CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 020717
`
`
`
`
`MEDICAL REVIEW! S)
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`

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`DIVISION OF NEUROPHARMACOLOGICAL DRUG
`PRODUCTS
`
`CLINICAL REVIEW OF NDA
`
`%
`
`Brand Name:
`
`Provigil
`
`Generic Name:
`
`modafinil
`
`Indication:
`
`narcolepsy
`
`{ :
`
`NDA Classification:
`
`18
`
`NBA Number:
`
`20-717
`
`Original Receipt Date:
`
`December 30, 1996
`
`‘ "
`
`Clinical Reviewer:
`
`Bob A. Rappaport, M.D.
`
`Review Comgleted:
`
`September 30, 1997
`
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`

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`TABLE OF CONTENTS
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`SECTION 1.0 MATERIALS UTILIZED IN REVIEW ..................................
`
`SECTION 2.0 BACKGROUND ..................................................
`SECTION 2.1
`INDICATION: .......................................
`SECTION 2.2
`RELATED IND'S AND NDA’S: ...........................
`SECTION 2.3
`ADMINISTRATIVE HISTORY: ...........................
`SECTION 2.4
`PROPOSED DIRECTIONS FOR USE: ......................
`SECTION 2.5
`FOREIGN MARKETING: ...............................
`
`SECTION 3.0 CHEMISTRY ....................................................
`
`SECTION 4.0 ANIMAL PHARMACOLOGY/TOXICOLOGY ...............................
`
`2
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`4
`
`4
`4
`4
`4
`5
`5
`
`7
`
`9
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`SECTION 5.0 DESCRIPTION OF CUNICAL DATA SOURCES ...........................
`SECTION 5.1
`STUDY TYPE AND DESIGN/PATIENT ENUMERATION: ........
`SECTION 5.2
`DEMOGRAPHICS: ....................................
`‘ SECTION 5.3
`EXTENT OF EXPOSURE ...............................
`
`10
`10
`11
`11
`
`SECTION 6.0
`
`SUMMARY OF HUMAN PHARMACOKINEI’ICS ...........................
`
`12
`
`SECTION 7.0 EFFICACY FINDINGS .............................................
`SECTION 7.1
`OVERVIEW OF CLINICAL STUDIES: ......................
`SECTION 72
`SUMMARY OF STUDIES PER‘IINENT TO EFFICACY: ..........
`SECTION 7.2.1
`STUDY C1538A/301/NA/US ....................
`
`Section 7.2.1.1
`Section 7.2.1.2
`Section 7.2.1.3
`
`Protocol Synopsis: ......................
`Statistical Analysis: .....................
`Protocol Amendments: ...................
`
`.......................
`Conduct of Study:
`Section 7.2.1.4
`Sponsor's Efficacy Results: ...............
`Section 7.2.1.5
`Reviewer’s Efficacy Discussion:
`...........
`Section 7.2.1.6
`SECTION 7.2.2
`STUDY C1538a/302/NA/US:
`...................
`
`Section 7.2.2.1
`Section 7.2.2.2
`Section 7.2.2.3
`
`Protocol Synopsis: ......................
`Statistical Analysis: .....................
`Protocol Amendments: ...................
`
`.......................
`Conduct of Study:
`Section 7.2.2.4
`Sponsor's Efficacy Results: ...............
`Section 7.2.2.5
`Reviewer‘s Efficacy Discussion:
`...........
`Section 7.2.2.6
`SECTION 7.2.3
`OTHER SUPPORTING CUNICAL TRIALS: ............
`
`.......................
`Study MOD-024:
`Section 7.2.3.1
`.......................
`Study MOD-025:
`Section 7.2.3.2
`Study M0094003: ......................
`Section 7.2.3.3
`Study MOD-026:
`.................... _.
`.
`.
`Section 7.2.3.4
`Study MOD-027:
`.......................
`Section 7.2.3.5
`Study MOD~028:
`.......................
`Section 7.2.3.6
`SECTION 7.2.4
`OTHER CUNICAL TRIALS: .......................
`
`14
`14
`14
`14
`
`14
`16
`17
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`22
`29
`38
`39
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`39
`42
`42
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`46
`54
`63
`63
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`SECTION 8.0 SAFETY FINDINGS ...............................................
`SECTION 8.1
`METHODS: .........................................
`SECTION 8.2
`SERIOUS ADVERSE EVENTS: ...........................
`SECTION 8.2.1
`DEATHS: ....................................
`SECTION 8.2.2
`NON-FATAL SERIOUS ADVERSE EVENTS: ...........
`SECTION 8.3
`ASSESSMENT OF DROPOUTS: - ..........................
`SECTION 8.3.1
`MODAFINIL EXPOSURE: ........................
`SECTION 8.3.2
`ADVERSE EVENTS: .............................
`SECTION 8.4
`OTHERADVEFISE EVENTS: .............................
`SECTION 8.4.1
`ADVERSE EVENTS OVERALL- .....................
`SECTION 8.4.2
`ADVERSE EVENTS BY GENDER: ...................
`SECTION 8.4.3
`ADVERSE EVENTS BY AGE: ......................
`SECTION 8.4.4
`ADVERSE EVENTS BY RACE .....................
`SECTION 8.4.5
`ADVERSE EVENTS IN PATIENTS WITH HEPATIC
`INSUFFICIENCY: ..........................................
`SECTION 8.4.6
`ADVERSE EVENTS IN PATIENTS WTTH RENAL
`INSUFFICIENCY: ..........................................
`SECTION 8.4.7
`ADVERSE EVENTS RELATED PREGNANCY, NURSING,
`LABOR AND DEUVERY: .....................................
`OTHER SAFETY FINDINGS: ............................
`SECTION 8.5
`CLINICAL LABORATORY EVALUATIONS: .............
`SECTION 8.5.1
`Section 8.5.1.1
`Clinical Chemistry:
`.....................
`Section 8.5.1.2
`Hematology:
`...........................
`Section 8.5.1.3
`Urinalysis:
`............................
`SECTION 8.5.2
`VITAL SIGNS: .................................
`SECTION 8.5.3
`BODY WEIGHT: ...............................
`SECTION 8.5.4
`ECG: ........................................
`SECTION 8.6
`DOSE-RESPONSE ADVERSE EXPERIENCE INFORMATION:
`.
`.
`.
`.
`SECTION 8.7
`DRUG-DRUG INTERACTIONS: ..........................
`SECTION 8.7.1
`INTERACTION WITH CLOMIPRAMINE:
`.............
`SECTION 8.7.2
`INTERACTION WTTH METHYLPHENIDATE: ..........
`SECTION 8.7.3
`INTERACTION WITH TRIAZOLAM: .................
`SECTION 8.7.4
`INTERACTION WITH CONCOMTTANT MEDICATIONS:
`.
`.
`.
`SECTION 8.7.5
`POTENTIAL DRUG-DRUG INTERACTIONS: ...........
`SECTION 8.8
`ADVERSE EFFECTS IN LONG TERM USE: ..................
`SECTION 8.9
`ADVERSE EFFECTS FOLLOWING WTIT-IDRAWAL OF THERAPY:
`..............................................................
`
`SECTION 8.10
`
`SUMMARY OF POTENTIALLY IMPORTANT ADVERSE EVENTS
`CONSIDERED RELATEDTO STUDY DRUG: .................
`
`3
`
`69
`69
`69
`69
`71
`73
`73
`77
`80 ;
`80
`85
`85
`85
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`‘
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`86
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`93
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`94
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`SECTION 9.0 W ..................................................
`
`96
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`SECTION 10.0 RECOMMENDATIONS .......................................... _.
`
`. .
`
`96
`
`APPENDICES ............................................................... 97
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`SECTION 1.0
`
`MATERIALS UTILIZED IN REVIEW
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`Table 1.
`
`Materials Utilized in Review
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`
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`
`
`
`
`
`
`
`
`
`
`
`
`Integrated summary of safety
`In; 5...0fl3n)3'.O3
`CT‘< E? Oa‘<
`I!(‘DU)'U0:l(I!(D F.O a.0 C(D(IIII.
`—§0H ID0.e:2 O3
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`SECTION 2.0
`
`BACKGROUND
`
`.
`
`The proposed indication for modafinil (Provigil) is:
`
`‘PROVIGIL is indicated to improve wakefulness in patients with excessive daytime sleepiness
`associated with narcolepsy.” [from “Annotated Labeling”, Item 2, Vol. 1.1.A, p. 00021]
`
`There are no related NDA’s. The only related lND’s are:_
` .
`
`W AQMINJSIBAJJMEHJSIQBI;
`
`Cephalon, Inc. licensed modafinil in 1993 from—tor develoiment in the us.
`
` .
` .
`and other territories. Modafinil received orphan drug designation
`for excessive daytime sleepiness associated with narcolepsy in 1993. Cephalon conducted it’s
`clinical pharmacology trials, safety trials and pivotal efficacy trials under lND _
` .
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` If response is not observed within 1 to
`
`3 weeks, daily dose may be increased
`to a maximum of 400 mg.
`
`
`
`
`
`
`
`Liver—isease
`
`Same dose adjustment as for adult.
`
`Maximum daily dose 400 mg.
`
`[based on sponsor’s Table 2.1.3 “Dosage and Administration”. Item 2, Vol. 1.1A. p. 00062]
`
`In addition, the sponsor has included the following paragraph to follow the above table in the
`product labeling:
`
`,
`( "
`'
`-
`
`"
`
`“No study has been specifically designed to evaluate the metabolism, safety, or efficacy of
`modafinil in geriatric or pediatric patients with narcolepsy. Experience in a limited number of
`patients (15) who were greater than 65 years of age in US Phase 1. 2, and 3 clinical trials
`showed a comparable incidence of adverse experiences compared to other age groups. Foreign
`studies in geriatric subject populations showed that doses of 150 to 400 mg per day were well
`tolerated and that patients 67 to 85 years of age metabolized modafinil more slowly than
`younger subjects; the data suggest that the initial dose in geriatric patients should be
`approximately half that of the adult initial dose (100 mg) and that a dose adjustment schedule
`should be similar to the adult schedule (a maximum of 400 mg) based on individual patient
`needs...
`
`'Modafinil was well tolerated in patients with hepatic insufficiency. Plasma levels of
`modafinil, however. were increased roughly 2-fold, and plasma levels of the inactive metabolite
`were decreased; the data suggest a decrease in the initial modafinil dose by half (100 mg) and
`that a dose adjustment schedule would be similar to the adult schedule ( a maximum of 400 mg)
`based on individual patient needs." [Item 2, Vol. 1.1A. p. 00062]
`
`WW
`
`Marketing authorization in France was granted in 1992, although the product was not
`commercially available there until 1994 when it received pricing and reimbursement
`authorization.
`Initially. modafinil could only be obtained through a prescription from a public
`hospital neurologist and dispensing hospital pharmacies. The prescribing requirementswere
`relaxed by the French Health Ministry in November 1995 in accordance with the schedule for
`
`(”
`
`exceptional drugs of restricted prescription. This requires that the prescription be restricted
`
`to specialists and physicians working in departments of neurology and public or private sleep .
`
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`centers, with dispensing by retail pharmacists. General practitioners may renew
`prescriptions, provided that the specialist carries out a clinical assessment every year, and
`that a specialized evaluation (polysomnography followed by a Multiple Sleep Latency Test) is
`performed every five years.
`
`Lafon filed a Multistate Application in October 1994 to: Belgium, Denmark, Greece, Ireland,
`Italy, Netherlands, Portugal, Spain, and the United Kingdom. Objections were raised by the
`member states and in October of 1996, responses were submitted to the CPMP for evaluation.
`At the time of submission of this NDA, approval was pending in 13/14 European countries,
`France being the only European state where the drug has been approved.
`
`The-licensee— submitted its_ marketing application in May
` .
` .
` .
`1993. The application was rejected due to a lack of sufficient data to assess efficacy.
`It was
`supplemented and resubmitted in August 1996, with approval pending.
`
`There have been no instances where approval has been refused due to issues re arding safety of
`the drug. Since the 1994 commercial availability of modafinil in _qhas not issued
` .
`
`any warning letters to the prescribing physicians.
`
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`SECTION 3.0
`
`Compound Name:
`
`Chemical Names:
`
` {
`
`
`
`The structural formula for modafinil
`
`is:
`
`
`
`(
`
`'The molecular formula is C15H15N028 and the molecular weight is 273.36. Modafinil appears
`
`as a white to off-white crystalline powder that is practically insoluble in water and
`cyclohexane.
`It is sparingly to slightly soluble in methanol and acetone...
`
` .
`
` .
`
`Modafinil is formulated as a tablet oontainin
` .
`
`100 m or 200 m of the active modafinil dru
`
` .
`
`CHEMISTRY
`
`modalinil
`
`2-[(Diphenymethyl)sulfinyl]acetamide
`2-(Benzhydrylsulfinyl)acetamide
`
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`Dr. Martha Heimann. the chemistry reviewer for this NDA, reports that one of the
`manufacturing sites has failed inspection and a second has not yet been inspected. The exact
`nature of the problems at the first site are not yet clear. Both sites are in Europe.
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`SECTION 4.0
`
`ANIMAL PHARMACOLOGY/TOXICOLOGY
`
`The sponsor has summarized the phann/tox data for modafinil in Section 2.5 of Item 2, Vol.
`1.1A of the NBA. The following is a condensation of that summary.
`
`Primary activity studies in the rat and in narcoleptic dogs demonstrated that modafinil
`maintains and/or promotes wakefulness in a dose-dependent manner.The pharmacological
`mechanism of action of modafinil has not been fully defined. Nonclinical studies have shown that
`modafinil is phannacologically distinct from amphetamine, methylphenidate, and other
`psychomotor stimulants.
`
`"
`
`Mouse and rat oral or intraperitoneal LDSO dose levels correspond to approximately 130 to
`260 fold higher levels than the projected maximum human therapeutic dose (400 mg/70 kg).
`The minimal lethal oral dose in dogs (300 mg/kg) represents an approximately 50 fold higher
`dose.
`
`
`
`Consistent observations across species at the high dose levels were body weight loss and
`increased liver weights. Also seen were microscopic evidence of hepatocellular hypertrophy
`and alterations in red cell parameters such as decreased erythrocyte counts, packed red cell
`volumes and hemoglobin levels, and increased reticulocyte counts and indications of
`erythropoiesis.
`In vitro assessment of hemolytic potential and evaluation of erythrocyte
`fragility did not indicate that modafinil has a direct effect on erythrocytes.
`
`The no effect levels (NOEL) observed in the rat ranged from 100 mg/kg/day in the 4 week study
`to approximately 20 mg/kg/day in the 26 week study.
`in the dog. the NOEL was less than 20
`mg/kg/day. These doses are at least 3 fold higher than the highest proposed therapeutic dose in
`humans, approximately 6 mg/kg or 400 mg to a 70 kg individual. The NOEL in the 52 week
`study in the rat and in the mouse and rat carcinogenicity studies was 6 mg/kg/day, comparable
`to the proposed maximum human therapeutic dose.
`
`The sponsor reports that lifetime carcinogenicity studies in mouse and rat found no evidence of
`treatment related difference in the incidence, type, or distribution of neoplastic lesions in
`either species. However. Dr. Aisar Atrakchi, the pharmacology/toxicology reviewer for this
`NDA has concluded. (with concurrence from the Center CAC-Exec
` .
`
` .
`
`No genotoxic or teratogenic potential, or reproductive or developmental toxicity were observed
`in standard animal models.
`
`The preclinical pharmacokinetic studies of modafinil in mice, rats, dogs, and rabbits have
`shown that its metabolism is stereospecific and involves cytochrome P450. Enzyme induction
`was observed in mice and dogs after daily doses at the highest levels used. Metabolism followed
`by excretion in the urine was found to be the predominant clearance pathway.
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`SECTION 5.0
`
`DESCRIPTION OF CLINICAL DATA SOURCES
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`10
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`SECTION 5-1 W
`
`The following table is based on the sponsor’s Table 2.8-1.
`Studies and Exposure” [Item 2. Vol. 1.1A, p. 00267].
`
`‘Overview of Modafinil Clinical
`
`Summary of All Studies Submitted to this NDA
`Table 3.
`,._._._~___——k.m_,
`
`Study Type
`
`Cephalon-sponsored
`
`
`Foreign, Non-Cephalon
`
`
`
`Number of Studies
`
`Modatinll-treateleotal ModafiniI-treated/Tot
`
`
`
`treated
`treated
`
`Number of Studies
`
`
`
`
`
`
`
`| I
`
`
`
`1
`
`2
`
`3
`
`Clinical Pharmacology
`
`|
`I Controlled and Uncontrolled
`I
`
`Indications other than
`narcolepsy
`
`Total
`
`Combined Total
`
`1 2
`232/271
`21
`529/558
`
`not applicable
`
`1 4
`
`761/829
`
`2 7
`334/363
`52
`533/539
`
`4 9
`8 3 7/1 2 3 7
`
`81
`
`1704/2139
`
`
`
`
`
`
`
`
`
`955
`2465/2 968
`
`The 2 controlled studies have population pharmacology components and uncontrolled (open label
`40 week continuation and 48 week extension) treatment periods. The controlled double blind
`studies include 369 patients treated with modafinil (558 total); the uncontrolled treatment
`periods are ongoing; safety data through June 15, 1996 are included in the data base. An
`‘ additional study (1 patient. idiopathic hypersomnia) was conducted under IND_
` .
` .
`
`The completed foreign, non-Cephalon sponsored studies in patients with narcolepsy are
`comprised of 2 controlled and 3 uncontrolled studies. An additional 5 studies (2 controlled, 3
`uncontrolled) are ongoing and are not included in the data base. These studies include
`narcolepsy and Idiopathic hypersomnia patients.
`
`The NBA includes information from the total of 149 studies: 95 studies are included in the
`
`integrated data base(s) (14 Cephalon sponsored and 81 foreign, non-Cephalon sponsored); there
`is also documented information from an additional 9 foreign, non-Cephalon sponsored studies
`that are ongoing (2 controlled. 3 uncontrolled, 4 other) and 45 , non-Cephalon sponsored
`studies that do not have available CRF’s (20 clinical pharmacology. 1 uncontrolled, 24 other)
`and are. therefore. non included in the integrated data base(s).
`
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`See Sections 7.2.1.4 and 7.2.2.4 of this review.
`
`WW
`
`See Section 8.3.1 of this review.
`
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`SECTION 6.0
`
`SUMMARY OF HUMAN PHARMACOKINETICS
`
`12
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`( ‘
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`Based on seventeen Phase 1 (9 Cephalon_, two Phase 2 (1 Cephalon; I
` .
` .
`_ ; and two Phase 3 (both Cephalon) studies. the sponsor has summarized the
` .
`human pharmacokinetics and bioavailability data as follows:
`
`'
`
`“Modafinil was well absorbed after oral administration. Peak modafinil plasma concentration
`occurred at 1-4 hr. The elimination half-life was between 9 and 14 hr after a single oral dose
`of 200 or 400 mg. Both modafinil and modafinil acid exhibited linear pharmacokinetics over a
`dose range of 50-499 mg. The oral bioavailability of a 200 mg tablet relative to a micronized
`aqueous suspension was close to 100%. The apparent volume of distribution (V/F) of modafinil
`(approximately 60 L or 0.8-0.9 L/kg) was larger than the volume of total body water (0.6
`L/kg). Females (35%) appeared to excrete less modafinil acid in urine than males (51%).
`The clearance of modafinil in males decreased slightly (approximately 10-20%) as the age
`increased. Stereospecific pharmacokinetics of modafinil enantiomers have been demonstrated.
`The d-modafinil enantiomer was eliminated faster (100-140 mL/min) than the I-modafinil
`enantiomer (35-50 mL/min). Modafinil was extensively metabolized after oral dosing by
`deamidation. oxidation, and aromatic ring hydroxylation. The total oral clearance of modafinil
`after a single dose was approximately 60 mL/min. Less than 10% of the modafinil dose was
`excreted in urine as the parent drug. Modafinil acid was the major urinary metabolic [sic]
`which accounted for 50-60% of the dose in males and 30-40% in females. Urinary excretion
`of modafinil sulfone was negligible. The remaining portion of the dose excreted in the urine
`appeared as the products of side-chain cleavage at the sulfur atom. The renal clearance of
`modafinil only accounts for 5-6% of the plasma clearance, indicating that modafinil is
`primarily eliminated by liver metabolism. Following a single dose of side-chain labeled 14C-
`modafinil, (mean :1: SD) 79.6 :i: 5.9% and 1.0 i 0.3% of the dose was recovered in urine and
`feces, respectively, over a period of 11 days.
`
`“After multiple once daily 200, 400, and 600 mg doses of modafinil, apparent steady-state
`plasma levels were reached after 2-4 days of dosing. The elimination half-life following the
`last dose of the multiple dose regimen was 13-18 hr.
`
`“Modafinil was moderately bound to plasma proteins (61-65%), essentially to albumin.
`presence of warfarin, diazepam or propranolol, modafinil did not change the binding
`characteristics of these three drugs of [sic] therapeutic concentrations. suggesting little or no
`interaction with these three drugs based on the absence of protein binding displacement with
`modafinil in vitro. Modafinil plasma protein binding was not affected by modafinil acid.
`
`In the
`
`“Food delays the absorption of modafinil (Tmax: 3.21 versus 2.05 hr) in Study MOD-022.
`However, the AUC and elimination tm are not different between fasted and fed conditions. A
`
`continuation of the analysis showed that there were no statistical differences in any of the
`pharmacokinetic parameters (Cmax. Tmax. AUCo.., CL/F. V/F and t1 ,2) for either I-modafinil or
`d-modafinil between fasted and fed conditions.
`
`C '
`
`'In a study involving patients with renal impairment. the elimination of modafinil acid was
`
`reduced after a single dose of 200 mg. Only 25% of the modafinil dose was excreted in urine as ,
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`In contrast, 45% of the modafinil dose was
`modafinil acid in patients with renal insufficiency.
`excreted as modafinil acid in the urine of healthy subjects.
`
`“In a multiple-dose study (200 mg/day) for eight days in patients with liver cirrhosis, the
`patients exhibited high modafinil AUC and extended 11/2, suggesting that the major elimination
`route of modafinil was liver.
`
`"In a single-dose pharmacokinetic interaction study with modafinil and methylphenidate, no
`clinically important alterations in the pharmacokinetic profile of modafinil or methylphenidate
`were noted. A delay in the oral absorption of modafinil was observed (Tmax of 2.9 versus 1.9
`hr). Similarly,
`in a single-dose pharmacokinetic interaction study with modafinil and a single
`dose of clomipramine, no clinically important alterations in the pharmacokinetic profile of
`modafinil or clomipramine were noted.‘
`[Item 2, Vol. 1.1A, pp. 00208-00209]
`
`Study MOD-020 was an open label, multiple dose, pharmacokinetic study in elderly male and
`female volunteers. Subjects received 300 mg modafinil per day for seven days. Plasma levels
`were determined on Days 1 and 7. The maximum plasma concentrations after the first dose
`were much higherthan those from a previous study in with healthy young volunteers. Plasma
`levels of modafinil obtained from Day 7 were higher than those of Day 1, which, the sponsor
`notes, suggests that accumulation might occur after seven days of daily dosing of 300 mg
`modafinil
`in elderly subjects.
`
`Protocol P1424 was a double blind, randomized, placebo controlled, multiple dose,
`pharmacokinetic study in healthy male volunteers. The results of this study were suggestive of
`enzyme induction at doses of 400 mg/d and above.
`
`The pharmacokinetic portions of the two pivotal Phase 3 efficacy trials, 01538a/301/NA/US
`(C301) and 61538a/302/NA/US (C302), were designed to evaluate the steady state plasma
`trough levels of modafinil and two well characterized metabolites, modafinil acid and modafinil
`sulfone.
`In Study 0301, after daily doses of 200 mg modafinil, plasma trough levels of
`modafinil and the two metabolites reached steady state by Week 3 and remained unchanged
`through Week 9. However, after daily doses of 400 mg of modafinil, the plasma trough levels of
`modafinil at Week 9 were significantly lower (approximately 20 %) than those of Week 3. The
`two metabolites did not show this difference. Also of note in Study C301, the plasma trough
`levels of modafinil sulfone were negatively correlated with age, suggesting the metabolism of
`modafinil to modafinil sulfone might be slower in older patients.
`In addition, plasma levels of
`modafinil sulfone from female patients in the 400 mg group were higher than those of male
`patients at Weeks 3 and 6.
`
`In Study C302, stable plasma trough levels of modafinil and the two metabolites were again
`noted after daily doses of 200 mg modafinil. Also, after daily doses of modafinil 400 mg, the
`plasma trough levels of modafinil decreased approximately 18% at Week 6 and 26% at Week 9
`compared to Week 3. The metabolites, again, did not show this difference. The plasma trough
`and discharge levels of modafinil and the two metabolites were not affected by age or gender.
`Plasma levels were significantly higher for females only at Week 3 at the time of clinic
`discharge.
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`14
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`SECTION 7.0
`
`EFFICACY FINDINGS
`
`MEWS;
`
`Two adequate and well controlled clinical trials have been submitted to this NBA in support of
`the sponsor’s claim for efficacy of modafinil in the treatment of narcolepsy. The first of these
`is C1538A/301/NA/US (0301). This was a randomized, placebo controlled. parallel group,
`double blind, multicenter trial in which patients were treated with one of two fixed doses of
`modafinil or placebo. The second controlled study, C1538a/302/NA/US (C302), was a
`randomized, placebo controlled, parallel group, double blind, multicenter trial in which
`patients were treated with one of two fixed doses of modafinil or placebo. This trial was followed
`by a two week discontinuation segment to study withdrawal effects. The primary efficacy
`variables for both Studies C301 and 0302 were 1) the average sleep latency at Endpoint on the
`Maintenance of Wakefulness Test. and 2) support for #1 by the Clinical Global Impression of
`Change Scale.
`
`In addition, the sponsor has submitted six other studies as supportive product efficacy, and
`numerous studies (as outlined in Sections: 5.1 and 7.2.4 of this review) in support of product
`safety.
`
`SEEQNLZ W
`
`SECTION 7.2.1
`
`STUDY C1538A/301/NA/US
`
`Section 7.2.1.1
`
`Protocol Synopsis:
`
`line; A Nine-Week Placebo-Controlled. Double-Blind, Randomized. Parallel-Group Study of
`the Safety and Efficacy of Two Fixed Doses (200 mg, 400 mg) of Oral Modafinil in
`Patients with Narcolepsy Followed by a 40 Week, Open-Label, Flexible-Dose
`Continuation Study
`
`‘The purpose of the double-blind phase of this study is to compare the safety and
`thegtiyes;
`efficacy of two fixed doses of modafinil and placebo in the treatment of patients with
`narcolepsy...
`
`'The purpose of the open label phase of this study is to collect additional
`information regarding the safety and tolerance of modafinil during extended exposure.’
`
`[ltem 8, Vol. 11,
`
`p. 04723]
`
`Wu:
`
`The double blind phase is a multicenter, parallel group, placebo controlled, fixed dose study of
`modafinil in patients with narcolepsy. The open label phase is a 40 week, flexible dose study.
`The double blind phase will begin with a screening period followed by randomization to either
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`placebo or one of two dosage levels of modafinil for a period of nine weeks. The protocol calls for
`three groups of 95 patients each to be randomly assigned to one of the three treatment arms.
`Approximately 15 patients are to be randomized at each of the twenty sites during a six month
`enrollment period. Eligible patients will receive a specified number of tablets to be taken daily
`for nine consecutive weeks in one of the following three treatment groups:
`
`15
`
`Group I
`Group ll
`Group III
`
`placebo
`modafinil, 200 mg/day
`modafinil, 400 mg/day
`
`Patients will take a single, daily, oral dose of study medication consisting of four tablets (4 x
`100 mg or 2 x 100 mg + 2 x placebo or 4 x placebo) in the morning (approximately 30 to 45
`minutes after a morning meal) for nine consecutive weeks.
`
`Patients eligible for the double blind phase will be male or female outpatients, 18 to 65 years
`of age, inclusive. Females must be either surgically sterile, two years postmenopausal, or,
`if of
`child bearing potential, using an acceptable birth control method. Patients must have a current
`diagnosis of narcolepsy. Nocturnal polysomnography and a Multiple Sleep Latency Test (MSLT)
`will be done at the Screen Visit unless they have been performed within the five years prior to
`screening. The diagnosis of narcolepsy must include the following characteristics: recurrent
`daytime naps or lapses into sleep that have occurred almost daily for at least three months, and
`a history of loss of postural muscle tone in association with intense emotion. i.e. cataplexy.
`Associated features may include: sleep paralysis, hypnogogic hallucinations, automatic
`behaviors, and nocturnal sleep disruption. The MSLT must document a mean sleep latency of s 8
`minutes. Eligible patients must demonstrate an absence of any medical or psychiatric disorders
`that could account for the excessive daytime sleepiness. Patients requiring routine use of
`anticataplectic medication will be excluded.
`
`Figure 1.
`
`Study Schemata
`
`VISIT NUMBER:
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`__1___z____a___§___5__§
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`END OF STUDY WEEK: W9
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`Sruov DAY:
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`-
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`-
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`-
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`-
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`(48° visit}
`
`{48" visit}
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`At the Baseline Visit, in addition to examination and laboratory studies, the patient will
`complete: an Epworth Sleepiness Scale; 'Steer Clear“ Performance Test training session; two
`nocturnal polysomnography recordings within 48 hours, one followed by a MSLT and the other
`followed by a Maintenance of Wakefulness Test (MWT); one “Steer Clear" Performance Test
`(SCPT); Patient's Daily Sleep Log; Baseline Signs and Symptoms; Quality of Life in Narcolepsy
`(QOLlN) patient inventory; and. Clinical Global Impression of Severity (CGl-S).
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`On-Study Visits (end of Weeks 1. 3 and 6 following the Baseline Visit) will include.
`
`in addition
`
`to vital signs and laboratory studies: HLA typing at Week 1; a nocturnal polysomnography
`recording; a MWT; a SCPT; the Clinical Global Impression of Change (CGI-C) Scale; the Epworth
`Sleepiness Scale; the Patient’s Daily Sleep Log; and, adverse experience and concomitant drug
`revrew.
`
`16
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`The Termination Visit will include, in addition to physical examination and laboratory studies:
`two nocturnal polysomnography recordings within 48 hours, one followed by a MSLT and the
`other by a MWT; one SCPT; the CGl-C; the Epworth Sleepiness Scale; the Patient’s Daily Sleep
`Log; the QOLIN inventory; and adverse experience and concomitant drug review.
`
`Patients entering the open label phase must have completed the double blind phase or at least
`two efficacy evaluations post Baseline of the double blind phase and terminated for reasons other
`than noncompliance or a study drug related adverse experience.
`
`Qualifying patients will begin the open label phase taking 200 mg/day of modafinil for one week.
`The dosage may then be adjusted at the investigator's discretion, but no daily dose may be
`increased by less than 100 mg or more than 200 mg every week. The minimum daily dose will
`be 200 mg and the maximum daily dose will be 400 mg.
`
`Section 7.2.1.2 Statistical Analysis:
`
`i
`
`(.
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`‘
`
`There will be two primary efficacy variables: 1) excessive daytime sleepiness measured as
`
`time awake on the MWT; and. 2) whether a reduction in excessive daytime sleepiness on the
`MWT is supported by the CGl-C, as assessed by an independent clinician.
`
`The original protocol calls for the following statistical analysis of the primary efficacy
`endpoints:
`
`“Change scores from baseline will be compared between treatment groups for variables having
`baseline evaluations. For the CGl-C, the actual score will be analyzed since no baseline value is
`assessed. Endpoint analyses will be performed to include data from all evaluated patients. Data
`by protocol evaluation periods including completers (Week 9 data) will also be analyzed.
`
`“Parametric analyses adjusting for investigator effect will be performed if the assumptions of
`normality are met. Parametric analyses will be performed as supportive evidence of treatment
`by investigator homogeneity. Two-tailed tests will be used to test study hypotheses. Mantel-
`Haenszel tests, having investigator as the strata. will also be performed for the CGl-C.” [Item
`8. Vol. 11, p. 04767]
`
`Secondary efficacy variables are:
`
`'To determine independently for each of two doses of modafinil, whether that dose (200
`1 )
`mg/day, 400 mg/day) compared to treatment with placebo produces beneficial effects measured
`by the MWT and the CGl-C. The effects established in testing the primary hypothesis may be
`
`C .
`
`attributable to both doses of modafinil or only to one treatment dose.”
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`2 )
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`“To determine whether modafinil/placebo differences in awake time and global clinical
`
`change are reflected in the tendency to initiate sleep [Multiple Sleep Latency Test, clinical
`version]; impaired vigilance [‘Steer Clear’ Performance Test]; and patient assessed general
`level of daytime sleepiness [Epworth Sleepiness Scale]."
`
`17
`
`'To determine whether modafinil/placebo differences in awake time and global clinical
`3 )
`change are reflected in the patient’s daily record of the severity and frequency of patient
`reported narcoleptic symptoms. the Patient's Daily Sleep Log."
`
`'To determine the effects of modafinil concerning patient health status and ability to
`4)
`perform daily activities, through evaluation of a Quality of Life in Narcolepsy Patient
`Inventory.”
`
`[the four items above from: Item 8, Vol. 11, p. 04740]
`
`The original protocol also states: “Statistically significant results are not required of secondary
`hypotheses C, D, E and F [1. 2, 3 and 4 above]. Failure to support secondary hypotheses wil