throbber
#17746 “My”. /
`Table1
`Summary of Exposure to Modafinil in Cephalon-sponsored and
`‘ Non-Cephalon-sponsored Studies
`
`Average Daily
`
`
`
`
`
`
`
`
`Cephalon-sponsored studies
`(Phase 1. 2. a; DB and CL)
`
`
`
`sponsored) studies‘
`
` Foreign (non-Cephalon-
`
`
`' gle subject (counted only once) who participated in two Cephalon-sponsored studies and was
`exposed to modaiinii 800 mg {or six days in protocol 102 (subject number 23) and to modalinll 200 mg (or 1 day in protocol 103
`(subject number 102) (or seven days of exposure at an average daily dose of 714 mg.
`1 Subject counts do not include 77 (15 + 62) exposures to modalinil for which insufficient information was available on CRF to
`unambiguously establish patient identity.
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`Ill,
`
`Conclusions
`
`Based upon our thorough review of all 1704 CRFs from subjects exposed to
`modafinil in 81 non-Cephalon-sponsored studies, we have determined that at
`
`least 1505 unique,
`
`identifiable subjects were exposed to modafinil
`
`in these
`
`studies. Adding to this the 760 unique subjects exposed to modafinil
`in
`Cephalon-sponsored studies, a total of 2265 subjects have been exposed to
`modafinil worldwide; 737 for 180 days or longer and 477 for 365 days or longer.
`
`I-47 ”
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`

`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS
`
`CLINICAL SAFETY REVIEW OF NDA RESUBMISSION
`
`MM
`
`Brand Name:
`
`Provigil
`
`Generic Name:
`
`Modafanil
`
`Sponsor:
`
`Cephalon
`
`Indication:
`
`NDA Number:
`
`Narcolepsy
`
`20-217
`
`Original Receipt Date:
`
`6/30 98
`
`Clinical Reviewers:
`
`'—
`
`Joel Freiman, M.D.
`
`"
`
`Review Completed:
`
`12/16/98
`
`- -
`
`mm
`
`7.
`
`L
`
`(,
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`1
`
`

`

` SECTION 8.0 SAFETY FINDINGS
`
`SECTION 8.1 METHODS
`
`This review of the safety of modafanil in the exposed population is centered on the
`3
`
`information provided by the sponsor in the Integrated Summary of Safety Update (NDA
`
`20-717 Resubmission June 30, 1998, Vol. 19) and a Response to FDA Request for
`
`Information, December 14, 1988. This update reviews safety from the following sources:
`
`1) OPEN—LABEL PHASE 3 CLINICAL TRIALS (C1538a/301/NA/US and
`
`C153a/3 02/NA/US combined; open-label and first extension)
`
`
`
`2) C1538a/201/AB/US (12 female subjects in phase B)
`i \
`
`3) C1538a/112PK/UK (26 male subjects)
`
`Other Sources of Safety Information: UK and Ireland Named Patient Program, Foreign
`
`Non-Cephalon-sponsored Study Results, Foreign Marketing Experience
`
`The database cut-ofi‘ date for the open-label and extensions of protocols 301and 302 is
`
`June 2, 1997. Additional information from all sources on deaths, discontinuations due to
`
`adverse experiences, and serious adverse experiences are provided through January 31,
`
`BEST POSSIBLE COPY
`
`BEST POSSIBLE COPY
`
`2
`
`

`

`1998 fi'om non—queried case report forms. A teleconference was conducted with the
`
`sponsor on November 17, 1998. The sponsor clarified the term ‘non-queried’ to mean
`
`that there is a complete accounting for all deaths, discontinuations and serious adverse
`
`experiences through January 31, 1998, however, complete verification and entry into the
`
`sponsor’s electronic database has not yet been completed.
`
`T's
`Narrative sumrriaries of new deaths and new adverse events leading to discontinuation
`
`were reviewed. Many of the tabular summaries were examined in their entirety.
`
`SECTION 8.2.SERIOUS ADVERSE EVENTS:
`
`SECTION 8.2.1
`
`DEATHS:
`
`One death occurred during extended open-label treatment in Study 302 (pat #1904). A
`
`38-year old man, who was receiving 400 mg/day of modafanil, died of a broken neck as a
`
`result of a snowmobile accident. This accident was assessed by the investigator as being
`
`possibly related to study medication. The sponsor provided the following explanation as
`
`to why the investigator attributed this death as possibly related to study drug
`
`(teleconference Nov. 17). At the time that the investigator was informed of the death, the
`
`investigator was not aware that a snowmobiling accident had occurred, only that the
`
`patient had died.
`
`No deaths were reported among subjects in study 201.
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`3
`
`

`

`No deaths were reported among subjects in study 112.
`
`SECTION 8.2.2
`
`NON-FATAL SERIOUS ADVERSE EVENTS:
`
`Fifty subjects reported SAE’s in open-label phase 3 clinical trials 301 and 302. Twenty-
`seven representfiipreviously unreported adverse experiences. Among the 27 previously
`
`unreported SAE’s 12 occurred after the database cutOff date. Each subject who had a
`
`serious adverse experience is listed in V0]. 19, Table 9, pp. 46-48 (Attachment 1). None
`
`of the experiences were considered probably related or related to study drug. There was
`
`no discernible pattern to the adverse experiences. Patient narratives are not provided for
`
`Q .
`
`subjects with SAE’s that did not also discontinue study medication.
`
`No serious or potentially serious adverse experiences were reported among subjects in
`
`study 201 .
`
`No serious adverse experiences were reported among subjects in study 112.
`
`SECTION 8.3 ASSESSMENT OF DROPOUTS:
`
`SECTION 8.3.1
`
`MODAFANIL EXPOSURE
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`4
`
`

`

`40-week and 48-week phase results are presented.
`
`A total of 209 patients had reached open-label extension week-48 by the data cut-01f
`3,
`date. Overall, 13% ofpatients discontinued due to lack ofstudy medication efficacy, 10%
`
`ofpatients discontinued due to adverse experiences. A complete accounting ofpatient
`
`disposition is presented in Vol. 19, Table 1, p. 33 (Attachment 2).
`
`Overall treatment exposure by average daily dose is presented in Vol. 19, Table 2, p. 34
`
`(
`
`(Attachment 3). Among the 478 patients studied the mean modafanil exposure was 419
`days, with an average dose of 305 mg/day, (V01. 19, Table 3, p 35).
`
`A total of 12 women with histories ofpolysiibstance abuse received one dose each of
`
`placebo, methylphenidate 45 mg and 90 mg, and modafanil 200 mg, 400 mg and 800 mg
`
`in study 201 .
`
`A total of 26 healthy men were enrolled in study 112 to examine the single-dose
`
`pharmacokinetics ofmodafanil 200 mg, and dexamphetamine 10 mg when given alone or
`
`in combination.
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`_*
`
`5
`
`

`

`SECTION 8.3.2
`
`NEW ADVERSE EXPERIENCES RESULTING IN PATIENT
`
`DISCONTINUATION
`
`The sponsor’s Vol. 19, Table 8, pp. 42-44 (Attachment 4) presents a summary of adverse
`
`experiences leading to discontinuation in open-label studies 301 and 302. New adverse
`
`experiences that resulted in discontinuation from study that were not previously reported
`1;
`in the double-blind or open-label phases of 301 and 302 include the following:
`
`1) Anemia, endometrial carcinoma, leukopenia with liver enzyme elevations,
`
`mood change, pruritis, somnolence and goiter occurred in one patient each.
`
`2) Congestive heart failure and cardiomegaly occurred in the same patient.
`
`3) Four unintended pregnancies; one patient used oral contraceptives alone, one
`
`patient used barrier method alone, one patient used both barrier and oral
`
`contraceptive methods, and one patient discontinued medroxyprogesterone3
`
`acetate injections 502 days prior to becoming aware that she was pregnant.
`
`4) Two patients experienced an increase in cataplexy
`
`Review of the narrative summaries did not reveal any to be clearly related to the study
`
`drug with the exception of the patient who became pregnant while on oral contraceptives
`
`alone. Proposed modafanil labeling notes that the effectiveness of steroidal
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`6
`
`

`

`contraceptives may be reduced with modafanil. The patient with elevated liver enzymes
`
`and leukopenia was judged by the investigator to be possibly related to modafanil and
`
`this case is presented in greater detail.
`
`A 39-year old (patient number 1202) had been diagnosed with narcolepsy for 1 year. In
`
`the double-blind phase he received placebo. In the open-label phase he received
`modafanil 100 (in 200 mg/day for 373 days. His only concomitant medication was ASA.
`
`Beginning on day 290 the patient was noted to have the following liver enzyme and
`
`hematologic abnormalities ALT 214 IU/L, AST 124 IU/L, GGT 100 IU/L, WBC 8.3 (
`
`37.9% neutrophils and 49.4 % lymphocytes). The patient last received study medication
`
`on day 373 because of persistent abnormalities and was discontinued from the study on
`
`day 388. The patient was seen in consultation by a hematologist on 3/ 19/96 and again
`
`3/25/96. The consultation note stated that the patient reported no history of alcohol abuse
`
`or any history of exposure to risk factors for viral hepatitis. The patient was felt to have a
`
`relative lymphocytosis, and elevated liver eiizymes which could be explained by the
`
`medication. No further follow-up is provided.
`
`SELECTED LFT”S (PATIENT 1202)
`
`AST (IU/L)
`
`ALT (IU/L)
`
`GGT (IU/L)
`
`Ref. (6-37)
`
`Ref. (8-48)
`
`Ref. (31-121)
`
`2/11/95
`
`
`
`Alk.Phos(IU/L)
`
`
`
`
` 0L baseline
`
`
`1 1/30/95
`
`
`
`
`day 290
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`7
`
`

`

`day 365
`
`3/7/96
`
`2/13/96
`
`day 388
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`
`
`8
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`
`

`

`SELECTED HEMATOLOGY (PATIENT 1202)
`
`WBC (X10E3/UL)
`
`Neutrophils (%)
`
`Lymphs (%)
`
`Ref. (4.1-12.3)
`
`Ref. (40.9 — 77%)
`
`Ref. (15.5 — 46.6%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`No subjects discontinued from study 201 due to adverse experience.
`
`One subject in study 1 12 discontinued due to syncope. This event occurred at visit one
`
`upon intravenous canulation prior to the administration of any study drug.
`
`SECTION 8.4 OTHER ADVERSE EVENTS
`
`Open-label emergent adverse experiences that were experienced by at least 5% of the
`
`safety population in any dosage group are summarized by the sponsor in Vol. 19, Table 6,
`
`p. 38 (Attachment 5). Most open-label emergent experiences did not appear to be dose-
`
`related. Mild to moderate headache was the most common adverse experience.
`
`Open-label adverse experiences that were drug related are presented in Vol. 19, Table 7,
`
`p. 40 (Attachment 6). Drug—related adverse experiences were greatest for the 200 mg/day
`
`APPEARS THIS WAY 0N ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`9
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`

`

`group, 45% verses 8% and 19% for the 400 mg/day and 300 mg/day groups respectively.
`
`Nervousness and anxiety were more frequent in the 200 mg/day group.
`
`The reporting of new adverse experiences decreased across time among all dosage groups
`
`(Vol. 19, Table 3.2.0, p. 212).
`
`3
`Among the 12 female subjects in study 201 the majority of adverse experiences were
`
`mild to moderate in severity (V01. 33, Appendix 4.0, Table 9.1B, pp. 4679-4695).
`
`Among the 26 subjects in study 112 the majority of adverse experiences were mild to
`
`moderate in severity (V01. 34, Appendix 5.0, Table 9.1 pp. 5139-5142).
`
`SECTION 8.5 OTHER SAFETY FINDINGS:
`
`SECTION 8.5.1
`
`CLINICAL LABORATORY EVALUATIONS
`
`The laboratory database for studies 30land 302 consists of values for laboratory tests at
`
`baseline, at each of the study visits, and at endpoint.
`
`SECTION 8.5.1.1
`
`CLINICAL CHEMISTRY - Liver
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`10
`
`

`

`Descriptive statistics and changes from baseline for blood chemistry parameters are
`
`summarized in Vol. 19, Tables 4.0.0 and 4.0.1, pp. 289-378 (studies 301 and 302). Shift
`
`tables for blood chemistry are found in Vol. 20, Tables 4.0.2, and 4.0.3, pp. 379-420.
`
`No clinically important mean values or changes from baseline in AST, ALT, total
`
`protein, albumin, or total bilirubin occurred at any ofthe visits for any of the treatment
`5.
`1
`
`groups.
`
`None ofthe mean alkaline phosphatase values were clinically important at any visit.
`
`However alkaline phosphatase showed gradual increases from baseline through week 88
`
`in a dose dependent manner (V01. 19, Table 10, p. 50).
`
`None of the mean GGT values were clinically important at any visit. However, GGT
`
`showed gradual increases from baseline at each visit in a dose dependent manner (V01.
`
`19, Table 1 1,9 p. 51, and Attachment 7). While none ofthe mean values were clinically
`
`significant at any visit, twelve subjects had clinically significant values (V01. 23, Listing
`
`4.0.0, pp. 1318-1438).
`
`At the request ofthe FDA the sponsor has provided additional information on patients in
`
`which the GGT test was clinically significantly elevated. This additional information is
`
`contained in a Response to FDA Request for Information dated December 14, 1998.
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`BEST POSSIBLE COPY
`
`ll
`
`BEST POSSIBLE COPY
`
`

`

`Among the 12 patients with clinically significant elevations of GGT, 7 patients
`
`experienced transient elevations which either normalized completely (2 patients) or
`
`partially normalized (5 patients). These seven complete or partial resolutions occurred in
`
`the setting of continued treatment (3 patients), discontinuation of treatment (2 patients),
`
`and dose reduction (2 patients). None of the patients with clinically significant elevations
`
`of GGT had concomitant clinically significant elevations of total bilirubin.
`s
`.
`'1
`
`Among the 12 patients with clinically significant elevations of GGT, 5 patients still had
`
`clinically significant elevations at endpoint. Endpoint refers to the last reported value in
`
`the 6/2/97 database.
`
`Two patients (301/ 1306; 301/1719), experienced non progressive clinically significant
`
`open-label endpoint elevations in the setting of clinically significant GGT elevation at
`
`double-blind baseline (patient 1306 baseline GGT 182 IU/L, open-label day 677 GGT
`
`239 IU/L; patient 1719 baseline GGT 230111/L, open-label day 633 212 IU/L). Both of
`
`these patients remained on modafanil 300 mg/day during open-label treatment.
`
`Two patients (301/2114; 302/1505) experienced resolving clinically significant elevations
`
`of GGT in the setting of elevated GGT at double-blind baseline. Patient 2114, a 36 year-
`
`old woman, had a double-blind baseline GGT of 151 lU/L. During treatment with
`
`modafanil 400 mg/day the maximal GGT was 464 IU/L at day 66. During open-label
`
`treatment (modafanil 400 mg/day), clinically significant elevations of GGT persisted to a
`
`maximum value of 447 IU/L at open-label day 109. In the setting of continued treatment
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`12
`
`

`

`(
`A
`
`with dosage reduction the last reported GGT was 267 IU/L on day 267. The patient did
`not elect to continue fiu'ther open-label u'eaunent. Patient 1505, a 60 year-old woman
`had a double-blind baseline GGT of 152 IU/L. During the double-blind treatment
`
`(modafanil 400 mg/day) the patient had persistent though stable GGT elevations. During
`
`open-label treatment (modafanil 300 mg/day) the maximal GGT value was 360 IU/L at
`
`day 286. At thelendpoint observation (open-label day 628) the GTT was 267 IU/L
`s
`occurring in the1 setting of dose reduction and discontinuation.
`
`One patient experienced a new—onset elevation off GGT to a maximum value of 259
`
`IU/L at open label treatment day 115.
`
`( -.
`
`Among subjects in study 201 no clinically significant values are noted during the
`treatment period (V01. 33, Appendix 4, Table 11.2B, pp. 4729-4760).
`
`Among subjects in study 112, no clinically significant values are noted during the
`
`treatment period (V01. 34, Appendix 5.0, Listing 7.3 pp. 5010-5035).
`
`SECTION 8.5.1.2
`
`CLINICAL CHEMISTRY - Kidney
`
`Among subjects in studies 301 and 302, no clinically important mean values or changes
`
`from baseline in kidney fimction tests (BUN, creatinine, uric acid) occurred at any ofthe
`
`visits.
`
`13
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`,,
`
`

`

`There were no clinically meaningful trends in the number of patients with shifis to values
`
`above ULN for kidney function tests.
`
`There was no pattern of increased frequency across study weeks, or apparent dose-related
`
`effects of the number of patients with clinically significantly abnormal values for BUN,
`
`creatinine, and uric acid (V01. 20, Table 4.0.3, pp. 408-420).
`
`F1
`
`Among 12 subjects in study 201 no clinically significant values are noted during the
`
`treatment period (V01. 33, Appendix 4, Table 11.28, pp. 4729—4760).
`
`Among subjects in study 112, no clinically significant values are noted during the
`
`treatment period (V01. 34, Appendix 5.0, Listing 7.3 pp. 5010-5035).
`
`SECTION 8.5.1.3
`
`CLINICAL CHEMISTRY — Electrolytes
`
`Among subjects in studies 301 and 302, no clinically important mean values or changes
`
`from baseline in any of the electrolyte tests, or cholesterol and glucose occurred at any of
`
`the visits or any of the mean dose groups.
`
`No clinically meaningful trends were apparent in the percentage of patients with shifts to
`
`values outside the normal limits for chloride, potassium, sodium, bicarbonate, calcium,
`
`phosphorus, or cholesterol and glucose.
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`14
`
`

`

`There was no pattern of increased frequency across study weeks, or apparent dose-related
`
`effects in the number of patients with clinically significantly abnormal values for
`
`chloride, potassium, sodium, bicarbonate, calcium, phosphorus, or cholesterol and
`
`glucose (V01. 20, Table4.0.3, pp. 408-420).
`
`Among 12 female subjects in study 201 no clinically significant values are noted during
`5.
`the treatment period (V01. 33, Appendix 4, Table 11.2B, pp. 4729-4760).
`
`Among subjects in study 112, no clinically significant values are noted during the
`
`treatment period (V01. 34, Appendix 5.0, Listing 7.3 pp. 5010-5035).
`
`SECTION 8.5.1.4
`
`CLINICAL CHEMISTRY — Hematology
`
`Descriptive statistics and changes from baseline forhematology parameters are
`
`summarized in Vol. 20, Tables 4.1.0 and 4.111, pp. 421-470 (studies 301 and 302). Shift
`
`tables for hematology values are summarized in Vol. 20, Table 4.1.3, pp487-493).
`
`No Clinically important mean values or consistent increases or decreases in WBC count,
`
`eosinophils, monocytes, or basophils occurred at any of the visits for any of the mean
`
`groups.
`
`None of the mean lympocyte or neutrophil percentages were clinically important at any
`
`visit.
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`IS
`
`

`

`No clinically important trends were apparent in the mean percentage of patients with
`
`shifts to values above or below the normal limits for WBC count or the percentages of
`
`neutrophils, lyphocytes, monocytes, basophils, or eosinophils.
`
`There was no pattern of increased frequency across study weeks, or apparent dose-related
`1
`effects in the ndmber of patients with clinically significant abnormal values for
`
`hemoglobin, hematoctrit, red blood cell count, white blood cell count, or the percent
`
`neutrophils, lyphocytes, eosinophils and basophils.
`
`Among 12 female subjects in study 201, two subjects had clinically significant monocyte
`
`counts of 17 and 15 percent (Vol. 19, Table 18, p. 63)
`
`Among 26 subjects in study 112, fifteen subjects had low lymphocyte counts during one
`
`or more treatment periods (V01. 34, Appendix 5.0, Listing 7.2, pp. 4984-5009).
`
`SECTION 8.5.1.5 CLINICAL CHEMISTRY — Urinalysis
`
`'
`
`'3
`
`Descriptive statistics and changes from baseline for urinalysis parameters are summarized
`
`in Vol. 20, Tables 4.2.0.A, 4.2.0B, and 4.2.1, pp. 494-520. Shift Tables for urinalysis are
`
`found in Vol. 20, Table 4.2.2 and clinically significantly abnormal values are summarized
`
`in Table 4.2.3.
`
`16
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`4_____————
`
`

`

`Among 12 female subjects in study 201, no clinically significant values are noted during
`the treatment period (Vol. 33, Appendix 4, Table 11.3B, pp. 4761-4786).
`
`Among 26 male subjects in study 112, no clinically significant values are noted. Results
`
`of screening urinalysis and mine pH at visits 1, 2, and 3 are presented in Vol. 34,
`
`Appendix 5.0, Listings 7.4 and 7.5 respectively.
`
`t1
`
`SECTION 8.5.2 .
`
`VITAL SIGNS:
`
`SECTION 8.5.2.1
`
`.VITAL SIGNS — Blood Pressure
`
`Among subjects in studies 301 and 302, no clinically important mean values or mean
`
`changes from baseline in any of the blood pressure measurements occurred at any ofthe
`
`visits.
`
`There were no clinically meaningful trends in the number ofpatients with clinically
`
`significant blood pressure measurements (V01. 20, Table 5.0.0).
`
`Among 12 female subjects in study 201, both methylphenadate and modafanil produced
`
`increases compared to placebo in supine and standing systolic and diastolic blood
`
`pressure as evidenced by increases in the AUC for change from 0 to 6 hours and
`
`maximum response within 6 hours ofdosing (Vol. 33, Appendix 4.0, Tables 8.3.1B,
`
`8.4. 13, 8.7.1, and 8.8.1B). Graphical presentations ofmean changes in blood pressure
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`17
`
`

`

`are presented in Appendix 4.0, Figures 3.3B, 3.4B, 3.7B, and 3.8B. These blood pressure
`
`increases were not clinically meaningful.
`
`Among 26 subjects in study 112, small increases in systolic and diastolic blood pressure
`
`were observed following administration of all three treatments (Appendix 5.0, Graphs 1,
`
`and 2).
`
`SECTION 8.5.2.2
`
`VITAL SIGNS — Pulse
`
`Among subjects in studies 301 and 302, no clinically important mean values or mean
`
`changes from baseline in any of the pulse or body temperature measurements occurred at
`
`any of the visits
`
`There were no clinically meaningful trends in the number of patients with clinically
`
`significant pulse or body temperature measurements (V01. 20, Table 5.0.0).
`
`Among 12 subjects in study 201, increases in the AUC of the change in standing and
`
`supine pulse rate compared to placebo were observed for all active doses except
`
`modafani1200 mg (Vol. 33, Appendix 4.0, Tables 8.5.1B, 8.9.1B and 8.9.2B).
`
`BEST POSSIBLE COPY
`
`Among 26 subjects in study 112, small increases in pulse were observed following
`
`administration of all three treatments (V01. 34, Appendix 5.0, and Graph 3).
`
`18
`
`BEST POSSIBLE COPY
`
`

`

`
`
`SECTION 8.5.3
`
`BODY WEIGHT:
`
`Among subjects in studies 301 and 302, there were no clinically meaningful mean weight
`
`values or mean change for patients. However, average body weight decreased with
`
`modafanil treatment by l to 3 pounds in a dose-related fashion, from open-label baseline
`
`to week 48 across the study period.
`3.
`l
`
`There were no clinically meaningful trends in the number of patients with clinically
`
`significant body weight changes from open-label baseline (V01. 20, Table5.0.0).
`
`SECTION 8.5.4
`
`ECG:
`
`Among subjects in studies 301 and 302, ECG status by visit, including shifts and
`
`frequency of clinically significant abnormal values are shown in Vol. 20, Table 6.0.0.
`
`Treatment with modafanil was not systematically associated with clinically meaningful
`
`ECG abnormalities. All recorded ECG abnormalities including those judged by the
`
`investigator to be not clinically significant were reviewed and no treatment-dependent
`
`pattern of abnormalities was found.
`
`No clinically meaningful trends were apparent in the number of patients with shifts from
`
`normal to abnormal for ECGs. There were no clinically meaningful trends in the number
`
`of patients with clinically significant ECG values (Table 6.0.0).
`
`19
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`

`

`Among 12 subjects in study 201, no clinically significant changes in ECGs were
`
`observed.
`
`Among 26 subjects in study 112, no clinically significant ECG changes were observed
`
`(V01. 34, Appendix 5.0, Listing 5.3, pp. 4932-4956).
`5,
`I
`
`9.0 ADDITIONAL STUDIES WITH SAFETY INFORMATION
`
`9.1 Cephalon Named Patient Program in the UK and Ireland
`
`As of 1/31/98 64 patients had started treatment with modafanil, 39 of who were
`
`continuing. Ten patients discontinued due to adverse experiences, two (both with
`
`worsening cataplexy) of which were serious. No deaths occurred. Patients who
`
`discontinued due to an adverse experience are summarized in (V01. 19, Table 22, p. 73
`
`and Attachment 8). Four ofthe 10 discontiriuations were due to worsening ofcataplexy;
`
`all were judged possibly or probably related to study drug. Case report forms were not
`
`used in this compassionate use program.
`
`9.2 Studies Conducted in Canada
`
`Five studies and one compassionate use program were ongoing or were initiated in
`
`Canada since the cut-off date for inclusion in the modafanil NDA-20-717.
`
`9.2.1
`
`Study 94003
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`20
`
`

`

`No deaths or serious adverse experiences were reported during the conduct of this study.
`
`Three patients discontinued due to adverse experiences and are summarized in Vol. 1
`
`9, Table 23, p. 74, and Attachment 9) Of note a 49 y/o patient taking modafanil 400
`
`mg/day had repetitive movements which were severe and felt probably related to study
`
`drug.
`
`9.2.2
`
`Special Access Program
`
`There were no deaths or serious adverse experiences reported during the Canadian
`
`compassionate use program. There were nine discontinuations due to adverse experiences
`
`which are summarized in Vol. 19, Table 24, p. 75 (Attachment 10). Of note two subjects
`
`reported palpitations and a third reported increased leg movements. Case report forms
`
`were not consistently used in this compassionate use program and are not provided.
`
`9.2.3 Military Studies in Canada
`
`There were no deaths or serious adverse experiences reported in four Canadian military
`
`studies.
`
`9.3 Studies Conducted by-
` .
`
`9.3.1 Discontinuations Due to Adverse Experiences Since NDA Filling
`
`Twenty-two subjects discontinued due to adverse experiences in a series of six studies
`conductedby” which are summarized in Vol. 19, Table 25, pp. 76-
` .
` .---------------------
`
`77 (Attachment 11). Two subjects had palpitations one of which also had increased blood
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`21
`
`

`

`pressure, and a third subject is reported to have had tachycardia. In addition, one subject
`
`is reported to have discontinued due to increased facial twitches.
`
`9.3.2 Serious Adverse Experiences Since NDA Filling
`
`Nine subjects had serious adverse experiences in a series of four studies conducted by
`
`— which are summarized in Vol. 19, Table 26, p. 78 and Attachment
` .
`5
`‘
`
`12).
`
`9.3.3 Serious Adverse Experiences and Discontinuations Due to Adverse Experiences
`
`Not Previously Reported in NDA 20-717.
`
`Five subjects with limited presentation in NDA 20-717 are summarized in Vol. 19, Table
`
`27, p. 79 (Attachment 13). Of note one patient each is reported to have experienced one
`
`of the following, mannerisms, myoclonic movements, automatisirns, and choreiforrn
`
`movements.
`
`Twelve subjects with potentially serious adverse experiences and not presented in NDA
`
`20-717 are summarized in Vol. 19, Table 28, p. 80 (Attachment 14). Only one patient
`
`among these twelve patients is known to have discontinued from study due to an adverse
`
`experience. A narrative for this patient was reviewed, however narratives are not
`
`provided for the patients who did not discontinue fiom study. Of note one patient each is
`
`reported to have experienced one of the following; clonic movements, movement
`
`disorder, dyskinesia, extrapyramidal syndrome, and tics.
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`22
`
`

`

`9.4 Foreign Post-Marketing Experience
`
`Five patients with serious adverse experiences are reported in Vol. 19, Table 29, p. 82
`(Attachment 15). Ofnote, one patient experienced anaphylactic shock on the first
`
`treatment day.
`
`9.4.1 Non-Sez'ious Adverse Experiences Reported Outside ofClinical Trials
`Forty-nine repdrts occurring outside of_sponsored clinical trials have been
` ., .
`
`documented. Adverse experiences that were considered possibly related, likely related, or
`
`very likely related to modafanil treatment were rash, sweating, pruritis, headache,
`
`agitation, anorexia, nervousness, and tacycardia.
`
`in a Response to FDA Request for information dated December 14, 1988. A review ofthe
`
`response follows. The review concentrates on the “dyskinesia” adverse events. The
`
`incidence of dyskinesia adverse events was 2% in the Cephalon sponsored US 9-week
`
`placebo-controlled trials with modafanil.
`
`BEST POSSIBLE COPY
`
`BEST POSSIBLE COPY
`
`

`

`dyskinesia, dystonis, extrapyramidal syndrome, hyperkinesia, hypertonia, hypokinesia,
`
`hypotonia, movement disorder, myoclonus, neck rigid, tremor, and twitch.
`
`The sponsor organized the review into the following sections:
`
`0 Serious Adverse Events Associated with “Movement Disorders”
`
`0 Discontinuation Associated with “Movement Disorders”
`0 Tremor (vei'batum terms such as tremulousness, hand tremors, etc.)
`
`o Hypertonia (verbatum terms such as jaw cleching, muscle spasm, etc.)
`
`o Dyskinesia (verbatum terms such as dyskinesia bucco-facial, abnormal movements,
`
`abrupt movements, involuntary tongue movement, etc.)
`
`- Hyperkinesia (vebaturn terms such as hyperactivity, restless legs, increased kinetic
`
`movement, etc.)
`
`0 Movement Disorders with < 1% Frequency in Modafanil Treated Subjects
`
`(hypokinesia, neck rigid, twitch, movement disorder, hypotonia, Akathisia,
`
`choreoatheosis, myoclonus, dystonia, and extrapyramidal syndrome)
`
`Results
`
`A total of 198 unique subjects among 2277 unique modafanil treated subjects (9%)
`
`experienced 250 events related to these terms verses 15 of 521 placebo subjects (3%)
`
`who experienced such events.
`
`There were a total of 67 modafanil treated patients who experienced 84 events of tremor.
`
`A total of 39 modafanil treated patients experienced 58 events of hypertonia. A total of
`
`I‘.\
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`24
`
`

`

`28 modafanil treated patients experienced 29 events of hyperkinesia. There were 43
`
`modafanil treated subjects who experienced 53 movement disorder adverse events.
`
`Serious Adverse Events Associated with “Movement Disorders”
`
`There was 1 “movement disorder” SAE in l modafanil treated subject in the Cephalon
`
`sponsored (CS) phase 3 trials and 2 movement disorder SAEs in 1 subject in the foreign,
`3
`non Cephalon sponsored trials (FNC).
`
`The SAE in the CS study involved severe “lower back muscle spasm” in a 60 year-old
`
`man related to lifting a lawnmower. The SAE in the FNC involved the accidental
`
`overdose (1200 mg of modafanil) in a' 15 year-old girl. She experienced 2 dyskinesia
`
`SAEs (COSTART verbatim terms “motoric crawling” and “abrupt movements”) of
`
`unknown severity. She was hospitalized and modafanil treatment discontinued. From the
`
`narrative it appears that the SAE resolved after one day.
`
`Discontinuations Associated with “Movement Disorders”
`
`There were 2 movement disorder discontinuations in the CS phase 3 studies and 1 in the
`
`CS phase 1-2 studies. One patient in the phase 3 studies experienced moderate muscle
`
`tension coded as hypertonia, the other patient experienced mild tremor. A 35 year-old
`
`man discontinued from the CS phase 1-2 study while receiving modafanil 400 mg b.i.d
`
`on day 9. The patient experienced hyperkinetic movements of the fingers (hyperkinesia),
`
`finger tapping, constant chewing motion of the jaw with throat clearing, and “tight body
`
`25
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`
`

`

`feeling” (hypertonia). These symptoms lasted 1.5 hours and the patient discontinued
`
`modafanil.
`
`There were 12 movement disorder discontinuations in the FNC studies. The events
`
`included tremor (2 subjects), akathisia (1 subject), hyperkinesia (4 subjects), dyskinesia
`
`(5 subjects).
`
`.
`
`i
`
`The 5 modafanil treated subjects who discontinued for adverse event coding to dyskinesia
`
`are summarized.
`
`0 An 82 year-old man experienced severe abrubt movements on day 2 while receiving
`
`modafanil 150 mg b.i.d. All events were continuing at the time of discontinuation.
`
`o A 36 year-old woman with a history of schizophrenia experienced sterotypic
`
`movements on day 5 while receiving modafanil 200 mg b.i.d. The AB was ongoing at
`
`the time of modafanil discontinuation.
`
`0 A 72 year-old man had 2 episodes of inCco-facial dyskinesia while receiving
`
`modafanil 300 mg/day. The first episode began at day 54. Modafanil treatment was
`
`interupted for 15 days. The patient had a subsequent episode on after re-starting
`
`modafanil (days to onset not provided).
`
`0 A 73 year-old woman experienced bucco-facial dyskinesia after three months of
`
`modafanil therapy (further information not available).
`
`0 A 15 year-old girl experienced motoric crawling and abrubt movements and was
`
`previously described.
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`26
`
`

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket