Dyskinesia
`
`There were 21 modafanil treated subjects who experienced 26 adverse events codiing to
`
`dyskinesia. The mean AE onset day was day 100 for the CS phase 3 group, with the onset
`
`day not known for the FNC studies. Fourteen of the events were considered to be related
`
`to study medication. No change in study medication was made for 15 events. Five
`
`subjects previously described discontinued study medication. The dyskinesia resolved
`3
`without residual in 18 events and in 8 events was ongoing at the time of discontinuation.
`
`Sponsor’s Conclusion (dyskinesia)
`
`The sponsor concludes that there does not appear to be an increased risk of developing
`
`“tardive dyskinesia” on modafanil. "Thirteen of the the dyskinesia AEs in the CS phase 3
`
`studies stopped while the patient was on modafanil or within two weeks of stopping
`
`medication. Two subjects are currently still on modafanil despite a dyskinetic AE. Both
`
`these AE’s are intermittent.
`
`Conclusion10.0
`
`From the available information provided by the sponsor it appears that modafanil treated
`
`patients experiencing dyskinesia is related to modafanil. This conclusion is based on the
`
`following evidence. There were no reports of dyskinsia adverse events among placebo
`
`treated patients. There appears to be a case of dyskinesia with re-challenge (72 year-old
`
`man, subject 876/F-04). Two patients experienced dyskinesia within a relatively short
`
`time while receiving high doses of modafanil (15 year old girl, subject Open/9-2/K11E;
`
`35 year-old man, subject 102/24) The dyskinesia resolved within a short time of
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`

`discontinuing modafanil in these two patients. Two patients remain on modafanil with
`
`intermitent dyskinesia, which presumably was not present prior to treatment.
`
`The information available on these cases reviewed by the sponsor is incomplete,
`
`especially with respect to factors such as coexisting illnesses, concomitant medications,
`
`and outcome, especially in patients fi'om the FNC studies. The sponsor states that thirteen
`l
`of the dyskinesia adverse events stopped while the subject was on modafanil or within
`
`two weeks of stopping medication, however the number in each group is not provided.
`
`As noted by the
`
`sponsor,
`
`several newly reported adverse
`
`experiences
`
`and
`
`discontinuations indicate the potential for hypersensitivity to modafanil.
`
`As recognized in the initial NDA review of studies 301 and 302, elevations in GGT and
`
`alkaline phosphatase continue to show mild elevations over time from baseline in a dose
`
`dependent manner. Several cases of clinically significant elevations of GGT were
`
`identified. For the most part these patients had elevated GGT at baseline. In most cases
`
`there was no associated elevation of AST or ALT. None of the cases were associated with
`
`clinically significant elevations of total bilirubin. The clinical significance of these GGT
`
`elevations is uncertain.
`
`Several additional cases of tachycardia and hypertension were reported in the update. In
`
`addition the pulse and blood pressure measurements from studies 201, and 112 indicate
`
`
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`clinically insignificant increase in pulse and blood pressure following modafanil
`
`administration.
`
`Overall, based upon the Integrated Summary of Safety Update, modafanil continues to
`
`have a benign safety profile.
`
`,
`
`i,
`
`*
`
`HFD-120
`
`NDA, 20-217
`
`HFD-lZO, Freiman, Katz, Hommany
`
`/S/
`/S/
`
`
`
`Joel Freiman, MD.
`Medical Reviewer
`
`R. Katz
`
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`

`NDA 20-717
`
`fl W769: If ME’MT’
`
`/
`
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`(-'
`
`Table 9. Summaryof Open-Label Serious Adverse Experiences
`(C1538al301lNA/US and C1538al302lNA/US)
`
`‘ Number Age Sex Adverse Experience'
`Modafinil 400 mgIStudy 301
`1104
`54
`M Pneumonia
`
`1211
`1419
`
`'
`
`60
`63
`
`M Joint disorder
`M Benign-tumor in colon
`and rectum
`
`Moderate
`Severe
`
`None
`None
`
`69
`
`1423
`
`F Pneumonia
`Lung cancer
`Modafinil 4,00 mngtudy 302
`‘
`3 46
`M Numbness in bilateral
`'
`upper and right lower
`extremities
`
`37
`
`50
`
`Skin carcinoma‘
`Accidental overdose
`Endometrial carcinoma
`Cerebrovascular
`aocident‘
`Carcinoma'
`
`Brain edema
`l
`lModafinil 300 mngtudy 301
`27
`M Bronchopneumoniacf"
`54
`M Kidney calculus‘
`51
`F Wheezing“
`Palpitations“
`Congestive Heart
`Failure“
`Cardiomegaly"d
`Neoplasia UG'
`(urogenital)
`intentional injury‘
`
`t _
`
`‘
`
`_
`
`(
`
`‘
`
`None
`Severe
`Life-threatening None
`
`Moderate
`
`None
`
`Mild
`NR
`Severe
`Severe
`
`None
`NR
`Remote
`Remote
`
`Life
`Threatening
`Severe
`
`None
`
`None
`
`Moderate
`Mild
`Moderate
`Severe
`Severe
`
`Severe
`Severe
`
`Life
`Threatening
`Severe
`Mild
`Moderate
`Moderate
`Moderate
`Severe
`
`Moderate
`Moderate
`Moderate
`Moderate
`Moderate
`
`Severe
`Moderate
`Severe
`
`None
`None
`Possible
`Possible
`Possible
`
`Possible
`None
`
`None
`
`Remote
`None
`Remote
`Remote
`None
`None
`
`Remote
`None
`None
`None
`None
`
`.
`
`None
`None
`
`3
`j
`'
`
`' "
`
`Remote
`
`_
`
`Chest Pain'
`Gunshot Wound‘E‘
`Retinal hemorrhage'
`Carcinoma'
`Agitation'
`Adjustment
`disorder/relational
`problems“
`Chest pain‘
`Hematoma'
`Bronchitis e
`Chest tightness“
`Coronary Artery
`Disease“
`Attempted suicide“
`Chest pain'
`Pal itations'
`
`'
`
`Cephalon. Inc.
`June18, 1998
`
`25
`
`IV _ 46
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`,~.-
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`n
`
`Mmoumaw I
`NDA 20—717
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`Table 9. Summary of Open-Label Serious Adverse Experiences
`(C1538al301/NAIUS and C1 538al3021NAIUS) (continued)
`
`Number A-e Sex
`
`Adverse Experience'
`
`Onse{
`(Stud Day)
`
`Severity
`
`Relationshito
`Stud Drug
`
`
` Modafinil 300 mngtudy 301 (continued)
`M Coronary
`216
`
`atherosclerosis“
`
`Quadruple bypass -
`
`surgery“
`I
`;
`
`Modafinil 300 mngtudy 302
`
`0106
`45
`F Hysterectomy surgery‘
`
`10212
`20
`F
`Pyelonephritis‘
`
`0306
`54
`M Accidental injury‘
`IM05
`26
`M Neoplasia‘
`
`Rhinitis'
`
`‘0504
`M Exertional dyspnea‘?
`‘
`Third Degree Atrio-
`Ventricular Heart Block“
`M Chest pain‘
`M Toxic encephalopathy“
`M Lower back muscle
`spasms“
`M Chest pain
`Chest pain
`Angina pectoris
`Speech disorder
`Abnormal vision
`Infection‘
`Myocardial infarction“
`Congestive heart
`,-,
`failure“
`i5
`
`60
`
`’
`
`42
`
`47
`26
`60
`
`52
`
`1505
`
`60
`
`F
`
`
`
`
`0908
`t 0909
`
`
`5 1002
`‘
`I 1206
`
`
`
`
`
`
`
`
`
`806
`
`813
`
`105
`23
`-32
`-38
`-38
`787
`836
`
`65
`762
`635
`
`381
`381
`571
`585
`585
`171
`739
`791
`
`125
`20
`540
`
`106
`176
`
`Severe
`
`None
`
`Severe
`
`None
`
`Severe
`Severe
`Severe
`Moderate
`Moderate
`Moderate
`Severe
`
`Severe
`Moderate
`Severe
`
`Moderate
`Moderate
`Severe
`Severe
`Severe
`Severe
`Mild
`Severe
`
`Severe
`Moderate
`Life
`Threatening
`Severe
`Moderate
`
`None
`Possible
`None
`None
`None
`None
`None
`
`None
`Remote
`None
`
`None
`None
`None
`None
`None
`None
`None
`None
`
`None
`None
`Possible
`
`None
`None
`
`
`
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`!
`
`...
`
`
`
`
`
`
`‘3 1519
`1704'
`1904
`
`
`
`53
`45
`37
`
`F Lung disorder‘
`F Accidental overdose‘
`M Accidental injury —
`
`63
`64
`
`M Lung disorder‘ .
`M Pneumonia‘
`
`2012
`
`2019
`
`
`Modafinil 200 mg] Study 301 _
`
`
`Possible
`Mild
`-87
`I 0410
`26
`F Leukopenia‘
`
`Possible
`Moderate
`829
`0505
`52
`F Thyroid goiter
`
`
`?
`Leukopenia‘
`-87
`Mild
`Possible
`
`;
`(neutropenia)
`
`
`
`
`
`31
`_ 1210
`F Pruritus
`Mild
`Possibl
`
`
`(1";
`
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`
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`June 18. 1998
`
`26
`
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`

`A 17746 LVLMB'IU '
`NDA 20-717
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`l
`
`.
`
`I.
`
`Table 9. Summary of Open-Label Serious Adverse Experiences
`(C1538aI301INAlUS and C1538al302lNAIUS) (continued)
`_*,,,7
`
`m7, MW-.._V,,_gm_..._fi_ “may”. “Weiefifii,viwfij
`
`Patient
`Number Age Sex Adverse Experience'
`Modafinil 200 mg/Study 301 (continued)
`1423
`67
`F Accidental lnjury“
`Cardiovascular
`
`r
`'
`disorder
`Cardiovascular
`disorder
`
`Lung edema
`
`Coronary artery
`disorder
`Cardiovascular
`
`3
`1911
`
`disorder
`M Headache
`
`32
`
`Onset
`(Stud Day
`
`Severity
`
`Relationship to
`Stud Drug
`
`'
`
`Threatening
`Moderate
`
`Life
`Threatening
`Life
`Threatening
`Life
`
`Threatening
`Moderate
`
`None
`None
`
`None
`
`None
`
`None
`
`None
`
`None
`
`
`
`‘
`
`Modafinil 200 mgIStudy 302
`0601
`35
`M Broken pelvis“
`53
`M Dyspepsia'
`53
`F Accidental ln'ury
`1516
`1.0
`a: COSTART coding symbol.
`b: Accidental overdose by patient's 2-year-old daughter. Information gathered from MedWatch.
`c: Occurred alter database cutoff.
`d: Adverse Experience Term from Case Report Form.
`e: Accidental overdose by patient's 3-year old son.
`Notes:
`
`Moderate
`Moderate
`Severe
`
`None
`Possible
`None
`
`_4
`
`(’ -
`
`'Previously reported serious adverse experiences are marked with an asterisk; new adverse experiences
`are indicated by bolded text.
`Patients 0211 from Study 301 and Patients 1906 and 1412 from Study 302 appear in error in Listing 3.0.1 as
`having serious adverse experiences. These patients are excluded from the above table.
`NR = Not reported.
`Source: Appendix 1.0. Listing 3.0.1.
`
`No new pattern or trend is apparent in this list of serious adverse experiences.
`
`’
`
`I :
`
`3.3.5 Clinical Laboratory Tests (C1538a/301/NA/US and C1538a/302/NA/US)
`
`. ,
`
`All values for laboratory tests collected at Baseline, at each of the study visits, and
`at Endpoint (defined as the last visit for all patients), as well as supplemental
`assessments
`and
`clinical
`laboratory
`normal
`ranges,
`are
`presented
`in
`Appendices 1.1 to 3.0. Cutpoints for clinically significant laboratory values are found
`in Appendix 10.0.
`
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`
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`

`NDA 20-717
`
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`#WMMEW 1’ L
`
`3.2 Patient Population - Open-Label C1538aI301INAIUS and
`C1538al302INAIUS
`
`3.2.1 Patient Disposition (C1538al301lNA/US and C1538a/302/NA/US)
`
`A total of 478 patients entered the 40-week open-label study. Of these patients, 302
`(63%) have completed the 40-week. 48-week, or are ongoing in further open-label
`extension. Overall, 13% of patients discontinued due to lack of study medication
`efficacy. Most of these were from the highest average dose group, as would be
`expected if patients moved to a higher dose in an attempt to reach therapeutic
`levels before discontinuing. Only 10% of patients discontinued due to adverse
`experiences. Most of these discontinuations were from the lowest dose group, which
`is also expected for patients sensitive to modafinil that would not want to risk
`increased severity or frequency of AEs by moving to a higher dose, or who might‘
`reduce their modafinil dose for safety reasons. The 40-week study has been
`completed, the 48-week study is ongoing, and further open-label extension phases
`are ongoing. Patient disposition is shown in the following table.
`
`Table 1. Open-Label Disposition of Patients* (C1538al301lNA/US and
`C1538a/302/NAIUS)
`
`
`
`Average Daily Dose
`;
`Modafinil Modafinil Modafinil Modafinil
`
`
`Combined *
`400 mg'
`300 mg”
`200 mgc
`
`
`N (%)
`N (%)
`N (%)
`N (%)
`
`
`
` % Patients started in open-label treatment
`112
`277
`89
`478
`l Discontinuations from open-label:
`;
`
`
`(5%)
`4
`18
`42 (38%)
`64 (13%)
`Lack of study medication efficacy
`22 (25%)
`18
`10 ( 9%)
`‘
`50 (10%)
`Adverse experience
`
`
`6
`(7%)
`8
`6
`(5%)
`3
`20
`(4%)
`Patient noncompliance
`8
`(9%)
`3
`10
`(9%)
`21
`(4%) '
`f
`Patient withdrew consent
`
`
`5
`(6%)
`2
`5
`(5%)
`l
`Lost to follow-up
`12
`(3%)
`0
`0
`1
`(1%)
`Protocol violation
`1 (<1%)
`;
`(2%)
`2
`(1 %)
`4
`2
`(2%)
`5 Other
`8
`(2%)
`.
`
`
`Completed 40-week or 48-week open4abel
`42 (47%) 302 (63%) ,
`36 (32%)
`224 (81%)
`
`
`
`
`t_,,___..____,,_w
`, ..
`treatment phases, or continuing in openlabel
`_ ,, fl
`3
`'From database up to 6/2/97 cut-off date.
`a: 400 mg: aversge daily dose 2350 mg
`b: 300 mg: aversge daily close 2250 mg and 650
`c: 200 mg: aversge daily dose <250
`
`(7%)
`(6%)
`(3%)
`(1%)
`(1%)
`
`
`
`._
`:‘7
`
`'
`
`
`
`3.2.2 Overall Exposure to Treatment (C1538al301lNA/US and C1538a/302/NA/US)
`
`A total of 478 patients were exposed to modafinil treatment for the first 8 weeks of
`open-label study; 209 patients had reached open-label extension week 48 by the
`data cut.off date. Overall treatment exposure by average daily dosage is presented
`in the table below.
`
`Cephalon, Inc.
`June 18. 1998
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`NBA 20-717
`
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`)4—‘171’ W0 bl- M an T‘ ’3
`
`Table 2. Open-Label Patient Exposure to Treatment
`(C1538al301lNA/US and C1538al3021NAIUS)
`
`Duration of
`Exposure
`
`.
`
`=
`'
`
`Modafinil
`400 mg
`n (%)
`
`Modafinil
`300 mg
`n (%)
`
`Modafinil
`200 mg
`n (%)
`
`Modafinil
`Combined
`n (%)
`
`112 (100%)
`
`277 (100%)
`
`89 (100%)
`
`478 (100%)
`
`CL Week 9-16
`
`103 (92%)
`
`252 (91%)
`
`CL Week 17—24
`
`85 (76%)
`
`243 (88%)
`
`64 (72%)
`
`59 (66%)
`
`419 (88%)
`
`387 (81%)
`
`CL Week 25-32
`
`68 (61%)
`
`242 (87%)
`
`57 (64%)
`
`367 (77%)
`
`(44%)
`
`C ‘7
`
`CL Week 33-40
`IOLE Week 1-8
`‘OLE Week 9-16
`IOLE Week 17-24
`IOLE Week 2562
`OLE Week 33-40
`‘
`OLE Week 41-48
`
`57 (51%)
`48 (43%)
`31
`(28%)
`27 (24%)
`24 (21%)
`19
`(17%)
`
`16
`
`(14%)
`
`241
`(87%)
`238 (86%)
`239 (86%)
`(85%)
`(82%)
`(76%)
`
`56 (63%)
`52 (58%)
`45 (51%)
`42 (47%)
`42 (47%)
`(42%)
`
`(37%)
`
`I
`
`(74%)
`(71%)
`(66%)
`(63%)
`(61%)
`(56%)
`
`,
`5
`,
`
`1
`
`OL = Open-label (40 weeks)
`OLE = Open-label extension (48 weeks)
`Source: Table 2.0.0
`
`In the 478 patients studied, there was a mean (SD) modafinil exposure of 416 (229)
`days. with an average dose of 305 mg/d. A summary of study medication exposure
`and actual average dose by mean dosage group is presented in the table below.
`
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`
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`

`NDA 20-717
`
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`AWN—6 H- Mom I" H
`
`,
`
`Table 8. Summary of Open-Label Adverse Experiences Leading to
`
`iscontinuation (C1538al301lNAlUSand C1538al302/NAIUS)
`. Relationship to
`Stud Drug
`
`'
`
`'
`
`'
`
`'
`
`Da
`
`Number Age Sex
`Modaflnil 400 mngtudy 301
`0502'
`53
`F Atrial arrhythmia
`ECG abnormality
`‘
`F Anemia
`63
`‘ 1201
`Modafinil 400 mngtudy 302
`25
`F Unintended
`pregnancy
`Emotional liability
`Depression
`Ventricular
`extrasystoles
`Unintended
`pregnancy
`Infection
`Nervousness
`
`6 °
`
`s
`
`54
`
`52
`
`27
`
`28
`64
`
`
`
`Moderate
`Moderate
`
`Possible
`Possible
`Remote
`
`Mild
`
`None
`
`Mild
`Mild
`Moderate
`
`Possible
`Possible
`Remote
`
`Mild
`
`None
`
`.
`
`. Moderate
`Moderate
`
`None
`Possible
`
`,
`
`‘
`
`-
`
`Severe
`
`Remote
`
`Severe
`
`Remote
`
`Moderate
`Severe
`Mild
`
`Probable
`Possible
`None
`
`Moderate
`
`Moderate
`Moderate
`Moderate
`Severe
`Severe
`
`Severe
`Severe
`Life
`Threatening
`Moderate
`Moderate
`
`Severe
`Severe
`Mild
`Mild
`Moderate
`Moderate
`Moderate
`Moderate
`Moderate
`Mild
`Moderate
`Mild
`
`Possible
`
`Possible
`Probable
`Probable
`Possible
`Possible
`
`Possible
`None
`None
`
`None
`None
`
`Probable
`Probable
`Probable
`Probable
`Probable
`Probable
`Probable
`None
`Probable
`Related
`None
`Probable
`
`I
`,
`.
`
`3
`
`' V
`
`50
`
`51
`
`55
`
`32
`
`51
`
`0 1
`*
`
`I
`r
`
`5 o
`
`(g
`
`‘
`
`‘
`
`'
`
`9 ;
`I
`
`Endometn'al
`carcinoma”
`Cerebrovascular
`accidentb
`Decreased Libido
`Arthralgia
`F Unintended
`pregnancy
`{lModafinil 300 mg/Study 301
`I
`25
`M Cataplexy
`‘
`Somnolence
`F Mood change
`Irritability
`F Palpitations“
`Congestive Heart
`Failureb‘d
`Cardiomegaly”“'4
`Neoplasia UG"
`Intentional injury”
`
`'9 '
`
`:
`
`1
`
`'
`
`Myalgia
`Unintended
`pregnancy
`Nervousness
`Apathy
`Headache
`Pain
`Dizziness
`Metronhagia
`Nervousness
`Infection
`Metronhagia
`Anxiety
`Somnolence
`Asthma
`
`
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`
`Table 8. Summary of Adverse Experiences Leading to Discontinuation
`(C1538aI301INAIUS and C1538al302lNAIUS) (continued)
`
`'
`
`Relationship to
`Stud Drug
`
`Drug Stop
`Da
`
`I
`
`,.
`< "
`
`3' Patient
`Number Age Sex Adverse Experience'
`Modaflnil 300 mgIStudy 301 (continued)
`2115'
`22
`F Anxiety
`2214'
`56
`F Tremor
`Cardiovascular
`disorder
`
`_ Modaflnil 300 mngtudy 302
`,
`35
`F Arthritis
`53
`’M Increased cataplexy“
`20
`iF Pregnancy“
`50
`iF Increased cataplexy“
`66
`M Sleep disorder
`Cataplexy
`M Diarrhea
`Nervousness
`Nervousness
`
`57
`
`37
`
`26
`
`20
`
`M Accidental Injury"
`
`F Unintended
`pregnancy
`F Unintended
`
`pregnancy
`l
`IModafinil zoo mngtudy 301
`0111'
`47
`F Chest pain
`22
`M Dizziness
`Headache
`Nausea
`SGPT increase
`Liver function
`
`63
`
`
`
`; .
`
`2
`
`abnormality
`Alkaline
`phosphatase
`increase
`Nervousness
`
`Depression
`Nausea
`Nervousness
`Palpitations
`Headache
`Alcohol intolerance
`
`‘
`
`Anxiety
`M Liver function
`abnormality
`Leukopenia
`verbatim: neutro
`
`‘
`0 3
`
`Mild
`Mild
`
`Probable
`Probable
`Probable
`
`Mild
`Moderate
`Moderate
`Moderate
`Moderate
`_ Moderate
`Moderate
`Mild
`Moderate
`
`Life
`Threatening
`Moderate
`
`Possible
`Possibly
`None
`Remote
`Probable
`Related
`Remote
`Remote
`Remote
`
`Possible
`
`None
`
`Moderate
`
`None
`
`Moderate
`Mild
`Mild
`Mild
`Moderate
`Moderate
`
`Possible
`Remote
`Remote
`Remote
`Probable
`Probable
`
`Moderate
`
`Probable
`
`Moderate
`
`Related
`
`Moderate
`Mild
`Severe
`Severe
`Mild
`Moderate
`
`Moderate
`Moderate
`
`None
`Probable
`Probable
`Related
`Possible
`None
`
`Related
`Possible
`
`Moderate
`
`Possible
`
`‘
`
`ur
`
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`PROVIGIL® (modafinil) Tablets: Safety Update
`
`f (
`
`Table 8. Summary of Adverse Experiences Leading to Discontinuation
`(C1538al301INAIUS and C1538al302lNA/US) (continued)
`
`
`
`'
`
`'
`
`'
`‘
`'
`
`Moderate
`Moderate
`Severe
`
`Severe
`Severe
`Moderate
`' Mild
`Mild
`Mild
`Moderate
`
`Relationship to
`Study Drug
`
`Drug Stop
`Da
`
`Possibly
`Probable
`Remote
`Probable
`Probable
`
`Related
`Probable
`Probable
`Probable
`None
`
`Probable
`Probable
`Related
`Related
`Remote
`Remote
`Possible
`
`Adverse
`‘
`Experience'
`l Number Age Sex
`Modafinil 200 rug/Study 301 (continued)
`Unintended
`pregnancy
`Prun'tusb
`0 1210
`Depression
`;
`Goiter
`' 1503
`Nervousness
`1901'
`Anxiety
`A.
`3
`Modafinil 200 mgIStudy 302
`0213‘
`39 i F Nausea
`[0219'
`22
`F Nervousness
`l
`Nervousness
`Somnolence
`Unintended
`pregnancy
`Asthenia
`Nervousness
`Nausea
`Vomiting
`Hemoptysis
`Melena
`Dyspepsia”
`COSTART coding symbol.
`This adverse experience also was coded as a Serious Adverse Experience
`These discontinuations occurred afler the database cut-off date.
`Adverse Experience Term from Case Report Form.
`
`29
`
`39
`
`29
`
`22
`
`( _
`
`1506'
`3:
`b:
`c:
`d:
`Notes:
`
`'Previously reported openolabel patient discontinuations are marked with an asterisk; new patient discontinuations are
`indicated by bolded text.
`Listing 3.0.4 includes all patients who discontinued study medication due to an adverse experience who may or may not
`have discontinued from the study due to adverse experiences. The above table and narratives found in Appendix 6.0
`include only patients who discontinued from open-label studies 301 or 302.
`Source: Appendix 1.0, Listing 3.0.4.
`
`9
`
`Though fewer than 11% of thetotal population discontinued from the open-label
`phase of the study, many of those that did (50%) were for Nervous System
`experiences. Complete narratives for each of the patients summarized in the table
`above who discontinued due to adverse experiences are found in Appendix 6.0.
`
`3.3.3.1 New Adverse Experiences Resulting in Patient Discontinuation
`(C1538a/301/NA/US and C1538al302/NAIUS)
`
`Adverse experiencesithat resulted in patient discontinuation from study that were
`not
`previously
`reported
`in
`the
`doubleblind
`or
`open-label
`phases
`of
`C1538al301/NA/US or C1538al302/NAIUS include the following:
`
`
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`PROVIGIL® (modafinil) Tablets: Safety Update
`
`j
`
`
`
`
`
`
`
`
`
`Modafinil
`Modafinil
`Modafinil
`Statistic . Modafinil
`
`
`400 mg
`300 mg
`200 mg
`Combined
`
`(n = 112)
`(n = 277)
`(n = 89)
`(n = 478)
`
`
`
`
`
`
`Number of Patients with at Least
`n (%)
`
`
`82 (92%)
`448 (94%)
`107 (96%)
`259 (94%)
`
`One Open-Label Emergent
`
`Adverse Experience
`‘
`
`Body as a Whole
`
`
`219 (46%)
`41 (46%)
`128 (46%)
`so (45%)
`n(%)
`Headache
`147 (31%)
`24 (27%)
`103 (37%)
`20 (18%)
`n(%)
`Infection
`‘
`
`
`77 (16%)
`10 (11%)
`54 (20%)
`13 (12%)
`n(%)
`‘
`Pain
`.
`60 (13%)
`8 (9%)
`42 (15%)
`10 (9%)
`n(%)
`Flu Syndromef
`2
`
`
`56 (12%)
`8 (9%)
`41 (15%)
`7 (6%)
`n(%)
`Accidental lnju'ry
`1
`48 (10%)
`8 (9%)
`29 (11%)
`11
`(10%)
`n(%)
`Back Pain
`'
`1‘
`33 ( 7%)
`4 ( 5%)
`24 (9%)
`5 ( 5%)
`n(%)
`Allergic Reaction
`
`
`Chest Pain
`n(%)
`2 (2%)
`15 (5%)
`10 (11%)
`27 (6%)
`l
`;
`‘ Abdominal Pain
`n(%)
`4 (4%)
`15 (5%)
`6 (7%)
`25 (5%)
`
`
`
`
`Fever
`n(%)
`2 (2%)
`15 (5%)
`3 (3%)
`20 (4%)
`‘ Neck Pain
`n(%)
`6 (5%)
`11
`(4%)
`3 (3%)
`20 (4%)
`§
`
`
`Cardiovascular
`
`
`
`
`
`=
`
`l
`
`
`n(%)
`n(%)
`
`n(%)
`n(%)
`n(%)
`n(%)
`n(%)
`n(%)
`n(%)
`
`2 (2%)
`1
`(1%)
`
`10 (4%)
`6 (2%)
`
`6 (7%)
`6 (7%)
`
`18 (4%)
`13 (3%)
`
`12 (11%)
`14 (13%)
`7 (6%)
`6 ( 5%)
`2 ( 2%)
`2 (2%)
`3 ( 3%)
`
`44 (16%)
`39 (14%)
`36 (13%)
`24 ( 9%)
`21
`( 8%)
`4 (1%)
`4 ( 1%)
`
`(12%)
`11
`1O (11%)
`14 (16%)
`6 ( 7%)
`8 ( 9%)
`6
`(7%)
`5 (6%)
`
`67 (14%)
`63 (13%)
`57 (12%)
`36 ( 8%)
`31
`( 7%)
`12
`(3%)
`12 ( 3%)
`
`Hypertension
`Palpitations
`
`Digestive
`
`Dyspepsia
`
`
`Tooth Disorder
`.
`Nausea
`
`
`Diarrhea
`
`
`Dry Mouth
`
`
`Anorexia
`Constipation
`
`
`
`
`Metabolic l Nutrition
`Peripheral Edema
`
`
`
`
`1
`Musculoskeletal
`Myalgia
`n(%)
`(7%)
`{’8
`(8%)
`21
`5 (6%)
`34 (7%)
`
`
`Arthritis
`n(%)
`‘4 (4%)
`16 (6%)
`0
`20 (4%)
`‘
`. Arthralgia n(%) 3 (3%) 11 (4%) 5 (6%) 19 (4%)
`
`
`
`
`
`
`
`
`Nervous
`
`
`
`Nervousness
`n(%)
`8 (7%)
`28 (10%)
`16 (18%)
`52 (11%)
`j
`Depression
`n(%)
`10 (9%)
`28 (10%)
`10 (11%)
`48 (10%)
`
`
`Cataplexy
`n(%)
`8 (7%)
`30 (11%)
`7 (8%)
`45 (9%)
`1
`Anxiety
`n(%)
`2 (2%)
`17 (6%)
`15 (17%)
`34 (7%)
`l
`Somnolence
`n(%)
`10 (9%)
`17 (6%)
`5 (6%)
`32 (7%)
`
`
`.
`Dizziness
`n(%)
`6 (5%)
`17 (6%)
`6 (7%)
`29 (6%)
`
`Insomnia
`n(%)
`2 (2%)
`15 (5%)
`9 (10%)
`26 (5%)
`2
`Respiratory
`Rhinitis
`Sinusitis
`
`Cough
`
`Pharyngitis
`
`Bronchitis
`
`Urogenital
`Urinary Tract Infection
`
`Dysmenorrhea
`
`a: 25% of the safety evalWafion
`Source: Table 3.1.0; Appendix 1.0. Listing 3.0.0.
`
`n(%)
`
`6 (5%)
`
`4 ( 1%)
`
`1
`
`( 1%)
`
`11
`
`(2%)
`
`'
`
`
`
`
`3
`‘
`
`
`
`15 (13%)
`6 (5%)
`7 (6%)
`9 (8%)
`4 (4%)
`
`50 (18%)
`36 (13%)
`32 (12%)
`20 (8%)
`25 ( 9%)
`
`9 (10%)
`1O (11%)
`6 (7%)
`9 (10%)
`7 ( 8%)
`
`74 (16%)
`52 (11%)
`45 (9%)
`39 (8%)
`36 ( 8%)
`
`4 ( 4%)
`3 ( 3%)
`
`
`
`
`
`( 5%)
`3%)
`
`
`
`4 ( 5%)
`5 .,
`
`
`
`
`
`
`n(%)
`n(%)
`n(%)
`n(%)
`n(%)
`
`n (%)
`n (%)
`
`" '
`
`
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`

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`PROVIGIL® (modafinil) Tablets: Safety Update
`
`é
`
`Table 7. Summary of Common' Drug-Relatedb Open-Label Emergent Adverse
`
`‘
`
`‘
`Number of Patients with at Least
`One Open~LabeI Emergent
`Related Adverse Experience
`
`Statistic
`
`Modafinil
`400 mg
`
`Modafinil
`200 mg
`
`n (%)
`
`9
`
`(8%)
`
`53 (19%)
`
`40 (45%)
`
`Modafinil
`Combined
`(n = 478)
`102 (21%)
`
`13
`
`(3%)
`
`;
`
`4000000000
`
`Oj—I
`
`,
`1
`
`- c
`
`-
`
`looooooo
`
`_
`
`( -
`
`Body as a Whole
`Headache
`Infection
`Pain
`
`.
`
`Flu Syndrome 3
`Accidental Injury
`Back Pain
`
`Allergic Reaction
`Chest Pain
`Abdominal Pain
`Fever
`Neck Pain
`Cardiovascular
`‘
`Hypertension
`5
`Palpitations
`Digestive
`Dyspepsia
`Tooth Disorder
`Nausea
`Diarrhea
`Dry Mouth
`Anorexia
`Constipation
`Metabolic I Nutrition
`‘
`Peripheral Edema
`lMusculoskeletal
`Myalgia
`Arthritis
`
`3
`f
`1
`
`Arthralgia
`‘
`Nervous
`Nervousness
`Depression
`Cataplexy
`Anxiety
`Somnolenoe
`Dizziness
`insomnia
`‘
`Respiratory
`Rhinitis
`Sinusitis
`
`Cough
`Pharyngitis
`Bronchitis
`Urogenital
`Urinary Tract Infection
`I smenorrhea
`
`0000000000“
`ON‘INU‘O-fiN-‘i
`
`d
`
`COOOOOOOOOOOO
`0Od-lO-fioo
`
`Aoro-n-noucoo?-
`
`(5%)
`(<1%)
`(<1%)
`( 3%)
`(2%)
`(<1%)
`(<1%)
`
`(15%)
`( 1%)
`1
`2 ( 2%)
`1o (11%)
`3 ( 3%)
`1
`(1%)
`5 (6%)
`
`b: Includes probably related and related events.
`
`
`
`
`
` ‘1 _ . Source: Table 3.1.2; Appendix 1.0. Listing 3.0.0.
`
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`”WW“ MEWT’ 7
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`PROVIGIL® (modafinil) Tablets: Safety Update
`
`Table 11. Summary of Open-Label GGT Mean Observed and Change From
`Baseline Values By Visit (C1538al301lNA/US and C1538al302lNAIUS)
`
`Parameter
`GGT (IUIL)
`
`Statistic
`
`Modafinil
`400 mg
`
`AverageDaIly Dose
`Modafinil
`Modafinil
`300 mg
`200 mg
`
`Modafinil
`Combined
`
`‘
`
`Observed Values at Open-label Baseline
`
`it
`
`n
`Mean 1 SD.
`
`110
`33.2 :l: 37.5
`
`271
`32.0 i 26.9
`
`86
`27.1 i 25.2
`
`i
`467
`31.3 i 29.4 ‘»
`
`
`
`Change from Open-label Baseline Values
`
`n
`Mean :1; SD.
`n
`Mean 1 SD.
`n
`Mean 1: SD.
`n
`Mean :1: SD.
`n
`Mean 1 SD.
`n
`MeaniSD.
`Source: Tables4.0.0and4..01: Appendix1.1
`
`.
`
`.
`
`107
`0.1 :t 15.3
`104
`‘7.7 :1: 22.4
`77
`10.4 :1: 28.1
`53
`10.9 :1: 23.1
`12
`16.4 t 37.6
`110
`86128.1
`
`265
`-0.02 i 9.1
`248
`6.7 i 21.9
`234
`8.0 1 25.6
`235
`5.6 i 21.4
`124
`11.2 i 18.3
`269
`5.51190
`
`79
`-0.3 110.3
`67
`3.0 t 10.3
`51
`3.4 1 11.0
`53
`6.3 :t 20.5
`21
`3.5 :1; 11.2
`82
`3.01202
`
`I
`
`451
`-0.03 :1: 11.0
`419
`6.3 120.7
`362
`7.8 :1: 24.7
`341
`6.6 i 21.6
`157
`10.6 t 19.8 I
`461
`5.81218
`
`.
`
`CY
`
`Shifts (C 1 538a/301/NA/US and C1538a/302/NA/US)
`
`There were no clinically meaningful trends in the number of patients with shifts to
`values above the upper limit of normal (ULN) for total bilirubin, or shifts to below the
`lower limit of normal (LLN) for total protein and albumin.
`
`Patients with shifts from baseline to above the ULN in alkaline phosphatase ranged
`from less than 1% at Week 2 to 7% at Week 88. A summary of patients with shifts
`to above the ULN in alkaline phosphatase is presented in the table below. Alkaline
`phosphatase values for individual patients are listedIn Appendix 1.1.
`
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`

`I WM 51) T- ?
`NDA 20-717
`PROVIGlL® (modafinil) Tablets: Safety Update
`
`6.2 Studies Conducted in Canada
`
`Five studies and one compassionate use program were ongoing or were initiated in
`Canada since the cut-off date for data inclusion in the modafinil NDA 20-717.
`Available
`information
`regarding deaths.
`serious
`adverse
`experiences
`and
`discontinuations due to adverse experiences are summarized below.
`
`6.2.1 Study 94003
`
`Draxis Study 94003 was a double-blind, placebo-controlled crossover study in ,
`patients with narcolepsy, conducted from January 25, 1995 to January 19, 1996. A
`long-term. open-label portion of the study was conducted from March 11. 1995 to
`May 25, 1996.
`
`i
`
`No deaths or serious adverse experiences were reported during the conduct of this
`study. Three patients discontinued due to adverse experiences during Part
`1
`(short-term). one of whom was taking placebo at the time. One patient discontinued
`due to adverse experiences during Part 2 (long-term). These discontinuations are
`summarized in the following table.
`
`Table 23. Discontinuations Due to Adverse Experiences in Draxis
`Study 94003
`
`Relationship Drug 1
`to Study
`Stop ‘
`Drug
`Day
`Probably
`Probably
`Probably
`
`|l I
`
`i I lll
`
`Probably
`
`,
`
`i
`
`Modafinil
`Patient
`Dosage
`Identifier Age Sex
`49 M 400 mg
`
`30 M 200 mg
`20 M Placebo
`41
`F Maximum
`
`Experience'
`Nausea
`Headache
`I t
`.
`Anxiety
`Repetitive ;,
`movements
`
`Rash
`Chest pain
`Headaches
`Melancholia
`
`'
`Moderate
`Moderate
`Moderate
`Severe
`
`Moderate
`Severe
`Severe
`Moderate
`Moderate
`
`Unknown
`Probably
`Probably
`Unknown
`Unknown
`
`= Not reported
`
`Narratives and case report forms for these patients are found in Appendices 11.1
`and 11.2.
`
`6.2.2 Special Access Prggram
`
`There were no deaths or serious adverse experiences reported during.the Canadian
`compassionate use program. There were nine discontinuations due to adverse
`experiences or pregnancy. as summarized in the following table.
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
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`June 18. 1998
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`

`NBA 20-717
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`H—Wfii—ch‘mgvr
`
`(0
`
`-' -
`
`Table 24. Discontinuations Due to Adverse Experiences in Draxis
`Compassionate Use Program
`
` 200 mg bid
`
` .
`
`l
`
`ll l lll l
`
`I!
`l
`
`
`
`‘
`(-
`‘
`
`1
`
`M
`
`1925
`
`200 mg bid
`
`disrupted sleep
`
`Incresede moveents
`Case report forms were not consistently utilized in the Draxis compassionate use
`program. Therefore. case report forms and patient narratives for this study are not
`provided.
`-
`
`l
`
`6.2.3 Militag Studies in Canada
`There were no deaths or serious adverse experiences reported in the four Canadian ..
`military studies: L40, L58. L136, and L188. One subject discontinued due to an
`adverse experience (“flu-like symptoms”) from Study L58, but had not been treated
`with modafinil.
`
`.
`
`--~
`
`6.3 Studies Conducted by Lafon
`
`Information regarding discontinuations due to AEs and SAEs from Lafon is provided
`through January 31, 1998.
`
`6.3.1 Discontinuations due to Adverse Experiences Since NDA Filing .-
` .
`Studies}
`Twenty-two (22) patients discontinued due to adverse experiences in a series of six
`studies conducted by— These patients are summarized in the
` .
`table below; case report forms (French and English translations) and narratives for
`these patients are found in Appendices 11.3 and 11.4.
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`Cephalon. Inc.
`June 18, 1998
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`
`l| l
`
`l
`
`Il i
`
`i l
`
`pregnancy
`
`100-200 mg bid
`
`dyspepsia
`
`200 mg bid
`
`visual disturbance
`
`200 mg. 100 mg bid
`
`depression (seasonal)
`
`200 mg bid
`
`unknown
`
`dyspepsia
`increased liver function test values
`
`palpitations
`possible depression
`
`300 mg qAM
`
`epistaxis
`
`100 mg "die”
`
`palpitations
`dysphoria
`insomnia
`
`

`

`NDA 20-717
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`
`Wile-54'0“ 3707/ H
`
`Table 25. Summary of Adverse Experiences Leading to Discontinuation:
` .
`Sponsored Studies
`
`Relationship Drug
`to Study
`Stop
`Day
`
`'
`
`NR
`
`NR
`
`NR
`
`NR
`
`NR
`
`NR
`
`NR
`
`NR
`
`Medium
`
`Probable
`
`Mild
`Intense
`Intense
`Intense
`Intense
`Medium
`Mild
`Medium
`NR
`NR
`Medium
`Medium
`Medium
`Medium
`Intense
`Intense
`Medium
`Mild
`Medium
`Medium
`
`Probable
`Probable
`Probable
`Possible
`Possible
`Possible
`None
`None
`None
`None
`Probable
`Probable
`Probable
`Probable
`Probable
`Probable
`Probable
`Probable
`Probable
`Probable
`
`NR
`Average
`Unobtrusive NR
`Unobtrusive NR
`Average
`Possible
`Average
`Possible
`Average
`Possible
`Average
`Average
`
`—I
`
`encomcoAAcn-n-s—naammNNMNM-a
`
`N0
`
`nuummgg
`
`'
`
`‘
`‘
`‘
`
`-
`
`Ir
`
` .
`
`03
`
`._.
`( a
`
`.
`
`‘
`
` .
` .
`
` .
`
` .
`.
`
` .
`
` .
` .
`
` .
`
` .
`
`Study E1029
`49
`F Placebo
`
`47
`
`Abdominal painl
`gastralgia
`Nausea
`200 mg BID Nausea
`Vomiting
`Asthenia
`Anorexia
`Hot Flashes
`200 mg BID Palpitations
`Tremors
`200 mg QD‘ Depression“
`Anxiety
`200 mg BID Nausea
`Ocular pain
`Insomnia
`Diarrhea
`Placebo
`200 mg BID Anxiety
`Insomnia
`
`200 mg BID Anxiety
`Myalgia
`Thoracic tightness
`Aggressiveness
`Study E1043lDoubIe-Blind Phase
`75
`F NR
`Increased stiffness
`Anxiety
`Sleep problems
`Nausea
`Flatulence
`Abdominal pain
`Headache
`
`NR
`
`Increased fatigue
`Increased blood
`pressure
`Palpitations
`
`Modafinil Adverse Experience
`Dosage
`
`‘
`‘ Patient
`Identifier Age Sex
` .
`Study E1027
`65
`M 200 mg QD Dyspnea”
`33
`F
`200 mg 00 Suicide“
`Study E1028
`31-
`19
`M NR
` .
`‘
`
`NR
`
`NR
`
`NR
`
`Acute delirious
`outburst
`Increased falls
`Increased hypnagogic
`hallucinations
`Increased facial
`twitches
`
`Hospitalization for
`asthma'
`
`(.0
`
`-
`
`Cephalon, Inc.
`June18. 1998
`
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`

`(
`
`.
`-
`( 7
`
`NDA 20-717
`PROVIGIL® (modafinil) Tablets: Safety Update
`
`A'W H'Msf W) T'
`
`L (
`
`Table 25. Summary of Adverse Experiences Leading to Discontinuation:
`-Sponsored Studies (continued)
` .
`
`
`
`Patient
`Modafinil
`Adverse
`Onset
`Relationship
`Stop
`
`: Identifier Age Sex Dosage
`Experience'
`'
`to Study Dru-
`
`
`Day
` .
`Study E1043/DoubIe-Blind Phase (cont)
`
`
` .
`
`75
`M NR
`Insomnia
`
`Tingling in lower
`
`
`extremities
`
`
`08
`Hyperionia
`Respiratory
`
`
`obstruction
`Tachycardia
`
`
`Instability on
`
`walking
`.
`
`Flatulence
`5
`
` .
`lg” - Study E1043I0pen-Label Phase
`602°
`‘
`M 400 mg 00 Angina pectoris
`60
` .
`
` .
`l
`Study E1044
`
`
`
`
` .
`"
`9
`M NR
`
`
` .
`Study E1047
`
`
` .
`Worsening
`8
`NR NR NR
`problem with
`
`
`attention and
`
`
`
`
`concentration
` .
`21
`Unobtrusive NR
`l
`1
`Headache
`
`
`
`
`J
`Average
`Likely
`1
`Asthenia
`
`
`
`This adverse experience also was coded as a Serious Adverse Expenence
`a:
`b: v This adverse experience was also separately reported to the Agence du Médicament as a spontaneous event outside
`of a clinical trial.
`This adverse experience resulted in death.
`c.
`Patient took 200 mg BID until onset of SAE symptoms. Dose was then reduced to 200 mg OD.
`d:
`e: Adverse experience information for this patient available as telephone contacts