Study MOD-024:
`
`Section 7.2.3.1
`
`This was a double blind, randomized. crossover trial of modafinil versus placebo performed in
`France by Dr. F. Laffont. Forty patients were included in the data base; thirty-four with
`Gelineau’s syndrome [narcolepsy] and six with “simple or atypical” hypersomnia. Study
`results are based on thirty-four of the Gelineau’s syndrome patients (four were excluded from
`the final analysis due to deviations from the overall mean results for efficacy parameters of
`greater than two standard deviations) and all six of the other hypersomnia patients. The study
`
`Efficacy analyses documented the following for patients with Gelineau’s syndrome:
`
`_
`
`.
`
`-
`
`0
`
`0
`
`0
`
`0
`
`-
`
`The number of nocturnal awakenings was less with modafinil compared with both the
`treatment-free and placebo periods; but this did not reach statistical significance.
`
`There was a statistically significant (p < 0.025) decrease in the number of yawns with
`modafinil compared to placebo.
`
`There was a statistically significant (p < 0.05) decrease in the number of diurnal sleep
`attacks with modafinil compared to placebo
`
`Modafinil did not affect nocturnal sleep time.
`
`Analysis showed no statistically significant difference between the periods for the
`number of cataplectic spells. However, patients whose concurrent tricyclic
`
`Analysis showed no statistically significant difference between the periods for sleep
`onset latency.
`
`20/30 patients preferred the modafinil period; 3 preferred the placebo period; 7
`expressed no preference.
`
`For patients with simple or atypical hypersomnia:
`
`-
`
`-
`
`-
`
`The number of diurnal sleep attacks decreased significantly with modafinil.
`
`There was no significant difference in the total nocturnal sleep time.
`
`The number of yawns decreased statistically significantly with modafinil in comparison
`to placebo.
`
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`-
`
`4/6 patients preferred the modafinil period and 2 expressed no preference.
`
`Section 7.2.3.2
`
`Study MOD-025:
`
`This Was a multicenter, controlled, double blind, crossover study versus placebo performed in
`France and Canada. Sixty-six patients with Gelineau's syndrome were included in the data base.
`Two patients were excluded due to incorrect inclusion by the investigator; however, for one of
`these patients, the information does appear in the data listings. A third patient participated in
`the early part of the study. then withdrew due to stress related to diagnosis of Wolff-
`Parkinson-White syndrome. He later insisted on being reinstated in the study. Only the earlier
`data for this patient was included in the analyses. Each patient received 300 mg modafinil/day
`in two divided doses, morning and midday, as either 100/200 or 200/100 for two weeks.
`These treatment periods were preceded by a two week run-in period on placebo and each
`treatment period was separated by a two week washout period on placebo.
`
`For the 63 patients analyzed, the following results were found:
`
`-
`
`0
`
`0
`
`0
`
`o
`
`-
`
`0
`
`0
`
`Based on vigilance diaries. while on modafinil, patients experienced a statistically
`significant decrease in the duration of daytime sleep periods (p = 0.002), the number of
`desires to sleep (p = 0.002), and the number of awakenings during sleep (p = 0.05).
`
`Results from these diaries also noted no significant effect demonstrated in the duration of
`sleep periods, the duration of periods of wakefulness during sleep, or the number of
`cataplectic attacks.
`
`There was a statistically significant (p < 0.001) increase in the sleep latency with
`modafinil on the MWT.
`
`There were no significant differences between modafinil and placebo in the following
`parameters on the sleep questionnaire: sleep time, ease of falling asleep, depth of sleep,
`recuperative quality of sleep, number of dreams, occurrence of pleasant dreams.
`estimation of sleep time, and occurrence of spontaneous awakenings.
`
`On a visual analogue scale for symptoms, there was no significant difference between the
`changes produced by modafinil and placebo in the following parameters: irritable, well,
`tired, drowsy.
`
`Also on a visual analogue scale, the overall therapeutic effect, as judged by the doctor and
`the patient, was statistically significant for modafinil (doctor. p = 0.0009; patient, p =
`0.0005).
`
`in the modafinil/placebo sequence, 14 patients preferred modafinil, 7 preferred
`placebo, and 1 did not express a preference: 22 wished to continue. 6 did not.
`
`in the placebo/modafinil sequence, 20 patients preferred modafinil, 4 preferred
`
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`.K ...I -..‘
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`. ...;_’L»_~...''—_......d'_4~_--n--n.‘-:2 . a; ‘:4.—..
`
`.‘
`
`‘_qv. ‘,
`
`_‘
`
`placebo, and 1 did not express a preference; all wished to continue.
`
`66
`
`Section 7.2.3.3
`
`Study MOD94003:
`
`This was a controlled, randomized, three period, cross-over study versus placebo performed in
`Canada. Seventy-five patients with narcolepsy were enrolled and 71 completed the full six
`weeks. One patient dropped out after baseline, not wishing to undergo the tests again. The other
`three patients dropped out due to adverse events: headache, anxiety, nausea and tics after two
`days on modafinil 400 mg; rash and mouth ulcers on placebo; and, chest pain on placebo.
`Patients received modafinil 200 mg, 400 mg or placebo in divided doses (morning and noon) for
`fourteen days.
`
`.
`
`For the patients analyzed, the following results were found:
`
`Primary:
`
`-
`
`0
`
`Modafinil 200 mg and 400 mg significantly increased the mean sleep latency compared
`to placebo on the MWT by 40% (p = 0.0002) and by 54% (p = 0.0001), respectively,
`with no difference between the two doses; no significant carry-over effect was detected
`(p = 0.593).
`
`Based on patient diaries, modafinil 200 mg and 400 mg significantly reduced the mean
`number of periods of sleep episodes and severe somnolence by 24% (p = 0.013) and by
`26% (0.007), respectively, with no difference between the two doses. No significant
`carry-over effect was detected (p = 0.815).
`
`Secondary:
`
`-
`
`-
`
`.
`
`0
`
`On the E88, modafinil 200 mg (p = 0.018) and 400 mg (p = 0.0009) both decreased
`the likelihood of falling asleep as measured by the total sleepiness score.
`
`The following results were from the FCRT which was not defined in the submission; nor
`were the exact nature of the individual results. Performance improved at 3 hours on
`both doses of modafinil, but not on placebo. Compared to placebo, patients had 41%
`fewer gaps on modafinil 200 mg (p = 0.026) and 44% fewer gaps on 400 mg (p =
`0.027). A decrease in the corresponding number of errors was not statistically
`significant. At 15 hours and 30 minutes, reaction times were slightly (11%) faster for
`both modafinil doses compared to placebo (p = 0.061 for 200 mg; p = 0.051 for 400
`mg).
`
`Actigraphy results were not available at the time of NBA submission.
`
`Based on the Global Evaluation, for the patients who had not taken stimulant medication
`prior to the study, a comparative decrease in excessive daytime somnolence was reported
`by 80% of patient on modafinil 400 mg, 66% on modafinil 200 mg, and 34% on
`.
`
`-
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`As a first choice. 50% of
`patients preferred the 400 mg period, 34% the 200 mg
`period, and 16% the pla
`selected the 400 mg do cebo period. As a first or second choice, 80% of patients
`se. 84% the 200 mg dose, and 36% the placebo period.
`
`The sponsor reports that, "Modafinil
`ytime somnolence and sleep attacks in
`narcolepsy patients with and witho
`ut cataplexy, and in patients with hypersomnia.” [item 8,
`Vol. 2, p. 00453]
`
`ytlme somnolence resolved in 75% of patients treated
`with modalinil.’ [Item 8, Vol. 2. p. 00454]
`
`SECTION 7.2.4
`
`OTHER CUNICAL TRIALS
`
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`\
`
`SECTION 8.0
`
`SAFETY FINDINGS
`
`the 2 ongoing open label extensions of the Cephalon controlled trials (through June 15, 1996
`d trials in non-narcolepsy patients (all non-Cephalon), and 25
`Nine of the non-
`
`non-Cephalon sponsored studies due loss of the CHF’s for those studies. [based on sponsor’s
`taxed data dated 9/8/97]
`
`r-
`L .
`
`‘
`
`and,
`
`June 15, 1996;
`
`1 )
`
`2 )
`3 )
`
`Cephalon sponsored, controlled, multicenter, Phase 3 studies in patients with
`narcolepsy: this includes double-blind and open label treatment periods through
`lndlvrdual Cephalon sponsored Phase 1 and 2 clinical pharmacology studies;
`AE, dosrng and limited demographic infon'natlon from all foreign, non-Cephalon
`sponsored. clinical studies wrth supporting CRF’s. the data from these foreign
`studies are subdivrded Into those studies wrth subjects who have narcolepsy
`and/or hypersomma (NA/HS) and those subjects With other disorders
`The sponsor used the COSTART classification system for coding the actual AE's as written on the
`
`CRF to the preferred terms.
`
`' -
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`
`'Listing of Subject Deaths'; Item 8, Vol. 3, p.
`The following table (sponsor's Table 8.9-22.
`01046) summarizes the available information regarding the five deaths.
`
`Table 32. Deaths: All Studies
`
`
`
`Information
`Duration of
`
`
`
`(age, gender.
`Therapy
`
`
`
`
`
` Subject K4
`40 yrs. F
`
`Amyotrophic
`lateral Sclerosis
`
`
`
`
`
` Subject IO!
` Pain
`
`Kidney Function
`
`
`Abnormality
`
` Flatulence
` Subject CR04
`
`65 yrs, F
`
`Major Depressive
` Subject 602
`
` Subject [6
`
`58 yrs. M
`
`
`Major Depressive
`E . isode
`
` Source:
`Table Following Text 23.2.0.
`Abbreviations:
`
`82 yrs, F
`
`
`
`68 yrs. F
`
`Age-assoc.
`
`Memory
`Impairment
`
`COSTART - Coding Symbols for Thesaurus ofAdverse Reaction; F - female; NE - not evaluated.
`‘
`Database indicated asthenia as the cause ofdeath; actual cause ofdeath according to patient narrative m due to
`myocardial infarction.
`Subject death not listed in database; information obtained fi'om narrative.
`Narrative indicated that “advanced cirrhosis ofthe liver could be totally responsible for the outcome.“
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`. wk“; -a».\«.‘\~‘-_»_-_ - .;_\~.-.4- -s- .-4 ._ .
`
`. VA
`
`~
`
`;
`
`,.
`
`'
`
`‘
`
`'
`
`'
`
`.
`
`_
`
`SECTION 8.2.2
`
`NON-FATAL SERIOUS ADVERSE EVENTS:
`
`7 1
`
`in subjects with NA/HS. Forty-
`s in the foreign,
`'n subjects with disorders other than NA/HS.
`Of the SAE’S reported, 32 were judged by the investi
`related, or related to study drug.
`'
`related and 34% (11/32) possibly related. One SAE (
`
`(20/32) were judged to be probably
`
`or Related] - By Study’“ Item 8 Vol.
`
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`

`.. L ,, ., - -_'....;'-‘-_ .
`
`'4 A—A ‘C—L;—bi-¢_&._;-‘_i‘g—‘.‘M‘A¥le..>_h-#|r~~.‘_ s_ ..4 V
`
`..'
`
`72
`
`
`
` Investlgltor's
`
`Study Subset
`
`Causality
`Study Number
`
`Assessment
`
`
`
`
`Cephllon Phase 3 Double-Blind
`
`Cl5383/30l/NA/US
`Chestl’uin
`odafinil 400
`Pmbable
`Resolved
`w/o
`Residual
`
`Modaiinil 400
`
`Possible
`
`--
`
`Dyspneu
`
`
`
`ClSBSaBOZ/Nuusn Ventricular“Wales
`
`Modafinil 400
`
`Modat‘mil 400
`
`Resolved
`w/o
`Residual
`
`Resolved
`w/o
`
`
`
`
`
`
`
`
`
`IResidual
`
`
`ModafinilZOO
`n Hypoventilation
`
`
`
`Modafinil400 “-
`
`
`
` I
`I
`Probable m I
`=Aggravation
`
`
`J
`Reaction
`-,
`nob-we
` 'I
`
`m»
`Mlmiy
`I
`
`
`
`
`r
`i
`
`
`
`Cephalon Phase l/2
`
`
`
`CEP-ZIOI
`
`CIS38a/IOZ/NA/US
`
`Foxeign, Non-NAIHS
`
`
`
`ECGAbnormal
`
`“Tachycardia
`78
`Psychosis
`
`Modafinil 800
`Modafinil 600
`
`Probable
`Pmbablc
`
`Resolved
`{gidual
`
`
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`73
`
`
`
`
`w/o
`
`
`
`
`
`I J S
`
`ource: Tables Following Text I5.l.0 and l5.2.0; Appendix SD! and 8.D.2.
`Notes: Table presents SAEs judged to be related (i.e.. defined 5 related. probably related. or possibly related) to study
`medication administration.
`Abbreviations:
`
`COSTART -= Coding Symbols for Thesaurus of Adverse Reaction Terms; wlo = without.
`‘ 2 5.45: reported in one patient at this dose with this causality and outcome.
`1’ Includes occurrences ofieukopenia and neutropenia. both coded to ‘leukopenia' under COSTART. Following identificuion
`ofthis case, a review ofall laboratory values for the double-blind studies for neutmphil values s l000/rnm’ (as a post-baseline
`event in the absence of pre-existing depressed neutrophil count) showed 3 cases in modafiniiotr'cated patients and 2
`placebo-treated patients (refer to Hematology section [Section 8.9.9.21).
`
`W W
`
`SECTION 8.3.1
`
`MODAFlNlL EXPOSURE:
`
`A total of 2305 subjects were treated with modafinil for a total of 497 subject-years. For
`subjects with narcolepsy/hypersomnia, exposure includes a total of 412 subject-years. 61
`subject-years in the Cephalon Phase 3 double-blind studies and 351 subject-years in the
`foreign. non-Cephalon sponsored studies. Most of these subjects received doses between 200
`and 400 mg/d and were treated for 90 days or less.
`In the Cephalon Phase 1/2 studies. 232
`subjects received modaiinil at doses between 200 and 800 mg/d, and 94% of these subjects
`were treated for fewer than 14 days. Some subjects in the foreign, non-Cephalon sponsored
`studies were treated with doses oi more than 1000 mg/d. The following table (sponsor's Table
`8.9-2. “Summary of Duration of Modatinil Use by Mean Daily Dose - Overall Exposure”; Item»
`
`-
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`Table 33. Serious Adverse Events: All Studies (continued)
`
`
`
`
`
`s
`
`?
`Investigator'a
`5
`Day of
`Causality
`Treatment /
`COSTART
`
`
`
`
`Dose (mg/d) Assessment Onset OutcomeTerm ‘m_______
`
`
`I Ruched T
`n-
`
`
`
`

`

`.
`ponsor notes that insufficient
`'
`to determine whether all su '
`'
`sponsored studies were unique.
`It should also be noted that a single daily dose w
`in the Cephalon sponsored studies, wh'
`morning and noon) was often administered
`-Cephalon sponsored studies.
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`(
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`.
`
`,
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`7 5
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` l
`
`2 ’
`
`Foreign, NA/HS: There are 3 subjects that received unknown drug.
`Foreign, non-NA/HS: There are 10 subjects that received unknown drug.
`‘
`All Studies: There are a total of28 subjects that received either no. other. or unknown drug.
`’
`Numbers ofsubjects listed in the placebo column represent those who received placebo only; subject who received
`‘
`both placebo and modafinil appear in the modafinil columns.
`Notes: Exposure in Cephalon Phase 3 Double-Blind studies represents information only from the 9-week double—blind
`treatment period. Data from the Cephalon Phase 3 Open-label studies are excluded; these data are provided in Table
`8.9.3 and Table Following Text 2.8.l. The 40-week continuation and 48-week extension open-label treaunent
`periods are ongoing.
`Abbreviation:
`1
`M-modafinil
`
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`With the inclusion of Cephalon Phase 3 open label data, the number of subjects in various study
`subsets treated with modafinil for six months or greater and for one year or greater is
`summarized in the table which follows (sponsor’s Table 8.9-3. “Number of Subjects Exposed
`to Modafinil for Six Months or Greater and for One Year or Greater”; Item 8, Vol. 3, p. 00979).
`
`t u
`
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`
`'
`
`.
`'V
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`
`e
`
`/.
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`

`
`
` ‘_ _
`
`Modafinil Dose and Duration
`
`200 to 400 mg/d
`
`77
`
`
`
` Source: Tables Following Text 2.0. l. 2. H. 2.2. l. 2.3.1 2
`
`.
`Notes:
`a 6 months is defined as 2180 days.
`2 1 year is defined as 2 336 days (48 weeks or 12 x 28-day months) forthe Cephalon-sponsored
`studies and 2 365 for the foreign. non-Cephalon-sponsored studies.
`It should be noted that data from the 9-week double-blind, 2-week withdrawal (applicable to Study
`ClS38a/302/NA/US only). and 40-week o
`‘
`'
`gh the data acquisition
`cut-offdate of 15 June 1996) treatment peri
`‘
`ods are included in this exposure table. The 40-week
`continuation and 48-week extension open-label treatment periods are ongoing.
`
`.4.l. 2.5. l, 2.6.]. and 2.8.].
`
`/
`
`SECTION 8.3.2
`
`ADVERSE EVENTS:
`
`The sponsor has provided the following table (sponsor's Table 8.9-18.
`‘AEs in Subjects Who
`Discontinued Due to AEs - By COSTART Terms”; Item 8, Vol. 3, p. 01034) in the ISS.
`
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`78
`
`
`
`to AE are shown as outcome of 'discontinued study' is not included on the adverse event record).
`Abbreviations:
`COSTART- Coding Symbols for Thesaurus ofAdverse Reaction; M I modafinil ; P - placebo; N- number.
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`It should be noted, however. that this table includes only AE’s in which the incidence of
`occurrence was 0.25% or greater (3 or more subjects reporting any AE in the Cephalon Phase
`
`/ .
`
`as would be expected.
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`79
`
`AE’s of Potential Clinical Concern (resulting in discontinuation, or
`Table 37.
`considered unrelated or
`remotely related to study drug)
`
` “IF,
`m un-,
`remotely
`
`
`
`
`
`.e 3 o .. 9. <
`releted
`
`releted
`
`-—-
`
`
`
`
`
`——-
`—--
`1—_-
`_—-
`——-
`“—
`—-
`
`_—
`
`—--
`
`——_
`—--
`—---
`—---
`
`~1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_——
`————
`—--—
`_--—
`——
`
`‘_,o_m._e_,,__d_SMAWMW,J
`
`
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`

`modafinil and developed moderate diastolic hypertension (BP before treatment =
`125/89 mm Hg supine. 122/91 mm Hg standing; after treatment = 143/103 mm Hg
`supine, 142/106 standing)
`
`2)
`
`Tachycardia: Subject 23 (21 year old male). Protocol CEP-2101 (same patient as #1),
`received 800 mg of modafinil and developed significant increases in pulse rate (PFi)
`eight hours after first dose (PR before treatment = 77/98. supine/standing; after
`treatment = 133/147. supine/standing). This subject also reported severe
`palpitations.
`
`3)
`
`Psychosis: Subject 78 (22 year old male). Protocol C1538a/102/MT/US, had no
`
`the pivotal clinical efficacy/safety studies, and 2) higher than the doses recommended for
`treatment by the sponsor in the labeling included in this NDA.
`
`WW
`
`SECTION 8.4.1
`
`ADVERSE EVENTS OVERALL°
`
`percentage of modafinil treated subjects reporting new or worsened AE’s later in the study. A
`similar dose response trend was seen in the foreign studies but was less pronounced.
`In these
`studies. the percentages of subjects reporting AE's in a given body system category tended to be
`similar in the placebo group and in all modafinil dose groups. with the exception of the > 425
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`whole, and the cardiovascular system.
`
`In the foreign
`
`The followin
`Term"; ltem
`Body system
`all study subs
`incidence of
`
`“Most Frequently Reported AE’s - By COSTART
`9 table (sponsor’s Table 8.9-10.
`8. Vol. 3, pp. 01002) compares AE's
`categories in which there was an inci
`ets combined, and COSTART preterr
`occurrence of at least 2.5% in all stu
`
`/
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`82
`
`Table 38. Most Frequently Reported AE's - All Study Subsets
`
`COSTART
`
`BODY SYSTEM
`
`Source: Tables Following Text 10.2.0. l0.3.0. l0.5.0. and l0.6.0.
`Abbreviations:
`COSTART - Coding Symbols for Thesaurus ofAdverse Reaction Terms; M - modafinil; N - number: P - placebo.
`Note: Table presents ME: by COSTART preferred term (presented as body system categories in which the incidence of
`occurrence was l0% or greater [arbitrary cut-OE; 74% ofsubjects reporting any AE] and COSTART preferred term
`categories in which there is an incidence of occurrence of at least 2.5% [arbitrary cut-03’; 90% of subjects
`reporting any A51) in all study subsets combined (r'.e.. Cephalon Phase 3. Cephalon Phase m. foreign.
`non-Cephalon—sponsored studies in subjects with NA/HS. or foreign. non-Cephalon-sponsoted studies in subjects
`with disorders other than NA/HS).
`
`The sponsor’s Table 8.9-11 (“incidence of Treatment-Emergent AEs Reported by 1% or
`Greater of Modafinil-Treated Subjects and at Greater Frequency than Placebo-Treated Subjects
`in Cephalon Phase 3 Double-Blind Studies'; item 8. Vol. 3, pp. 01004-01005). reproduced
`below, shows that the most commonly observed AE’s in modafinil treated subjects (not seen at
`an equivalent incidence in placebo treated subjects) were: headache, nausea, dian'hea, dry
`mouth, anorexia, nervousness. dizziness, rhinitis, and pharyngitis. The most frequent AEs
`occurring in modafinil treated subjects compared to placebo treated subjects were headache and
`nausea. The difference between the two treatment groups was comparable in the two Phase 3
`studies With the exceptions of headache, observed primarily in Study 301 and respiratory ..
`system AE's, observed primarily in Study 302.
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`Table 39. AE’s Reported by 1% or Greater of Modafinll Treated Subjects and at
`Greater Frequency than Placebo Treated Subjects - Cephalon Phase 3 Double
`Blind Studies (continued)
`
`84
`
`
`
`
`
`
`CARDIOVASCULAR
`
`Hypotension
`
`Hypertension
`Vasodilation
`
`."\..
`
`UROGENITAL
`
`Urination Abnormal
`
`Urine Retention
`
`
`
`SPECIAL SENSES
`
`Ejaculation Abnormal‘
`
`Amblyopia
`Vision Abnormal
`
`METABOUC/NIH'RIHONAL
`
`Hyperglycemia
`Albuminuria
`
`
`
`
`Joint Disorder
`
`
`
`it
`
`MUSCULOSKELEI'AL
`Source: Tables Following Text 6. l .0.
`'Events reported by at least I96 of PROViGiL'treated patients that were more frequent than in the plawoo group are included;
`incidence is rounded to the nearest l%. Patients who had at leastoneepisode ofan eventdun'n; themtdy period are represented
`in the table. The adverse experience terminology is coded using a standard modified COSTART Dictionary Events for which the
`PROVlGIL incidence was at least 1%. but equal to or less than placebo are not listed in the nble. Thee events included the
`following: infection. had: pain. pain. hypothermia. abdominal pain. flu syndrome. allergic motion. fever. asdtatia. accidental injury.
`general edema. tachycardia. palpitations. migraine. vattricular extrasystole, hradyeardia. dyspepsia. tooth dborder. constipation.
`flatulence, increased appetite. gastroenteritis. Gl disorder. eechyrnosis. anemia. leukocytosis. peripheral edema. iocrwed weight
`increased SGOT. myalgia. arthritis. arthralgia. somnolenee. thinking abnorrmlity, leg cramps. sleep disorder. hallucinations.
`hypalrinesia. deaased libido. incensed cough. sinusitis. bronchitis, pnetmonia. rale sweating. pntt'iurs. skin disorder. psoriasis.
`earpain. eye paimeardisorderJastepervet-sion. dymnha‘mnnuymhfcctiorxpywiajunanniacynidgmdmhed
`rnenses’.
`' Elevated iiva enzymes.
`’ Incidence adjusted for gender.
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`Q A
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`SECTION 8.4.2
`
`ADVERSEEVENTSBYGBVDER:
`
`
`
`Although there were inconsistent differences in the percentages of female and male subjects
`reporting AE’s in some subcategories of studies (for both the modafinil and placebo treated
`groups), there were no consistent or significant qualitative differences between female and male
`subjects in the body system categories of AE’s SAE's, or related SAE’s reported.
`
`SECTION 8.4.3
`
`ADVERSE EVENTS BY AGE:
`
`All subjects less than or equal to 16 years of age were in the foreign studies, in particular the
`non-NA/HS studies. While the percentage of pediatric subjects reporting AE’s was consistently
`lower than percentage of adult subjects reporting AE’s, the total N for the pediatric population
`is too small for adequate comparison. Fourteen SAE's were reported in the foreign, non-NA/HS
`studies which all came from one pediatric subject who took twelve 100 mg modafinil tablets in a
`15 hour period.
`
`I
`
`The percentages of adult subjects reporting AE’s were greater in the modafinil group than in the
`placebo group for all study subsets. The percentages of subjects in the adult group reporting
`AE's classified as serious were similar in the modafinil and placebo groups. With the exception
`of the foreign. non-NA/HS studies, adult subjects reporting AE’s judged as serious and related
`tended to be in the modafinil treated groups.
`
`‘
`
`(’
`
`i'
`
`The large majority of the geriatric subjects (greater than or equal to 65 years of age) were
`from the foreign non-NA/HS studies.
`In those studies, there was a slightly greater percentage
`of modafinil treated and placebo treated subjects reporting AE's in geriatric subjects compared
`to the adult and pediatric groups.
`
`Study MOD-020 was an open label pharmacokinetics and safety study in twelve permanently
`hospitalized, elderly subjects with “deficit psychologicaI-pathologioal symptoms" performed
`in France. Modafinil was administered at 300 mg in the am. on Days 1 and 7, and 150 mg bid
`on Days 2 through 6. Of note in this study, Cm, measured on Day 1 was almost double that
`recorded in healthy young volunteers in Study MOD-018. All twelve patients experienced AE’s,
`the most common being: restlessness, sleeplessness and anxiety. One subject withdrew because
`of insomnia, nervous irritation, brusque movements, and feeling emotional. There were no
`SAE’s. Reportedly these AE’s decreased over time during the study.
`
`In general, there were no consistent or significant qualitative differences between the different
`age groups in the body system categories of AE's, SAE’s, or related SAE’s reported.
`
`SECTION 8.4.4
`
`ADVERSE EVENTS BY RACE:
`
`‘ "
`
`In the Phase
`lnfonnation regarding race was obtained only from the Cephalon sponsored studies.
`3 studies, the percentages of Black, White or Other subjects reporting AE's were similar in the
`modafinil and placebo groups, with the exception of Other subjects in the placebo group who had
`a lower percentage of subjects reporting AE’s. However, this group was represented by a small
`number of subjects. The percentages of subjects reporting SAE's or SAE’s related to study drug
`were also comparable in the three groups.
`
`I
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`.-_... -........4.~g 4 v-u--.‘_&4.4_~h__.. -.4_-n.a._'.4. ‘A_.. A-
`
`86
`
`A higher percentage of Black subjects in the modafinil group (89%) reported AE’s compared to
`White subjects (72%) or Other subjects (67%) in the Phase 1/2 studies. Of note. 55% of
`Black subjects in the placebo group reported AE's compared to 19% of White subjects; no Other
`subjects received placebo. The sponsor suggests that this finding is due to the fact that many of
`the Black subjects were from Study 01538a/201/AB/US. a study of the abuse potential of
`modafinil in known substance abusers. This study maximized the AE profile of modafinil by
`employing doses as high as 800 mg/d and by eliciting reports of AE’s via questionnaires.
`
`In general, there were no consistent or significant qualitative differences between the different
`racial groups in the body system categories of AE's. SAE's or related SAE’s reported.
`
`SECTION 8.4.5
`
`ADVERSE EVENTS IN PATIENTS WITH HEPATIC INSUFFICIENCY:
`
`Nine subjects with severe hepatic insufficiency due to cirrhosis were studied in the foreign
`trial MOD-021. They received modafinil 200 mg/d for eight days. Plasma levels of modafinil
`were higher in these subjects compared to healthy subjects tested in Study MOD-019. One
`subject died during the study due to worsening of encephalopathy. This event was judged not to
`be related to modafinil. There were no other SAE’s reported. There was a significant increase
`in mean prothrombin level in one subject and there were significant increases in blood urea
`levels in two others. These abnormalities were judged not to be related to modafinil
`administration.
`
`SECTION 8.4.6
`
`ADVERSE EVENTS IN PATIENTS WITH RENAL INSUFFICIENCY:
`
`Ten male subjects with severe chronic renal failure who were not receiving dialysis were
`studied in the foreign Study P1595. They received a single 200 mg dose of modafinil following
`an overnight fast. The phan'nacokinetic profile of modafinil in chronic renal failure patients
`was reportedly similar to that seen in healthy subjects in Study MOD-022, with the exception
`that there was an increase in the plasma concentration of the acid metabolite. The sponsor
`reports that there were no SAE’s and no clinically significant alteration in laboratory or
`clinical safety parameters in this patient group.
`
`SECTION 8.4.7
`
`ADVERSE EVENTS RELATED PREGNANCY, NURSING. LABOR AND DEUVERY:
`
`No human studies were conducted specifically to evaluate the effects of modafinil on female
`reproductive function. There were seven normal births which occurred in patients who
`received modafinil during pregnancy. One subject (#2009) in Study C1538a/302/NA/US was
`treated for approximately two months with modafinil 400 mg/d when she developed abdominal
`pain and vaginal bleeding and had a positive pregnancy test. Just over a month later she had a
`spontaneous abortion. This was her third spontaneous abortion.
`
`The sponsor reports that there were no reports of patterns of AE’s that indicated that modafinil
`adversely affected the menstrual cycle, fertility, or the normal course of pregnancy or
`lactation. However, they do note that the potential for modafinil to cause induction of liver
`enzymes at doses of 400 mg/d or higher, may result in decreased efficacy of minidose
`estroprogestational hormonal contraceptives.
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`87
`
`SECTION 8.5.1
`
`CUNICAL LABORATORY EVALUATIONS:
`
`include those results in the data base.
`
`Table Following Text 25.0.0, Item 8, Vol. 5, pp. 02000-02002. A copy of that table is
`included as Appendix II of this
`
`review.
`
`Section 8.5.1.1 Clinica
`
`%) subjects with significantly
`.2%) subject with significantly elevated total bilirubin levels.
`
`causes likely to explain the el
`evation (medical history,
`concomitant medications), and a number of subjects she
`remained on study drug.
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`\_.
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`1
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`groups, by‘ study type subset, are
`
`Treatment-E
`
`‘
`
`8 8
`
`Subjects with I Specifi
`Number Abnorml
`l/Number Assessed (Va)
`
`Cephllon Pins: 3 Double-Blind
`
`j
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`Cephalon Plan: In Source:
`
`Abbreviations:
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`(
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`‘
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`8 9
`
`Table 41.
`
`
`
`Frequency ofSpecific Laboratory Abnormality
`
`Number Abnorm
`
`al/Number Assessed ('4)
`
`
`
` Source:
`
`Abbnvinions:
`AP‘IT - activated partial lhl’om
`WBC - white blood cell count.
`
`boplmin lime;NR-notmeorded; PT-
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`90
`
`-
`
`-.~
`
`
`
`less than 101° F
`Temperature
`90 to 180 mm Hg
`Systolic blood pressure
`50 to 105 mm H
`Diastolic blood pressure
`50 to 120 bpm
`Pulse
`Clinically important shifts from the normal range were
`Temperature
`Systolic blood pressure
`Diastolic blood pressure
`Pulse
`
`‘
`
`(,
`
`“ '
`
`the double blind studies.
`
`onfirm that these episodes do
`eatment groups compared to the placebo groups of
`
`SECTION 8.5.3
`BODY WEIGHT:
`There was no difference between the modaf
`clinically significant change from Baseline in body
`'
`'
`'
`inil treated and placebo treated subjects with a
`n 2 (1 /o) placebo treated subjects. A
`ase In body weight was observed in 5 (1%) modafinil treated subjects and 7
`(4%) placebo treated subjects.
`823
`
`SECTION 8.5.4
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`,_,
`..
`‘_
`..,
`.
`.
`.-
`,_
`.
`--.. -.---..-.~. -“A. .4 -__-.u-_~-‘—-._.__.‘_~_‘--u‘ ..... .
`-,
`
`
`
`WWW
`
`The sponsor reports that in the Cephalon sponsored Phase 3 studies there was a slightly higher
`incidence of AE’s at the 400 mg/d dose compared to the 200 mg/d dose in the body system
`categories for which AE’s were most frequently reported. is. nervous system, body as a whole,
`and digestive system. There was only one AE, headache, for which the difference in incidence
`was > 5%
`
`.
`
`among
`
`128mm
`
`SECTION 8.7.1
`
`INTERACTION WITH CLOMIPRAMINE:
`
`_
`
`(
`
`Study C1538a/107/PK/UK, a Cephalon sponsored study performed in the U.K., examined the
`pharmacokinetics and safety of coadministration of modafinil and clomipramine in 18 normal,
`healthy subjects. This study was undertaken because clomipramine is often used in subjects
`with narcolepsy for the treatment of cataplexy. Combined treatment with clomipramine 50
`mg/d and modafinil 200 mg/d did not affect the pharmacokinetics of either drug. There were no
`deaths or SAE’s. There were a total of 75 reported AE’s; 37 of which occurred with
`clomipramine alone. and 27 of which occurred with combined treatment. There were no
`clinically significant changes in ECG, clinical chemistry. hematology or urinalysis parameters.
`ln subjects receiving combined treatment, the sponsor reports a significantly greater increase
`in systolic blood pressure than occurred with either treatment alone (12.4 mm Hg for combined
`treatment; 6.4 mm Hg for modafinil alone; 5.7 mm Hg for