(3
`
`RESULTS
`
`A total of 273 patients were randomized, with 271 receiving treatment.
`The following chart displays patient flow (adapted from Dr. Rappaport,
`page 48):
`
`Patients randomized
`Patients treated
`Patients in Efficacy
`Analysis
`Completers
`
`Modafinil 400
`
`Modafinil 200
`
`Placebo
`
`1
`
`90
`89
`
`90
`89
`
`93
`93
`
`86
`84 (93%)
`
`83
`77 (86%)
`
`88
`82 (88%)
`
`Patients were not included in the efficacy analysis, as noted above,
`because they did not have at least 1 on-treatment assessment consisting
`of both measures (MWI' & CGl-C).
`In this study, most of the dropouts were
`in the 200 mg/day group.
`
`Groups were comparable at baseline on demographics and disease
`parameters.
`In particular, patients enrolled in this trial were on average
`41-42 years old with a mean duration of symptoms of about 22-25 years
`(with a mean time since diagnosis of 7-8 years).
`
`Groups were also relatively comparable at baseline with regard to prior
`medication use and disease severity, although there was a slight
`maldistribution on the CGl-S between the Modafinil 400 and 200 mg
`groups.
`Specifically,
`there were fewer slightly ill patients in the 400
`compared to the 200 mg groups (13% vs 22%, respectively), and more
`markedly ill patients in the 400 compared to the 200 mg groups (35% vs
`23%; see Dr. Rappaport's review, page 51-52).
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`Primary Outcomes
`
`Sleep Latency (MWT)
`The following table displays the results:
`
`Placebo (N=88)
`M 200 mg/d (N=95)
`M 400 mg/d (N=86)
`
`l
`
`6.0
`6.1
`5.9
`
`Endpoint
`5.4
`8.3
`7.9
`
`P-value
`<0.001
`<0.001
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`
`outlined In the followmg table
`
`n of change scores, as
`
`Modafinil 400 Modafinil 200
`(N=86)
`(N=83)
`Very much improved
`6%
`8%
`28%
`25%
`Much Improved
`27%
`24%
`Minimally lmproved
`30%
`33%
`No change
`6%
`8%
`Minimally Worse
`3%
`1%
`Much Worse
`.
`0%
`0%
`Very Much Worse
`0.02
`0.01
`P-value
`The model used baseline severity as a covariate With no other covanates
`
`Placebo
`(N=88)
`0%
`14%
`24%
`48%
`10%
`5%
`0%
`
`used
`
`I
`
`»
`
`(
`
`and Placebo, res
`
`'
`
`,
`and 38%. for Modafin
`. These differences yielded
`of <0.01. The differences
`
`il 400, Modafinil 200,
`p-values for each
`between each dose
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`Although the Sponso
`analyses were reported. f
`
`gas in favor of drug, no statistical
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`0 and 1/185 (0.5%) of placebo patients, respectively. No other single
`adverse event was responsible for more than 0.5% of patients
`discontinuing treatment with modafinil
`in these studies, although 3% of
`patients reported discontinuing treatment due to ADRs involving the
`Nervous System, with ADRs of the Body as a Whole accounting for
`discontinuation of 1.4% of patients, Digestive System ADRs accounting for
`discontinuation of 1.1% of patients, and Respiratory System ADRs
`accounting for discontinuation of 0.8% of patients.
`Dr. Rappaport reproduces the sponsor’s summary table of discontinuations
`due to ADRs (reprinted in his review as Table 36, page 78) in the US as
`well as foreign databases, excluding Cephalon sponsored Phase 3
`uncontrolled experience. Unfortunately,
`the comparative dropout rates
`(drug vs placebo) due to specific events in the foreign controlled trials
`cannot be examined, because it appears that the sponsor has combined
`controlled and uncontrolled data in the same table. Nonetheless, as
`presented here, no single ADFi accounts for more than 0.6% of dropouts in
`the foreign narcolepsy patients (N=533), or 2.1% (insomnia) in the foreign
`non-narcolepsy patients (N=1171).
`in all of these foreign studies, the
`Nervous System was the body system in which the greatest number of
`events leading to discontinuation occurred (6.4% of patients in the
`foreign, non-narcolepsy patients).
`
`SERIOUS ADVERSE EVENTS
`
`In Cephalon sponsored Phase 3 controlled trials, 9/369 (2.4%) of modafinil
`treated patients experienced a serious adverse event. compared to 5/185
`(2.7%) of placebo treated patients. Of the 9 modafinil treated patients,
`the sponsor considered 6 patients to have experienced a serious adverse
`event that was possibly, probably, or presumably definitely related to
`treatment (see Dr. Rappaport’s Table 33, page 72).
`
`Dr. Rappaport has reviewed all narrative summaries of all ADRs resulting
`in discontinuations as well as those for all serious ADRs, regardless of
`the investigators’ causality assessments.
`In his view, only 3 events (in 2
`patients) were both clinically significant and likely related to treatment;
`they occurred in patients in Cephalon sponsored Phase 1,2 studies.
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`98 at baseline to 133-147) 8 hours
`rtension (125/89 at baseline [supine]
`
`Event
`Headache
`Nausea
`Rhinitis
`Diarrhea
`Nervousness
`Pharyngitis
`Dry Mouth
`Anorexia
`Dizziness
`Depression
`Anxiety
`Lung Disorder
`Cataplexy
`Insomnia
`Paresthesia
`LFT Elevation
`Amblyopia
`Chest Pain
`Vision Abnormal
`Dyspnea
`
`,
`
`(
`
`"~'
`
`Modaflml % (N=369)
`50%
`13%
`11%
`8%
`8%
`6%
`5%
`5%
`5%
`4%
`4%
`4%
`3%
`3%
`3%
`3%
`2%
`2%
`2%
`2%
`
`.
`
`18
`
`Placebo % (N=185)
`40%
`4%
`8%
`4%
`6%
`3%
`1%
`1%
`4%
`3%
`1%
`2%
`2%
`1%
`1%
`2%
`1%
`1%
`0%
`1%
`
`.
`
`.,
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`
`' Modafinil
`
`Placebo
`
`Hypotension
`Hypertension
`Neck Pain
`Chills
`Vomiting
`Dyskinesia
`Hypertonia
`
`.
`
`2%
`2%
`2%
`2%
`2%
`2%
`(2%
`
`1%
`0%
`1%
`0%
`1%
`0%
`0%
`
`,
`
`in the foreign. non-narcolepsy patients, a total of 11 %...reported
`example,
`insomnia, presumably,
`though,
`including uncontrolled experience-see Dr.
`Rappaport’s Table 38, page 82).
`'
`
`( h
`
`400 mg/day.
`
`LABORATORY VALUES
`
`sponsored studies.
`
`Clinical Chemistry
`
`- .
`
`routine chemistry test (see Dr. Rappaport’s Table 40, page 88). There was
`a dose dependent increase In any elevation of GGT in these studies
`(placebo-5%, 200 mg/day-4%, 400 mg/day-10%), although, as noted by Dr.
`Rappaport. a number of these patients had abnormal screening or baseline
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`life time in vwo carcinogenicity studies,
`Specifically, the study
`, because the doses
`
` .
`
`
`
` .
`
` .
`
` .
`
` .
`
` .
`
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`he results of an
`ogenicity assay, and appropriate
`I agree.
`
`Of interest is her finding that levels of
`sumed to be inactive) were markedly
`mpairment (N=1o, mean Clcr=16.6)
`12) after a single 200 mg dose. Specifically,
`unchanged, modafinil acid AUC increased by 8
`
`Additionally, patients with '
`half-life and Cmax after 8 days of 200
`dose; Days 2-7, 100 mg BID) compared
`
`21
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`data for the database that includes the Cephalon sponsored Phase 3
`uncontrolled studies (the entire safety database). As has been noted, for
`example, we cannot know from the sponsor’s presentation how many
`patients received doses close to 400 mg/day for at least 6 months.
`
`The fact that much of the foreign data was gained with twice a day dosing
`is problematic.
`it is not immediately obvious that a daily dose of 400 mg,
`given as 200 mg twice a day, provides relevant data to support the safety
`of a 400 mg/day dose, given as a single dose (the dosing regimen shown to
`be effective).
`
`For these reasons (lack of additional benefit of a 400 mg/day dose,
`inadequate description of the exposure at the higher dose, potential
`inability of the foreign data to support the safety of this dose),
`I
`recommend that the product be labelled for use as a single 200 mg daily
`dose.
`If the sponsor can adequately describe sufficient safety experience
`at a single dose of 400 mg, a statement to the effect that such a dose is
`reasonably well tolerated may be permitted in labeling, but
`it may not be
`recommended as a dose that is likely to be more useful than the 200
`mg/day dose.
`
`Additionally, as Dr. Rappaport points out in his review (page 87), the
`sponsor has not submitted laboratory data for the foreign studies; they
`must do so.
`
`Finally, the Pharmacology and Biopharmaceutics comments should be
`transmitted to the sponsor.
`
`RECOMMENDATIONS
`
`The sponsor should be sent an Approvable letter with attached draft
`labeling.
`
`‘
`
`(
`
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`/S/
`
`
`
`Russell Katz, MD.
`
`23
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`
`
`Cc:
`
`NDA 20-717
`
`HFD-120
`
`HFD-120/Katz/Leber/Rappaport/Malandrucco/Fitzgerald
`
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`REVIEW AND EVALUATION OF CLINICAL DATA
`
`NDA 20-717
`
`Sponsor:
`
`Drug:
`
`Proposed indication:
`Material
`submitted:
`
`Cephalon. lnc.
`
`Provigil (modafinil) Tablets
`Narcolepsy
`
` .
`
` .
`
` .
`
`’-7"
`\ _
`
`above AE’s was consudered senous and all resolved
`There were four SAE’s listed one case each of hemlplegia, gastritis hemorrhagic
`malaise and asthenia. All of these were listed as imputabllity doubtful "
`
`of 200 mg/d None of the
`
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`..A._:...-‘. -~.‘-_I
`
`..
`
`1" _-
`
`, - .
`
`t
`
`,
`
`_
`
`.
`
`. a
`
`'
`
`.
`
`_
`
`.
`
`.
`
`("‘x
`
`not defined.
`
`sed on chronological and semeiologlcal criteria which are
`The “Number of Treatments Days” ta
`defined
`
`Most patients improve
`indicated by a 14% di
`discontinuation rate d
`
`'
`
`'
`
`'
`
`t at 200 to 400 mg daily doses as
`'
`'
`
`' might be a nootropic agent.‘ There
`has been no evidence supporting it's abuse found by
`or by Interpol. since it's introduction in 1994.
`
`administration in rodents...an
`subjects...However,
`in long
`of clinically meaningful, dose-related. or predict
`human narcolepsy subjects.’
`
`C?" '
`
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`Discontinued'
`
`Completed all treatments
`
`Evaluable for safety
`
`
`
`
`
`Number of Subjects
`
`
`
`
`
`
`
`
`Evaluable for abuse liability
`
`
`
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`somnolence, euphoria, anorexia
`
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`Conclusions:
`
`(‘
`
`Recommendations:
`
`No action is indicated at this time.
`
`/S/
`
`
`
`‘-~\_ .Bob A. RaSEaBSE,_A-AH_
`Medical Reviewer
`November 18, 1997
`
`cc:
`
`orig. NDA
`”F9420 "'9
`HFD-t 20
`Leber
`Ion:
`
`r‘ 1
`
`'
`
`Rappapon
`Malandrucco
`
`.
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`

`NDA 20-717
`ADDENDUM 11/20/97
`
`Cephaion, inc.
`
`(modafinil) Tablets
`Provigil
`Narcolepsy
`Original NDA
`
`Sponsor:
`
`D
`
`rug:
`
`Proposed indication:
`Material
`submitted:
`
`MWT
`
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`/S/
`
`
`
`ob A. Rappaport, MD.
`Medical Reviewer
`November 20, 1997
`
`0‘:
`
`orig. NDA
`HFD-120 file
`HFD-120
`Leber
`Katz
`Rappapo
`Malandrucoo
`
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`

`NDA 20-717
`ADDENDUM 12/11/97
`
`s po n s o r:
`
`Cephalon, lnc.
`
`D r u g:
`Proposed indication:
`
`Material
`
`submitted:
`
`Date received:
`
`Provigil
`
`(modafinll) Tablets
`
`Narcolepsy
`
`Original NDA
`
`1 2/30/96
`
`As part of the Patient Daily Sleep Logs, subjects recorded the following:
`1.
`Total minutes of sleep during day (naps)
`
`'
`
`(I ,
`“
`
`2.
`
`3.
`4.
`5.
`
`6.
`7.
`8.
`
`9.
`
`10.
`
`1 1.
`
`Number of episodes of unwanted sleep
`
`Number of episodes of desire for sleep
`Number of cataplexy attacks
`Number of minutes to fall asleep
`
`Number of minutes of sleep before first awakening
`Number of minutes awake (not counting time to fall asleep)
`Number of hours slept
`
`Number of times awakened
`
`Number of hypnagogic hallucinations; and
`
`Number of episodes of sleep paralysis
`
`in regard to #’s 4. 9, 10 and 11, the common associated symptoms in narcoleptics, the sponsor
`
`reported the following:
`
`Study 301:
`
`\ ~
`
`averages of 1.31 and 0.96 cataplectic attacks per day,
`0.79 for the placebo group. The incidence of daily repo
`
`g and 200 mg groups had
`respectively at Baseline, compared with
`rted cataplectic attacks decreased during '
`
`'
`
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`/S/
`
`
`
`BEERTEEEEaSSETME”
`Medical Reviewer
`December 11, 1997
`
`001
`
`orig. NDA
`HF0-1 20 file
`H F 0-1 20
`
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`#2:"
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`Malandruceo
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`Memorandum
`
`December 1, 1997
`
`Food and Drug Adflinmuon
`
`Addressees (below)
`thia McCormick, M D , Director
`CfisronofAnesthetic, CrmcalCareandAddrcuonDrugProducts(RFD-170)
`Michael Kle
`Ph.D., Team Leader
`ontrolled Su stances Evaluatron Team (HFD-l70)
`
`DATE
`
`TO:
`THRU:
`‘
`FROM
`
`SUBJECT
`
`Attached is the document entitled Basisfor the Recomme
`Modafinil in Schedule IV
`IledSubstances Act (CS'A).
`NDA #20-717 sponsored by Cephalon, In .
`
`.
`W M.
`ODEIII/P. Botstein/ B. Collier
`ODEI/R. Temple
`HFD-l/ J. Woodcock/ M. Lumpkin
`HFY-l/ S. Nightingale/N. Reuter
`
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`(NDA #20-717).
`with excessive daytime sleepiness a
`[(diphenylmethyll- sulphinylacetamide], molecular formula C,,H,,NSO,, with a m
`PROVIGIL" is a tablet containing 100 mg or 200 mg of modafinil. PROVIGIL“
`olecular weight of 273.
`Cephalon, Inc. The dnrg has been marketed in France, the
`is sponsored by
`Belgium, Denmark, Greece, Ireland, ltaly, Netherlands,
`ugh approvals are pending in Canada,
`Portugal, Spain and the U.K.
`
`nce from the schedules of the
`if it is appropriat , the Secretary must make three
`to schedule a substance in the CSA. The findi
`potential, legitimate medical use, and dependence liability.
`ngs relate to a substance's abuse
`
`I”. Modafinil produces psychoa
`
`and displayed some
`d less potent than
`
`_ a
`
` .
`
` .
`
` .
`
` .
`
` .
`
` .
`
` .
`
` .
`
`
`
`ould not likely be
`as are cocaine, methylphenidate, and
`
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` amphetamine.
`
`ix. Relative potency differences between modafinil and other CNS psychostimulants are significant.
`Although in primates modafinil functioned as a positive reinforcer at doses 22- and 66-folds lower than
`the proposed therapeutic dose (400 mg/day; 6.67 mg/kg), it is considerably less potent than
`amphetamine and methylphenidate.
`x.
`In preclinical drug discrimination studies, modafinil only partially discriminated to cocaine and d-
`
`amphetamine.
`
`act directly on any single neurotransmitter system, but rather, modafinil appears to indirectly affect
`dopaminergic, serotonergic and GABA systems, or a combination of these systems and requires an
`intact al-adrenergic system. The drug's effects on the dopaminergic system appear to be mediated by
`its ability to modulate GABAergic transmission. Using microdialysis in the nucleus accumbens,
`modafinil (30, 100 and 300 mg/kg, s.c.) dose-dependently increased the release of dopamine while
`decreasing the release of GABA in rats. Local infusion of the GABA, antagonist phaclofen, the GABA
`A agonist muscimol, and the GABA reuptake inhibitor SKF589976A decreased modafinil-induced
`release of dopamine from the nucleus accumbens.
`In contrast, the GABA. agonist baclofen increased
`the modafinil-induced release of dopamine
`
`.
`"
`
`than 37% of the binding to any of the panel of receptors tested. These included the following types of
`sites: adenosine, adrenergic, benzodiazepine, dopamine (non-selective), GABA, and GABA... glutamate
`AMPA, kainate, NMDA, glycine site, and MK-801), strychnine-sensitive glycine, histamine (H1 and H2),
`muscarinic (non-selective, central and peripheral), nicotinic, 5-HT, sigma, opiate (non selective), ion
`channels (i.e., calcium channel, (L and N), chloride channel, potassium channel (ATP sensitive, voltage
`sensitive and insensitive”, NE, and 5-HT uptake/transporter, and second messengers systems
`(adenylate cyclase, inositol triphosphate and protein kinase C).
`
`Modafinil (0.1mM) displayed some binding affinity for the dopamine receptors; and it showed 100%
`inhibition of dopamine uptake (lCso = 3.10uM; K, = 1.93 uM). Modafinil also lacked affinity for the A,
`or A2 adenosine receptors. Modafinil (0.001 - 10.0 uM) did not inhibit the binding of l’HlDPCPx (A,
`receptors) or [’HJCGS-21680 (A2 receptors) to the adenosine receptors In whole brain membranes
`preparations (except cerebellum).
`’
`
`‘ -
`
`studies included evaluation of norepinephrine ('H-desipramine in rat cortex), serotonin (’H-Citalopram)
`and dopamine (’H-mazindol in rat striatum and ’H.WIN in guinea pig striatum) uptake sites. Except for
`binding at the dopamine uptake site, binding inhibition was not obtained.
`In radioreceptor studies using
`‘H-mazindol, the affinity of modafinil for the dopamine uptake site was approximately five-fold lower
`than affinity of cocaine, 16-fold lower than d-amDhetamine, 30- and 60-fold lower than the affinity
`showed by nomifensine and GER-12909 [KilnM): 2.050130, vs. 375 2 28 for cocaine; 132 for d-
`amphetamine; 68 :t 10 for nomifensine and 241 5.6 for GBR 12909] (Table l).
`
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`688 12909
`
`24
`
`d-Amphetamine
`
`
`
`
`
`
`
`“-
`m-
`
`132m~n2a4°mm —-_
`———--
`
`
`
`m-an 6,300 m 8,300
`—— >1.°oo.ooo
`55,000 m
`
`
`
`
`Modafinilsulfone—— 68,000
`
`than nomifensine
`
`
`
`In contrast to observations with d-amphetamine (IOuM). modafinil (1O uM) did not
`of d-amphetamine.
`stimulate release of [’Hldopamine from the synaptosomes.
`In rat striatal slices preloaded with ’H-
`dopamine, the ability of modafinil (300 MM), cocaine (3-30 ,uM), d-amphetamine (3.0-30.0 MM), and
`nomifensine (30-300 uMl to increase spontaneous and electrically-evoked release of dopamine was
`evaluated. Under basal conditions, modafinil was less potent than nomifensine (10 and 30 uM) and
`ase. Using electrical stimulation to stimulate
`modafinil was less potent than nomifensine (10 and
`
`K .
`\_,
`
`'
`
`methamphetamine . Modafinil (30-300 malkg)
`promoted EEG-defined wakefulness in a dose-dependent manner. Modafinil was less potent than
`methamphetamine in inducing a state of wakefulness; a dose of 300 mg/kg of modafinil was
`equipotent to 1.0 mg/kg of methamphetamine.
`In contrast to methamphetamine, modafinil did not
`produce an increased drive for compensatory sleep (i.e., NREM).
`In another study, the effects of
`modafinil (64 and 128.0 mglkg, i.p.) and d-amphetamine (2.5 and 5.0 mg/kg i.p.) on sleep/waves
`
`'
`
`~
`
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`cycles (duration), slow wave sleep (SW8), paradoxical sleep (PS) and wakefulness were evaluated in
`Sprague Dawley rats (Touret er al ., 1995). Both modafinil and d-amphetamine dose-dependently
`increased wakefulness; modafinil was
`approximately 51-times less potent than d-amphetamine. Similar
`effects were seen with 128 mg/kg modafinil and 2.5 mglkg amphetamine. d-Amphetamine
`wakefulness was followed by recovery of lost PS rebound on the day of administration, whereas
`modafinil did not produce this effect.
`in contrast to doamphetamine, modafinil did not affect the sleep
`patterns of the rats one day post-treatment.
`In modafinil-treated rats, sleep pattern on post-injection
`day was similar to that of controls, while that of d-amphetamine-treated rats was modified.
`The effects of modafinil on arousal were also evaluated in sleep deprived rats. Results from this study
`demonstrated that modafinil was effective in reducing preexisting sleep deficit brought on by forced
`wakefulness and the accumulation of additional REM sleep debt incurred during sleep deprivation.
`When modafinil (100 and 300 mglkg) was administered to rats deprived of sleep for six hours,
`modafinil prolonged EEG-defined wakefulness without increasing NREM sleep or the desire to recover
`lost NREM. At a dose of 300 mg/kg. the amount of lost NREM and REM recovered after the extended
`period of sleep deprivation was reduced by modafinil. Modafinil at a dose of 300 mglkg did not alter
`levels of sleep, wakefulness, or locomotor activity two days post-treatment.
`
`In another rat study, effects of modafinil on sleep/wake cycles were examined in anesthetized rats.
`Modafinil (32.0 to 250 mg/kg) increased the duration of wakefulness and the latency to the first
`appearance of REM sleep in a dose-dependent manner. The SWS was also decreased in a dose-
`dependent manner. Modafinil (64 and 128 mg/kg) and d-amphetamine (2.5 and 5.0 mg/kg) produced
`similar results on recovery of paradoxical sleep in rats implanted with electrodes. Modafinil and d-
`amphetamine each caused a dose-dependent increase in wakefulness.
`in contrast to d-arnphetamine,
`the wakefulness induced by modafinil was not followed by recovery of lost paradoxical sleep.
`Effects of modafinil on sleep and wakefulness were examined in two standard dog models.
`in the
`English bulldog model of hypersomnolence, the effects of modafinil (10.0 mg/kg, i.v.) on sleep
`[parameters measured included total sleep time; sleep latency (total minutes till onset of NREM); sleep
`disordered breathing index] and wakefulness were evaluated. Modafinil significantly (p 5 0.005)
`produced marked wakefulness and increased sleep latency (346 :t 105 min for modafinil vs 71 :1: 40
`min. for vehicle control).
`In the dober
`mans narcoleptic model, the effects of modafinil
`(0.125-10.0 mg/kg, i.v.) and d-amphetamine (2.5-200.0 ug/kg, i.v.) on cataleptic sleep locomotor
`activity, and cardiovascular parameters were examined. Modafinil at a dose of 10.0 mg/kg and d-
`amphetamine 200 pig/kg showed equal efficacy in increasing wakefulness and
`decreasing sleep in both the normal and narcoleptic dogs. Unlike d-amphetamine, modafinil
`significantly reduced REM in both normal and narcoleptic dogs. Modafinil, up to 10 mg/kg, had no
`effects on suppressing or decreasing cataplexy.
`
`’,.
`
`mg/kglinfusion in one monkey; 0.05 mg/kg/infusion in three monkeys) under a fixed-ratio 10 schedule
`of dmg delivery. Using the standard substitution procedure, vehicle (ethanol-emulphor), saline.
`modafinil (0.03, 0.1, and 0.3 mglkg/injection), d-amphetamine (0.01 or 0.03 mg/kg/injection), and I-
`ephedrine (0.1 mg/kg/infusion) were substituted for cocaine. Once stable responding was obtained,
`test drugs were substituted for four consecutive days. Between substitutions, the monkeys were
`returned to cocaine baseline conditions for at least three sessions.
`Modafinil functioned as a positive reinforcer at doses that were 22- and 66-folds lower than the
`proposed therapeutic dose (400 mg/da
`y; 6.67 mglkg).
`In all monkeys, at least one dose of modafinil g
`maintained number of infusions above
`the range of infusions obtained for saline and vehicle. Modafinil
`at a dose of 0.3 mg/kg/injection was s
`elf-administered by all four monkeys; and 0.1 mg/kg/infusion
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`modafinil was self-administered by two monkeys. These doses of modafinil were self-administered at
`rates equal to or greater than the rates of baseline cocaine infusions; Generally, as the dose of
`modafinil was increased, the number of infusions-obtained first ine’reased and then decreased for the
`monkeys self-administering modafinil, resulting in an inverted U-shaped function relating infusion
`number to dose. As the dose per infusion was increased, intake (mglkg/1 -hr session) of modafinil
`increased; the mean intake of modafinil for all four monkeys ranged from 0.4 mglkg to 34.7 mglkg at
`the 0.03 mglkg/infusion and 0.3 mg/kg/infusion, respectively.
`
`The pattern of responding maintained by modafinil differed from that observed with cocaine. Analysis
`of the within session time course of cocaine infusions under baseline conditions revealed that in three
`of four monkeys, the greatest number of infusions occurred during the first quarter of the session. The
`fourth monkey maintained responding for cocaine at a similar rate throughout the entire session.
`ln
`contrast, when modafinil (0.1 and 0.3 mglkgfinjection) was available, in some monkeys the rate of self-
`administration was the greatest in the first 2 quarters of the session; whereas in some monkeys it was
`distributed fairly evenly throughout the entire one hour session.
`
`As a positive test, d-amphetamine and l-ephedrine were substituted for cocaine in threemonkeys.
`Results clearly showed that both d-amphetamine and l-ephedrine maintained rates of responding higher
`than that of saline: that is, they were positive reinforcers.
`In all three monkeys, the mean number of
`d-amphetamine and I-ephedrine infusions were comparable to the cocaine baseline.
`
`To assess the role of the adrenergic system in the reinforcing effects of modafinil, an antagonism test
`with prazosin was conducted. Prazosin (0.1 mglkg) was administrated intravenously 15 minutes prior
`to the self-administration substitution session with modafinil (0.05 and 0.3 mglkg/injection) or vehicle
`(1 :1 ethanol:emulphor). Prazosin had no significant effect on modafinil maintained behavior.
`
`W Drug discrimination studies are routinely used to
`demonstrate whether or not a new drug is recognized as being pharmacologically equivalent to known
`drugs of abuse.
`In animals, if a new drug exhibits similar stimulus properties to known drug of abuse,
`there is a strong possibility that the new dmg would be similarly abused by humans. The stimulus
`properties of modafinil were evaluated in rats trained to discriminate cocaine from saline and in another
`group of rats trained to discriminate amphetamine from saline.
`
`The discriminative stimulus properties of modafinil were evaluated in rats trained to discriminate
`cocaine (10 mg/kg, ip) from saline in a two-lever operant procedure under a fixed-ratio (FR) 32 schedule
`of reinforcement during daily 30—minute sessions. After criterion was established, substitution tests
`were conducted. On substitution test sessions, doses of modafinil (3.0-250 mglkg; 30 minutes
`pretreatment time), d-amphetamine (0.1-3.0 mglkg, 10 minutes pretreatment time), or Lephedrine (3.0
`- 30.0 mglkg, 10 minutes pretreatment time) were administered prior to the behavioral session. To
`assess the role of the adrenergic system in the discriminative stimulus effects of modafinil, an
`antagonist test session with prazosin was conducted after the substitution test sessions were
`completed, in a similar manner as described above. During the antagonism test, prazosin (0.3 mglkg)
`alone or prazosin (0.3 mglkg) 10 minutes prior to 250 mglkg of modafinil was evaluated. The
`behavioral session was conducted 30 minutes after the subjects received the modafinil injection and 40
`minutes after receiving prazosin only. Both d-amphetamine and l-ephedrine dose-dependently
`substituted for the stimulus cue of cocaine. The highest dose of d-amphetamine tested elicited 100%
`cocaine-lever responding; whereas the highest dose of l-ephedrine tested only elicited approximately
`80% cocaine-appropriate responding and this was associated with marked behavioral disruption (i.e., a
`substantial decrease in rate of responding).
`'
`
`Following modafinil (3-100 mglkg) substitution for cocaine, subjects responded exclusively on the
`saline lever. However, cocaine-appropriate responding was observed when 150 and 250 mglkg of
`modafinil was tested. Modafinil (150 mglkg) only substituted for cocaine in one out of six rats tested;
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`four of six rats elicited cocaine-lever responding at a dose of 250 mg/kg. However, this high dose
`tested also reduced rates of responding by 59% as compared to control response rate.
`
`In the antagonism test, prazosin (0.3 mg/kg) was studied alone and in combination with modafinil (250
`mglkg). Prazosin alone elicited exclusively saline-appropriate responding. When prazosin was
`administered 10 minutes prior to modafinil, prazosin failed to attenuate either the cocaine4ike
`discriminative stimulus effects or the response rate effects of this dose of modafinil.
`
`The discriminative stimulus properties of modafinil were evaluated in rats trained to discriminate d-
`amphetamine (1.0 mg/kg, ip) from saline in a two-lever operant procedure under a FR 32 schedule of
`reinforcement during daily 30-minute sessions. After criterion was established, substitution tests were
`conducted. Substitution test sessions were conducted with modafinil (10.0, 30.0, 100.0, and 250.0
`mg/kg), and d-amphetamine (0.1, 0.3, 1.0 and 3.0 mg/kg). d-Amphetamine dose-dependently
`substituted for the training dose (1.0 mg/kg) of d-amphetamine. Only saline-appropriate responding was
`observed when 10. 30, and 100.0 mg/kg of modafinil was substituted for d-amphetamine. Partial
`amphetamine-appropriate responding was elicited by 250.0 mg/kg of modafinil; only 51 .496 d-
`amphetamine-lever responding was measured. However, a substantial decrease in rates of responding
`was observed and one rat died within 5 hours of modafinil administration.
`
`W Modafinil has been studied in adult (17-65 yrs) patient populations, for use in
`treatment of narcolepsy in a dosage of 200-400 mg/day. No study has been specifically designed to
`evaluate the metabolism, safety, or efficacy of modafinil in geriatric or pediatric patients with
`narcolepsy.
`
`Safety and efficacy were assessed in two 9-week placebo-controlled, double-blind, randomized,
`parallel-group studies of safety and efficacy of 200 mg and 400 mg of oral modafinil in patients with
`narcolepsy followed by a 40-week, open-label, flexible-dose continuation study with and without a 2-
`week discontinuation segment between the blinded and open label parts of the study.
`The protocol called for three groups of 95 patients each to be randomly assigned to one of three
`treatment arms. Eligible patients received a specified number of tablets to be taken daily for 9
`consecutive weeks. Of 285 patients randomized, 283 (99%) received study medication and were
`considered to be evaluable for the safety analyses. Two patients were not evaluable. One patient was
`discontinued soon after due to a history of illicit drug use and a positive urine drug screen; the patient
`did not report medication use, but when drug supply was returned 12 tablets were missing. The
`database did not include study medication of AE data (other than a note stating patient did not have
`any AE’s) (0.35% possible drug abuse in clinical trial). The other patient was discontinued when the
`investigator determined that the patient did not meet inclusion criteria. Fourteen patients (15%) in the
`modafinil 400 mg group discontinued study compared to 3 patients (3%) in the modafinil 200 mg group
`and 5 patients (5 96) in the placebo treatment group. Eleven of 14 patients who discontinued from
`modafinil 400 mg group did so because of AE's. None of the patients in the placebo group and one
`patient in the modafinil 200 mg group discontinued because of AE's. During the study, the blind for
`Patient 1403 was broken by the investigator because of concerns that the patient had taken another
`stimulant.
`
`mm For the majority of study sites (12/18), the mean sleep latencies were higher in
`both modafinil treatment groups (200 mg, 400 mg) compared to the placebo group. Patients in the
`modafinil 400 mg treatment group were able to stay awake for a significantly longer time and had
`greater clinical improvement. Patients in the modafinil 400 mg and 200 mg treatment groups were
`able to stay awake significantly longer as measured by all parameters when compared to patients in
`the placebo treatment group.
`
`Patients were asked to provide subjective responses by estimating how long they were able to stay
`awakeat the end of each test period. Modafinil 400 mg, 200 mg and combined treatment groups all
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`exhibited significantly more patients reporting staying awake at Endpoint than patients in the placebo
`group (p < 0.050). Patients in both active treatment groups had significantly greater improvement
`than patients in the placebo group at each visit. Patients in the modafinil 400 mg treatment group had
`significantly greater improvement than patients in the modafinil 200 mg treatment group only at Weeks
`3 and 6. No significant differences Were found between the two active treatment arms. Higher
`numbers of patients in the two active treatment groups, compared to patients in the placebo group,
`responded positively to questions regarding ‘feelings about life as a whole", 'quality of life during the
`past week”, 'general health', 'social functioning', 'productivity', "bodily pain', and 'driving capability‘.
`None was reported statistically.
`.
`
`Discontinuation evaluations at the end of Weeks 10 and 11 include recording of concomitant
`medications and AE’s. Effect of modafinil treatment was assessed by analyzing change from Week 9
`to 11 within modafinil dose groups, and by comparing modafinil/placebo patients to placebo] placebo
`patients at Week 11.
`
`Of the 273 patients randomized, 271 (99%) received medication and were evaluable for safety
`analyses. Two patients were not evaluable for safety or efficacy analyses. Two patients had positive
`urine drug screens and returned all study medications unopened. Approximately 50% of the patients in
`each treatment arm reported light to moderate use