`
`Discriminative Stimulus Effects In Cocaine-Trained Raxs.
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`15
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`'40
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`--
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`* Modafim'l
`fi— d-Amphetamina
`‘G— l-Ephedn’ne
`
`é
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`17
`Four rhesus monkeys were trained to self-administer cocaine
`REINFORCING EFFECTS.
`(0.02 mg/kg/infusion in 1 monkey; 0.05 mg/kg/infusion in 3 monkeys) under a fixed-ratio 10
`schedule of drug delivery. USing the standard substitution procedure, vehicle (ethanol-
`emulphor), saline, modafinil (0.03, 0.1 , and 0.3 mg/kgfinjection), d- amphetamine (0.01 or 0.03
`mg/kg/injection), and l-ephedrine (0.1 mg/kgfinfusions) were substituted for cocaine once stable
`cocaine infusions did not vary more than 20% among sessions) were obtained. The test drugs
`were substituted for four consecutive days.
`In between substitution tests, the monkeys were
`returned to cocaine baseline ‘conditions for at least 3 sessions.
`Under baseline conditions, coc‘aine (0.02, 0.05 mg/kgfinfusion) maintained rates of responding
`that was higher than that of saline vehicle in every animal (Figure 3, as copied from the
`sponsor's submission). The within session time course of cocaine infusions under baseline
`conditions are presented in Figure 4 (as copied from the sponsor's submission).
`ln 3 of the 4
`subjects, the greatest number of infusions occurred during the first quarter of the session; the
`fourth monkey, responding for cocaine was maintained at a similar rate throughout the entire
`session.
`
`administered by all 4 monkeys; and 0.1 mg/kgfinfusion modafinil was self-administered by two
`monkeys. These doses of modafinil were self-administered at rates equal to or greater than the
`rates of base-line cocaine infusions. Generally, as the dose of modafinil was increased, the
`
`In some monkeys,
`The pattern of responding maintained by modafinil is presented in figure 4.
`modafinil (0.1 and 0.3 mg/kg/infusion) self-administration was the greatest in the first 2
`quarters of the session; whereas in some monkeys it was distributed fairly evenly throughout
`' the entire one hour session.
`
`d-amphetamine and l—ephedrine maintained rates of responding higher than that of saline; that
`is, they are positive reinforcers.
`In all 3 monkeys, the mean number of d-amphetamine and
`l-ephedrine infusions were comparable to the cocaine baseline.
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`FIGURE 3.
`
`Reinforcing Effects of Modafinil in Primates.
`
`18
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`FIGURE 4.
`
`Modafinil's Pattern of Responding in Cocaine Maintained Primates.
`
`19
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`COCNNE SALNE W 0.03
`
`MOOAFINIL
`0.1
`
`MW
`i Mi:
`iii W
`
`ii
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`i L L
`
`5 §
`
`SUCCESSIVE 15-MINUTE SEGMENTS
`
`The within-session distribution of cocaine [0-02
`Figure i.
`ng/kg/infusi-‘on (111102)
`or 0.05 ng/kq/infusion (K1145, H1106.
`H1099),
`saline,- vehicle
`and
`nodat‘inil
`(0.03,
`0.1.
`0-3
`nq/kq/intusion)
`intusions for each of the 4 monkeys.
`Each bar
`represents the mean percentage of the total number of
`infusion:
`obtained during each 15-min segment of
`the last
`three 1-hour
`sessions at each condition. Bars representing cocaine infusions
`are the mean
`to:
`the last
`1 days of
`a1]. cocaine baseline
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`-.,-. --..‘ u“- mfl—u‘.u_._.n ,_....-...
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`v-
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`Study Report N9 DRR-SG-Z:
`drug self-administration.
`
`Study of the addictive properties of modafinil by intravenous
`
`20
`
`Objective:
`
`To determine if modafinil can initiate and maintain self-administration behavior
`in rats.
`
`
`
`The rats were surgically prepared with siliastic catheter (0.28 mm i.d.; 0.61 mm o.d.) under
`ether anesthesia. The external
`jugular vein was catheterized. Catheters were routed
`subcutaneously from the catherized vein and exited in the mid scapular area.
`The rats were trained to self-administer their respective training drug during daily 1-hr
`experimental sessions. Animals obtained infusions by poking their nose into the active hole
`within the operant chamber.
`During the acquisition phase (Day 1 to 11) of the study, a FR
`1 schedule of reinforcement resulted in drug delivery. During day 11 to day 10, an inter-
`session progressive ratio schedule was initiated. During this period the FR requirement for drug
`infusion was progressively increased. The progressive ratio schedule was as follows: 2 days
`(Days 11 and 12) at FR 3; 3 days (Days 13 ~16) at FR 6; and 3 days (Days 17-19) at FR 10.
`Results presented in Figure 1 and 2 have shown that in comparison to cocaine, modafinil did
`not initiate self-administration during the acquisition phase of the study. As shown in figure
`1, the number of injections significantly increased over the days and by the fifth day of
`acquisition, stable responding was observed. During the progressive ratio phase of the study,
`stable responding for modafinil was not observed.
`In contrast, as the FR value was increased
`in the cocaine group, the animals increased their responding in order to maintain a constant
`number of injections per session.
`S
`
`CONCLUSION. Modafinil did not initiate or maintain self-administration behavior in rats.
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`Study Report N‘2 ORR-9648: Study of the addictive potential of modafinil by drug-induced
`
`place conditioning.
`
`Objective:
`
`To evaluate the abuse potential of modafinil
`
`preference model.
`
`in the drug-induced place
`
`and 2.0 mg/kg). Results from this study demonstrated that in contrast to d-amphetamine,
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`In contrast to the results from Dr. Balster's laboratory, preclinical studies conducted by Dr.
`Michel LeMoal did not suggest that modafinil has abuse potential. Modafinil did not initiate
`self-administration behavior in rats nor did it induce place preference.
`It is important to point
`out that despite the negative results from these studies, the potential of abuse of modafinil
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`CLINICAL ABUSE LIABILITY ASSESSMENT
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`23
`
`Clinical Investigators:
`
`Site:
`
` .
` .
`
`Objectives:
`
`To evaluate the potential abuse liability of orally administered modafinil using
`methylphenidate as a reference agent.
`
`Male (n= 24; 30-46 years old) and female (n=12; 30-40 years old) subjects
`Subjects.
`with a history of polysubstance abuse that included cocaine.
`
`Modafinil 100 mg tablets: modafinil placebo tablets; methylphenidate
`Study Medication.
`45 mg capsules and methylphenidate placebo capsules. Patients received tablets and capsules
`during the study (combinations of 8 tablets plus 2 capsules per day).
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`SUBJECTIVE SCALE - SUBJECT RATING
`1. Addiction Research Center Inventory (ARCI )2 49 Item questionnaire contains 5 overlapping
`subscales derived from the original 102-item ARCl. Subject is instructed to select which
`5 responses best describes how he feels right now. Response for each item was scored
`as follows: (=1) 'not at all', (=2) 'maybe", (=3) 'a little', (=4)" moderately', (=5) 'an
`awful lot"
`'
`The subcales of the ARC; were:
`0 Amphetamine Scale consistin
`stimulant).
`
`
`
`
`
`
`
`
`g of 11 items that measure amphetamine~like effects (i.e.,
`
`I
`
`Benzedrine Group (86) consisting of 13 items that identify drugs with amphetamine-like
`properties.
`
`0 Morphine-Benzedrine Group (MGB) consisting of 16 items that identify drugs with
`euphoric properties.
`
`Pentobarbital-Chlorpromazine-Alcohol Gr
`drugs with sedative properties.
`LSD-Specific Group consisting of 14 items that identify drug with hallucinogenic and
`dysphoric properties.
`
`oup (PCAG) consisting of 15 items that identify
`
`0
`
`( _
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`\ ~.
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`‘-
`
`2. Drug Rating Questionnaire:
`
`A 4-item questionnaire which ask the subject if she/he:
`
`0
`
`0
`
`Feel
`
`the drug
`
`Likes the drug
`
`0 Dislikes the drug
`
`0
`Feel high
`For each item the subject was to indicate how she/he felt at the time by darkening a circle
`along a continuous line of 42 circles (equivalent to a 100-mm visual scale). The scale was
`anchored with descriptors 'not at all" and ”awful a lot'
`
`3. Drug Identification Questionnaire: This is a ten-item questionnaire where the subject is
`asked if the drug felt like that of other drugs (i.e., morphine, chlorpromazine, LSD,
`amphetamine, PCP, valium, barbiturate, etc). For each item, the subject is instructed to
`select which of 5 responses best describes how he feels right now. Response for each item
`is scores as follows; "not at all" (=1). ”maybe" (=2), '8 little' (=3), 'moderately' (=4),
`and ”an awful lot' (=5).
`
`This is a 22
`'
`4. Specific Drug Effect Questionnaire:
`-item questionnaire that ask the
`subject
`if the drug is producing certain drug effec
`ts (i.e., skin itching, sleepiness,
`nervousness, dizziness, depression, hallucinations, etc.). For each item the subject and the
`observer were instructed to select one of five responses that best described how she/he
`felt at the time of assessment. The responses were scored as follows: not at all (= 1);
`maybe (= 2); a little (= 3), moderately (= 4) and a lot (= 5).
`
`.,‘
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`C
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`SUBJECTIVE SCALES - OBSERVER RATING:
`
`25
`
`A 4-item questionnaire asks the observers if subject feel
`1. Drug Rating Questionnaire:
`the drug, likes the drug, dislikes the drug, or feel high. For each item the subject was to
`indicate how she/he felt at the time by darkening a circle along a continuous line of 42
`circles (equivalent to a 100-mm visual scale). The scale was anchored with descriptors
`“not at all" and 'awful a lot'.
`
`A 22-item questionnaire that ask the observer
`2. Specific Drug Effect Questionnaire:
`if the subject has certain drug effects (i.e., skin itching, sleepiness, nervousness, dizziness,
`depression, hallucinations, eth.
`For each item the subject and the observer were
`instructed to select one of five responses that best described how she/he felt at the time
`of assessment. The responses were scored as follows: not at all (= 1); maybe (= 2); a
`little (= 3), moderately (= 4) and a lot (= 5).
`
`OTHER MEASURES:
`
`Total estimated calories for the noon meal and evening meal.
`2. Calorie Count:
`3. Physiologic Measures: The following measures were obtained prior and following drug
`
`administration:
`
`-
`
`0
`0
`
`Pupil size
`
`Supine and standing blood pressure and pulse rate
`Body temperature
`
`' Respiratory rate
`
`4. Safety Assessments
`
`5. Adverse Events
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`C.
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`RESULTS.
`
`26
`
`On the Amphetamine (Stimulant) Subscale in the males group, maximal response for modafinil
`800 mg was observed at 1 hour, being greater than that of modafinil 200, modafinil 400 and
`placebo and a short stimulant effect is noticed within the first hour after the administration of
`800 mg of modafinil (Table 1, Fig. 1). 0n the same Scale in the female group the maximal
`responses for modafinil 200 mg and 800 mg were greater than that of placebo (Table 2, Fig.2).
`
`Table 1. Changes from baseline score for the amphetamine scale (n=24, males).
`
`
`
`FIGURE 1 .
`
`CHANGES FROM BASELINE SCORES FOR THE
`AMPI'IETAMINE SCALE (n=24, Males)
`
`
`
`MEANCHANGES
`
`FROMBASELINE
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`27
`
`
`
`CHANGES FROM BASELINE FOR THE AMPHETAMINE
`SCALE ( n=12, Females)
`
`MEANCHANGESFROMBASELINE
`
`
`
`—O—Placebo
`
`-l— ME 45 mg
`
`+ME 90 mg
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`,-—)(—MO 200 mg
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`+MO 400 mg
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`—o—MO 800 mg
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`identified as an
`On the Benzedrine (Stimulant) Subscale of the ARCl, modafinil was not
`amphetamine-like by the male subjects
`(Table 3, Fig. 3). Methylphenidate 90 mg was
`identified as a stimulant within 1 hour post-dosing.
`In contrast, the female subjects, identified
`modafinil 200 mg as a stimulant (Table 4, Fig. 4). The maximal response for modafinil 200 mg
`
`28
`
`
`MEANCHANGESFROMBASELINE
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`CHANGES FROM BASELINE SCORES FOR THE
`BENZEDRINE SCALE (n=24, Males)
`
`HOUR
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`29
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`(_
`
`FIGURE 4.
`
`CHANGES FROM BASELINE SCORES FOR THE BENZEDRINE
`SCALE (n = 12, Females)
`
`
`
`MEANSCHANGES
`
`
`FROMBASELINE
`
`i
`
`
`+ME 90 mg i
`
`
`+M0200mg:
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`modafinil 400 mg produced negative responses (Table 5, Fig.5). A dose-dependent effect for
`this measure was apparent for both methylphenidate and modafinil. As observed in the
`amphetamine scale the peak effect for modafinil 800 mg occurred within 1 hr. The response
`for modafinil 800 mg was between that of methylphenidate 45 mg and methylphenidate 90
`mg.
`In the female group.
`the response for modafinil 8
`mg was greater than both
`methylphenidate doses and modafinil 400 mg.
`(Table 6, Fig. 6). Consistent with the results
`on the Benzedrine and Amphetamine Scales, no dose-dependent pattern of effects was
`
`
`
`MEANCHANGEFROMBASELINE
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`31
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`
`
`CHANGES FROM BASELINE SCORES FOR THE MORPHINE-
`BENZEDRINE SCALE (n =12, Females)
`
`MEANCHANGESFROMBASELINE
`
`
`_,_Placebo
`
`+ME 90 mg
`
`
`
`+ME 45 mg
`
`
`
`_.__ MO 800 mg
`
`
`
`+ MO 200 mg
`
`+ MO 400 mg
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`On the Pentobarbital-Chlorpromazine-Alcohol (Sedation Scale of the ARCl), in both males and
`females the maximum responses for all doses of methylphenidate and modafinil were similar
`
`to that of placebo.
`
`32
`
`
`
`CHANGES FROM BASELINE SCORE FOR THE LSD SCALE
`(n=24, Males)
`
`MEANCHANGESFROMBASELINE
`
`HOUR
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`MEANCHANGEFROMBASELINE
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`
`
`[+Placebo
`'_._ ME 45 mg
`L1,. ME 90 mg
`§+Mo 200 mg
`§+MO 400 mg
`f.._Mo 800 mg
`
`
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`The Drug Rating Questionnaire is a 4-item questionnaire in which the subject indicates ”drug
`liking", ”drug disliking" and if 'felt the drug's effect" and whether ”felt high”. To the question
`"Feel the drug", in males, both doses of methylphenidate and the 800 mg dose of modafinil
`
`methylphenidate 45 mg and 90 mg and a dose-dependent effect was observed for modafinil
`and methylphenidate ( Fig.1 0).
`FIGURE 9.
`.
`
`MEANCHANGESFROMBASELINE
`
`_._ Placebo
`
`
`
`
`
`_._ ME 45
`
`+ ME 90
`
`
`
`—x— MO 200
`+ MO 400
`
`
`_._ MO 800
`
`FIGURE 10.
`
`CHANGES FROM BASELINE SCORE FOR DRUG RAlTlNG- "
`Feel the Drug"- (n =12. Females)
`
`14
`
`
`
`
`
`
`
`MEANCHANGESFROMBASELINE
`
`
`
`
`_._ ME 45 mg
`
`
`..._ MO 800 mg
`
`
`._°_ ME 90 mg
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`_,¢_ MO 200 mg
`
`—x— MO 400 mg
`
`
`
`
`_._ Placebo
`
`HOUR
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`35
`
`slightly higher than those of
`for modafinil 800 mg was hig
`occurred at 2.5 hours.
`
`both dose of methylphenidate (Fig. 12). The maximal response
`her than the response produced by methylphenidate 90 mg and
`
`FIGURE 1 1 .
`
`‘,
`
`CHANGES FROM BASELINE SCORE FOR DRUG RATING -' Like
`the Drug Effect- (n= 24, Males)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`+ ME 90
`
`+MO 200
`
`
`
`MEANCHANGES
`
`FROMBASELINE
`
`FIGURE 12
`
`
`_._ Placebo
`
`+ ME 45
`
`
`
`
`+ MO 400
`
`+MO 800
`
`
`
`
`
`FROMBASELINE
` MEANCHANGES
`
`
`
`
`I+MO 800 mg.
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`CHANGES FROM BASELINE SCORE FOR DRUG RAlTlNG- "
`Like the Drug Effect"- (n =12, Females)
`
`
`
`
`
`_._ Placebo
`
`
`
`+ ME 45 mg
` + ME 90 mg
`
`
`
`+ MO 400 mg
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`36
`
`FIGURE 13.
`
`CHANGES FROM BASELINE SCORE FOR DRUG RAITING-
`"Dislikg the drug effect"- (n=24, Males)
`
`FIGURE 14.
`
`CHANGES FROM BASELINE SCORE FOR DRUG RAITING-
`"Dislike the drug effect"-
`(n =12, Females)
`
`,
`
`16
`
`14
`
`12
`
`MEANCHANGES
`
`FROMBASELINE
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`‘
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`MEANCHANGESFROMBASELINE
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`+Placebo
`+ME 45 mg
`;
`+ME 90 mg
`-—x—Mo 200 mg;
`+MO 400 mg;
`
`-o—MO 800 mg 5
`
`
`
`"
`
`
`
`ORE FOR DRUG RATING-
`=12. Females)
`
` B
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`Iq—Placebo
`g—a—ME 45 mg
`+ME 90 mg
`f—x—Mo 200 mg
`S—i—MO 400 mg
`5—..M0 800 mg
`
`
`
`
`
`majority of subjects for both doses of methylphenidate and for modafinil 400 mg and 800 mg.
`17 subjects (71%) out of 24 recognized modafinil 800 mg as stimulant; 14 (58%) out of 24
`recognized modafinil 400 mg as stimulant and 10i42%) out of 24 recognized modafinil 200 mg
`
`Drug Response Questionnaire. In drug response questionnaire, male and female subjects
`reported ‘body feels different, changed',
`'nervous' and 'stomach turning" following
`administration of methylphenidate and modafinil compared to placebo. Subjects also reported
`
`methylphenidate and modafinil reduced caloric intake at the noon meal relative to placebo, and
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`39
`
`CONCLUSION.
`
`Results from this clinical study demonstrated that modafinil produced psychoactive and
`euphoric effects and feelings consistent with other scheduled CNS stimulants. Also, a gender
`difference was observed on some of the subjective measures following modafinil treatment.
`0n the Amphetamine Subscale, both males and females reported that modafinil elicited
`stimulant-like responses.
`In male subjects, modafinil produced stimulant and euphoric effects
`with a very rapid onset in a dose-dependent manner. The responses of 800 mg of modafinil
`were in general intermediate to methylphenidate 45 and 90 mg. Females reported that 200
`and 800 mg of modafinil elicited stimulant effects. The responses elicited by 200 and 800
`mg of modafinil were greater than those observed with placebo and methylphenidate 45 and
`90 mg. On the Benzedrine (Stimulant) Subscale, only the females reported that modafinil
`elicited stimulant-like effects at a dose of 200 mg. The peak time of stimulant effects were
`similar to methylphenidate (90 mg); The maximal response for modafinil (200 mg) was
`observed at 1.5 hours, while the maximal response for methylphenidate (90 mg) was 1.0 hours
`post-dosing.
`
`Results from the Pentobarbital-Chlorpromazine-Alcohol (Sedation Scale) Subscale were similar
`to those observed with placebo. Modafinil. and methylphenidate did not elicit sedative-like
`effects.
`
`Some dySphoric effects were associated with modafinil. On the Lysergic Acid Diethylamine
`(Dysphoric or Hallucinogenic) Subcale, both 800 mg of modafinil and 90 mg of
`methylphenidate produced elicited similar dose-response curves.
`
`These studies demonstrated that on subjective measures of abuse liability in male subjects,
`modafinil produced stimulant and euphoric effects with a very rapid onset in a dose -related
`manner. Also, in this group. the responses for modafinil 800 mg were in general intermediate
`to methylphenidate 45 and 90 mg. Although,
`in female subjects, no dose related effects were
`observed for modafinil 200 mg and 400 mg on subjective measures of abuse liability, modafinil
`produced stimulant and euphoric effects; and it was recognized as a stimulant by the majority
`of subjects.
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
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`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
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`
`
`
`40
`
`' dication of slight worsenin
`
`'
`
`-type withdrawal syndrome.
`daytime sleepiness, based on
`y drug,
`
`Information regarding
`vents were reported in the
`and one at 600 mg).
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`—
`
`
`
`,a.
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
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`(f)
`
`-
`
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`BEST POSSIBLE COPY
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`Table 5 .
`
`A55 in Subjects Who Discontinued Due to AEs - By COSTART Terms
`
`42
`
`
`
`Cephalon
`
`Cephalon
`
`
`
`Phase 3 DB
`Phase 1/ 2
`
`
`
`
`
`
`NERVOUS
`SYSTEM
`
`
`
`
`
`
`
`
`Nervousness
`
`
`
`
`_7 «2» M27 «12»
`
`CNS Stim
`
`Sleep
`Disorder
`
`2 (<1)
`
`BODY AS A 247 (67)
`WHOLE
`
`183 «50) 74 «40) mm 23 «4»
`
`Pain
`
`
`m 47 (13)
`
`
`n is,
`
`Aes ASSOCIATED WITH LONG TERM USE: Forty of 478 (8%) subjects discontinued due to
`AEs in the Phase 3 open label studies compared to 5% in the Phase 3 db studies. This small
`difference is likely due to the significantly longer duration of the open label trials (52 weeks vs
`9 weeks). AEs leading to discontinuation were similar in the double blind and open label
`studies.
`17 of the 478 (4%) subjects in the open label studies discontinued because of
`nervous system AEs:
`including nervousness (7 subjects), anxiety (4), depression (3) and
`
`‘
`
`'
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`
`
`cataplexy (2 subjects). Other long term studies (1 year or longer) resulted in 7 of 10 subjects
`withdrawing or being discontinued due to the following AEs: salivation disorders, restless legs,
`In another study, 319 subjects received 50 to 600 mg per day, and readjusted most commonly
`to a maintenance dose in the 100 to 300 mg/d range. Duration of treatment ranged from 1
`month to 10 years.
`81 subjects received modafinil for 1 year or greater and 37 subjects
`received modafinil for 3 years or greater. 67 Subjects reported a total of 319 A55: including
`irritability, sleep disorders, headaches, and gastric pain.
`10 Subjects withdrew for the
`following Aes: depression, gastric pain, asthenia, dyspnea, nervousness, cutaneous eruption,
`anorexia and “poor tolerance. There were 3 serious AEs: myocardial infarction, cranial trauma
`and abdominal surgery for stenosis.
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`
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