofmodafinil has been invesu'gated in 6 healthy
`volunteers who received a single oral dose ofside-chain labeled'c-modafinll (200 mg).
` .
`Approximately 80% and ~1% ofthe total dose were recovered in 11-day period in urine
`and feces, respectively. Unchanged modafinil accounted for 5% ofthe total radioactivity
`attached page). Modafinil acid, the deamination product from the parent drug, is the
`major metabolite identified in urine (accounts for ~ 40%). The other metabolites,
`
`In vitro metabolism: Human liver microsomal studies revealed that (l) the major
`renally excreted metabolite, modafinil acid, was not produced from CYP catalysis; (2) the
`. minor metabolite in human, modafinil sulfone, was produced via CYP3A catalysis; (3)
`modafim'l inhibits CYP2C19 activity.
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`In humans, modafinji at dose higher than 400 mg showed enzyme induction on
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`Modnfinilend Modnfinil Metabolites identified by LC/MSIMS Techniques In
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`Food intake did not show any effect on the bioavailability ofmodafinil, or the
`pharmacokinetics of the two enantiomers. Therefore, modafinil can be administered
`without consideration to food.
`
`Gender Study:
`In young healthy volunteers, a slight gender difi‘erence in metabolite modafinil
`acid excretion was demonstrated, but is oflittle clinical significance. In the pivotal study
`on patients with narcolepsy (n>30), no gender difference on plasma concentration of
`modafinil was observed.
`
`Age Study:
`In a single dose study, 12 elderly male subjects showed slightly lower clearance of
`modafinil (by 20%), compared to the young male volunteers (n=12). But all the other
`pharmacokinetic parameters were comparable between the two groups. In a study of 12
`elderly patients with narcolepsy (n=12, 6M & 6F), the plasma concentrations at steady
`state were comparable to those in the young subjects. No study on elderly female
`subjects were conducted. But overall, the age efi‘ect on modafinil pharmacokinetics did
`not seem to be prominent
`
`Hepatic Impaired Subjects:
`This was an open trial on PK ofmultiple dosing ofmodafinil (2 x 100 mg for 8
`days) on 9 subjects (6 men and 3 women) with severe liver cirrhosis. Six healthy male
`subjects (from another multiple dosing study), who received the same dose and regimen
`of modafinil as the hepatically impaired patients, served as controls. On Day 1 and Day
`8, a single dose of200 mg ofmodafinil was given in the morning, but fiom Day 2 to Day
`7, the drug was given as one tablet in the morning and one at noon. PK parameters are
`altered in severely hepatic impairment patients: tm was doubled (from 13.6 hr to 27.7 hr),
`total volume of distribution was decreased (from ~80 L to ~60 L), and Cm at steady state
`was doubled (from 3.7 ug/ml to 7.9 jig/ml). Despite the change of PK parameters, the
`hepatic insufficient patients had a good tolerance to the drug. A reduction by one-halfin
`the dosage of modafinil is suggested in the patients with severe liver disease. No study
`was conducted on mild and moderate liver impairment patients.
`
`Impaired Renal Subjects:
`This study was a single 200 mg dose, non-randomized, open label study
`conducted in 10 male subjects with severe chronic renal failm'e (mean Cl,==l 6.6 i 2.2
`ml/min. All patients had a history ofrenal disorder, 4 had hypertension, 1 had glaucoma
`and l of dyspepsia). Twelve healthy male voltmteers from another study served as
`controls for this group of renal impaired patients. Severe chronic renal failure did not
`significantly influence the PK ofmodafinil, compared to the PK in normal volunteers.
`The inactive metabolite, modafinil acid, accumulated considerably in renal patients
`(AUCM increased by >8 fold and T1,z increased by >2 fold). But the clinical implication
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`of toxicity from modafinil acid, upon chronic administration of modafinil, was not
`known. The sponsor claimed that dose adjustment in this population was not necessary.
`
`Drug-Drug Interactions:
`(a) In Vivo:
`Modafinil and Clomipramine
`This is a single-center, 3-way double-blind crossover study involving 18 healthy
`male volunteers. Six subjects received one single dose of clomipramine at 50 mg on Day
`1 and 200 mg modafinil (2 x 100 mg tablets) once daily fiom Day 1 to Day 3. Six
`subjects received the same dose of clomipramine alone on Day 1 and 2 placebo tablets for
`modafinil for 3 days. The other group of 6 subjects received 1 placebo capsule for
`clomipramine on Day 1 and modafinil (2 x 100 mg tablets) once daily from Day 1 to Day
`3. There was a 2-week washout period between each treatment phase (tm of
`clomipramine > 24 hr). Plasma samples were collected for modafinil upto 108 hrs and
`clomipramine upto 72 hrs, which is, in this reviewer’s opinion, too short to cover the
`elimination phase. Though it appears that there is no drug interaction between
`clomipramine and modafinil, in the reviewer’s opinion, the poor study design and the
`large variation on clomipramine plasma concentration may contribute to failure in
`detecting any potential interaction.
`Recently, a case report on a 60 year old female taking long term treatment of 100
`mg clomipramine showed drug interaction with 200 mg modafinil. Sufi‘ering from
`cataplexy, she was put on 100 mg clomipramine with steady state concentration of
`clomipramine and its active metabolite desmethyl clomipramine of 129 and 208 ng/ml
`respectively. Under 200 mg modafinil, the blood level of clomipramine and desmethyl
`clomipramine increased to 158 and 238 ng/ml, respectively, although the dose of
`clomipramine was decreased to 75 mg.‘ Under 400 mg modafinil, the blood level of
`clomipramine and desmethyl clomipramine increased to 210 and 449 ng/ml, respectively,
`causing the discontinuity of clomipramine administration.
`
`Modafinil and Methylphenidate
`This is an open 3x3 Latin square, randomized, cross-over study in 21 healthy male
`volunteers (3 groups of 7 subjects). All the drugs were given as sm‘gle doses. In one
`treaunent group, methylphenidate (immediate release) at a dose of 4 x 10 mg and
`modafinil at a dose of 2 x 100 mg were given to the subjects concomitantly. In other
`treatment groups, modafinil (2 x 100 mg) or methylphenidate (4 x 10 mg) was given
`alone, separately. The results show that the coadministration of these two medications
`did not change the PK of either agent, except that methylphenidate administration caused
`a smallincrease (~l hr) on modafinil T“, which may result'in a delayin modafinil oral
`absorption.
`
`(b) In Vitro:
`In vitro studies were conducted in human liver microsomes to investigate the
`possible inhibitory efi‘ect on CYP enzymes by modafinil at concentrafions 5 to 250 M,
`covering the range of therapeutic concentrations. Diflemnt substrates with specific
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`reaction to CYP enzymes were employed at concentrations equal to their Km/2, Km and
`4 Km in the incubation. The results show that modafinil has little or no capacity to
`inhibit the major CYP enzymes, with the exception of CYP2C19. Modafinil
`competitively inhibits CYP2C19 with Ki of 39 1.1M, the concentration can be achieved
`afier multiple dosing of 400 mg ofthe drug. This indicates that drugs whose rates of
`elimination depend on CYP2C19, especially ones that have narrow therapeutic index,
`would have a great potential to interact with modafinil to result in significant clinical
`consequences.
`An in vitro study using freshly isolated human livers was conducted to investigate
`the induction potential of chronic dosing of modafinil on various CYP enzymes.
`Although there is a large variation of enzyme activities among untreated and treated
`human hepatocytes, increased activities of CYPlA and CYP3A by incubating modafinil
`for 72 hours with these hepatocytes were observed at its pharmacologically relevant
`concentrations (10-100 uM). A case of drug-drug interaction between modafinil and
`cyclosporine was reported on a 43 year old female organ transplant patient. After one
`month administration of 200 mg/day modafinil, cyclosporine blood level was decreased
`by 50%. The interaction was postulated due to the increased metabolism of cyclosporine,
`since the bioavailability of the drug was not changed.
`
`Bioequivalence Study:
`A single-center, open, randomized, 4 x 4 Latin Square cross-over study was
`conducted to compare the bioequivalence of the to-be-marketed tablets at 2x100 mg and
`1x200 mg strengths to the 2x100 mg tablets used in clinical trials. Comparison of CM,
`AUCON, and AUC 0, on log transformed scale demonsu’ated the bioequivalence of TBM
`tablets and the one used in clinical trial.
`
`Dissolution:
`pH-solubility profile of modafinil showed that dissolution of modafinil was not
`different in_media_- Hydmchlofic
` .
` .
`acid at 0.1 N was chosen by the sponsor to be the dissolution medium. Dissolufion
`testing was performed using USP-II at_at 37 °C. One hundred and 200 mg
` .
`modafinil tablets were dissolved in 900 ml dissolution media. Biobatches representin
`various strengths ofmodafinil indicated that_ofthe drug is released ini
` .
` .
`
`Dissolution method and specification:
`Apparatus:
`USP 2
`addle)
` .
`.
`Speed:
`900 ml of 0.1N HCl
`Medium:
`Temperature:
`37 °C
`Specification:
`Not less that- in-
` .
` .
`
`Assay:
`
`st
`
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` C
`
`Quantitation ofmodafinil, its enantiomers and metabolites in human biological
`samliles were conductedby—followed by_on reverse column
` .
` .
` .
`Validation for each assay method was performed and found to be
`with
`acceptable for its specificity, sensitivity, accuracy, precision and stability.
`
`Formulation:
`
`Modafinil
` .
`Com Starc
`
` .
`
` .
`
`Substancemafi-
`
`Mm“?
`
`Magnesium Stearate
`
`
`
`OCPB Briefing: Nov. 18, 1997
`Attendees: Drs. Lesko, Fisher, Heimann, Balian, Al-Habet, Huang, Mehta, Chen, Lazor
`Blaschke, Katz, Rappoport, Hepp, Tammara, Baweja, Yuan.
`
` ., /S/
`
`
`Primary Reviewer: Rae Yuan, Ph. I
`/S/
`Team Leader: Ray Baweja, Ph.D _
`
`Office of Clinical Pharmacology and Biopharmaceutics/ Division I
`
`Date of Signature: ”/17/77
`
`l/// 7/7 7
`
`CC list: NDA 20-717 (NME): HFD-120; HFD-860 (Yuan, Baweja,
`Malinowski); CDR (Barbara Murphy)
`
`'
`
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`”3
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`/
`
`\
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`Povidone
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` .
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`'
`
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`Croscarmellose Sodi
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`

`
`
`OCPB PK LABELING
`
`Pharmacokinetics of modafinil:
`DRAFT LABELING
`
` ., DRAFT LABELING
`
`Distribution:
`DRAFT LABELING
`DRAFT LABELING
`
`Metabolism-
`DRAFT LABELING
`DRAFT LABELING
`
`DRAFT LABELING
`., DRAFT LABELING
`
`
`DRAFT LABELING
`
`DRAFT LABELING
`
`Special Populations:
`Gender Efi'ect:
`DRAFT LABELING
`DRAFT LABELING
`
`1'.
`
`~ ..\
`
`\
`
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`

`--._.__..-_ _ 4_.‘_ -_._...‘___.._'_.~."‘.._‘_s_—L——h-——h.—-.“ -»-4.-
`
`.4-
`
`.’_..-
`
`_._
`
`Age Effects:
`DRAFT LABELING
`DRAFT LABELING
`
`*
`
`Race Effect:
`DRAFT LABELING
`DRAFT LABELING
`
`‘
`
`DRAFT LABELING
`
`/‘
`
`'\
`
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`
`DRAFT LABELING
`
`PRECAUTIONS:
`
`Precaution/Drug Interactions:
`
`DRAFT LABELING
`DRAFT LABELING
`
`DRAFT LABELING
`
`
`

`

`h— .-__~‘V._ ---.«
`
`(
`
`DRAFT LABELING
`DRAFT LABELING
`
`'r
`
`DRAFT LABELING
`DRAFT LABELING
`
`DRAFT LABELING
`
`DRAFT LABELING
`DRAFT LABELING
`
`‘
`
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`

`APPENDIX A. REVIEWED INDIVIDUAL STUDY
`
`W‘\
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`1
`
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`

`

`
`
`. _.A .-~ ‘_'.—--k _
`
`,
`
`'
`
`-.-_
`
`—'
`
`- ._-
`'
`
`—-—¢
`
`,...-...-
`‘
`
`.._..-_.-
`
`sx_.._.‘.r_...-n
`
`In Vivo Metabolism
`
`1. Mass Balance study: A MassBalance and Metabolism Study of'C-Modafinil
` .
`(100 uCi) Following the Single Dose Administration ofa 200 Mg Oral Suspension
`(C1538a/lll/PK/US)
`,
`
`Objectives:
`To determine the excretion and metabolism ofModafinil using mass balance
`methodology.
`~
`
`Study Design and Sampling:
`It was an open-label, single-dose study to determine the excretion and metabolism
`ofmodafinil after a single oral dose of200 mg 'C-Modafinil (100 uCi) in 6 healthy male
` .
`volunteers.‘2 was labeled on the B-position on modaflnil. Radioactivity recovery and
` .
`concentrations ofmodafinil and two metabolites, modafinil acid and modafinil sulfone,
`were assessed in plasma, mine and feces.
`
`Figure l. The Chemical Structure of IC-Modafinil
` .
`
`“"” indicates the position ofradiolabeled carbon.
`
`The dosage regimen and sampling schedule ofthe study were as following:
`
`Subjects received a single oral dose of one 30 ml. oral
`suspension containing 200 mg modafinil labeled with 100
`uCi of carbon- followed by three 30 ml. rinses of the
` .
`dispensing container and ingested for a total of 120 ml.
`distilled water.
`
`Preparation of dosing solution:
`
`of Hicronized
`60.88 mg of. .c-Modafinil and 1272.9
` .
`Modafinil mixed with 200 mL ofi oral suspension.
` .
`30 mL each was placed into a separate glass bottle for
`each participant.
`
`‘1:
`
` .
`
` .
`
` .
`
`oral su
`
` .
`
`dino‘v
`
`'
`
`-
`
`'
`
`exit for
` .
`
`' 1'
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`

`4&5..- _
`
` .
`
` '
`
`els ofparent drug and
`to beinplasmathanto be boundtoRBC. The distribmionmtio
`ofCue/C,(=Total RBC radioactiVity/I‘otalplasmaradioactivity) difl‘ers inin '
`and in in viva (0.39).
`
` .
`
` .
`
` .
`
` .
`
` .
`
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`

`Comments:
`
`1- Further analysis on
`'rate ofAUC (AUC
`I
`AUCwWisp AUCW add/AUCW
`ndiouumy, 311d AUC
`not identified in thymine/AUG»...m)confirmed that ~3o% ofm1 drug was
`mu 5 E58 8E§S
`Q5§ ’6’ 5i3 5§ E9. E38.
`
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`

`
`
`In via-a: SpikingW Whole Blood
`-
`.
`s
`modafinil (Me activity «19.59 "out?!“ ”In SM‘:Wm!“ M5 “8/1110 «'6
`
` .
`: I}: viva: Follmng Mminisu-afion ofa single on] Dose (20°
`.
` .
`
`WEE: Excretion otRadioa'ctivity, Modafinil, Moda '
`as % Modafinfl Dose Excreted)
` .
`
`
`
` .
`
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`ATTACHMENT A4
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`3,: Mean (:51). n=6) Ph'm‘¢°k‘"°fi° Pm °
`allowing
`Modafin‘
`'
`_ gallon of a Single Oral Dose (200 mg) of%
` .
`nanny Mam
`Suspension (100
`
`
` ., .
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`100
`
`
`
`11"” (hm post dose)
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`moon: C1538a/lll/PK/Us: Phamaooldnetickepon
`
`Report 99-95-031
`
`w. Cumulative Wkldioufivfly. Modafinil and
`
` .
`
`'
`
`
`
`
`
`Cumulative“/0DoseExcrctedIn"Hue
`
`-‘.
`,1
`
`1E.
`
`
`
`80
`
`6C
`
`40
`
`20
`
`0
`
`50
`
`150
`100
`The (hours post dose)
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`250
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`

`Shoe“
`
` .
`
`AUOO-inf
`
`Ratio (M) Ratio (MA) Ratio (MS)
`ucmmmmmyAucm
`43%
`24%
`
`1.0%
`
`Mod. Add Mod.
`
`uc
` .
`
`%otMo %0fM.A. %otM.s.
`'
` .
`
`‘r-ir:
`
`.
`
`
`
`
`
`' *
`
`_
`
`-
`
`-.
`
`Ratio (M) Ratio (MA) Ratio (MS)
`
`uc........,/Aucm,
`
`
`62%
`22%
`
`0.0%
`
`TotalRad Mod
` .
` .
`
`Mod.AoidMod.Sutt Auca'R)%omo %otMA %atM.s.
` .
` .
`
`Auco-tnt
`
`'(M)Ratio(MA) Ratio(MS)
`ucga......,/Aucm
`
`6.0%
`
`144
`168
`192
`Subj. 3
`Time
`
`0
`0.5
`
`1 2 3 4 6 9
`
`12
`
`2_4
`36
`4a
`72
`96
`120
`
`144
`160
`192
`
`. _.
`
`‘\ '
`
`Page 1
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`Total Radioactivity. Modafinil. Modafinil Acid, and Modaflnil Sulfone in Plasma
`Subj. 1
`Time
`Total Rad Mod
`Mod. Add
`sumo %o{M.A. %otM
`0
` .
`4.95
` .
`6.52
`6.32
`5.69
`5.08
`3.62
`2.59
`1.95
`0.61
`0.37
`0.21
`0.08
`0.04
`0.03
`0.02
`0.02
`0.02
`
`0
`0.5
`1
`2
`3
`4
`6
`9
`g
`24
`36
`43
`72
`96
`120
`144
`166
`192
`Subj. 2
`Time
`
`0
`0.5
`
`1 2 34
`
`6
`
`9
`
`12
`
`24
`3_6
`4a
`72
`96
`120
`
`.
`
`-» ~
`
`( Q '.
`
`._
`
`“
`
` .
`Total Rad Mod
` .
` .
`
`

`

`2 3 4 6 9
`
`12
`
`2_4
`36
`46
`72
`96
`120
`
`144
`168
`192
`Sub]. 5
`Time
`
`O
`0.5
`
`1 2 3 4 6
`
`9
`12
`
`36
`48
`72
`96
`120
`
`-.
`
`,
`. a
`
`“ -
`
`144
`168
`192
`Sub). 6
`Ttme
`
`TotalRad Mod
`0 t
` .
`0.5
`
`1 2 3 4 6 9
`
`12
`
`g;
`.36
`43
`72
`96
`120
`
`144
`168
`
`
`
`
`
`
`
`
`-
`
`(>
`
`Sub]. 4
`
`Time
`
`TotalRad Mod
`
`ModMAcidMod 8qu AUG
`
`
`
` .
`
` .
`
`0
`0.5
`1 f
`
` .
`
`Sheen
`
`%ofMO SeofMA. %ofM.S.
`
`'
` .
`
`
`
`
`
`
`
`
`tio (M) Ratio (MA) Ratio (MS)
`UCa...,,......,IAUCm
`45%
`21%
`
`7.0%
`
`TotalRad Mod
` .
` .
`
`Mod. AddMod.
`
`AUC .R %ofMO %ofMA 9601M.
` .
` .
`
`
`
`
`AUCO-tnf
`
`Mod.Add Mod.
`
` .
`
`(M) Ratio (MA) Ratio (MS)
`
`U60..." .myAUCm
`
`UCCI'.R)%ofMO %ofMA %ofM.S Total
` .
` .
`
`9.8%
`
`
`
`
`.
`MOO-hf
`
`(M) Ratiomw R-fioms)
`”Chan-«JAM
`23%
`
`5.6%
`
`P0902
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`_- -,e_.‘..- «.21. .-.M -
`
`w——_' m. an '7-.V. 77:-
`
`l
`
`2. Identification and Profiles of Modafinil and Modafinil Metabolites in Urine from
`Human Subjects Administered a Single Oral Dose of ['C] Modafinil (DM-96-029)
` .
`
`Objectives:
`To identify and quantify the metabolites of modafinil in urine following a single
`oral administration of200 mg dose containing 100 pCi of 2-HI]-Modafinil.‘
` .
`
`Study Design and Samplingi
`The study had an open-label, non-randomized, single dose and single phase
`
`design.
`
`rm“ “‘4‘”?
`.
`.
`.
`.
`b [(W‘ff/éubjects received a single oral dose of30 mL ofdosrng suspensron containing
`200 mg modafinil labeled with 100 pCi ofcarbon-l4. ingestion ofthe dosing solution was
`followed by ingestion ofthree 30-mL rinses ofthe dosing container.
`
`W41“? 30422;?“ description ofthe samples taken for analysis is presented in the
`P—hanaacolciaetie Report for the study (DP-95-031); since the purpose ofthis report is to
`
`present the metabolite identification in urine, on