`
`
`
`
`
`
`
` Heart failure, Pain, Kidney
`Function Abnormality,
`flatulence
`
`
`'
`
`Asthenia'
`
`Table II.
`
`Deaths: All studies.
`
`'5
`
`...........
`.-\-
`m... m
`
`82wF(”two") “-
`
`65 yrs F (major
`depressive episode)
`
`68 yrs F (Age assoc.
`Memory impairment
`
`58 yrs M (major
`depressive episode)
`
`' Database indicated asthenia at cause of
`“ Narrative indicated that “advanced cirrhosis of liver could be totally responsible for
`outcome.‘
`
` Effects of discontinuation from
`modafinil were assessed in a pivotal efficacy and safety study, wherein patients were taken off drug
`during a 2-week period before start of an open label extension period. Frequency of new AE's was
`comparable between subjects discontinued from placebo. 200 mg/day modafinil, and 400 mg/day
`modafinil. Patients who completed the 9 week double-blind phase, or who terminated for reasons
`other than noncompliance or a medication related adverse event, then participated in a 2-week double-
`blind withdrawal phase before entering the open label phase. Patients were randomized to a
`withdrawal period as follows: 20% in the 400 mglday group; and 20% in the 200 mg/day group.
`
`The Adverse Event profile for the withdrawal phase was not significantly different for patients who
`were withdrawn from modafinil treatment compared to those who continued to receive placebo. There
`was no specific evidence of an amphetamine-type withdrawal syndrome; however since approximately
`80% of the subjects were receiving concomitant CNS active medications (including other stimulants),
`the significance of this data is questionable.
`
`Effects of discontinuation from modafinil were also assessed in Parkinson's disease patients and normal
`subjects. As seen in the pivotal efficacy and safety studies, no withdrawal syndrome was associated
`with modafinil. Parkinson's disease patients treated with 200 or 300 mg/d of modafinil for 21 days
`experienced no withdrawal symptoms during a 7-day observation period. Likewise, normal wbiects
`treated with 200 to 1000 mg of modafinil for 7 days were observed during a withdrawal period of 3
`days. The only AE possibly possin related to withdrawal was occurrence of drowsiness in 718
`patients who completed dosing in the 1000 mg/day group.
`
`The body system with the greatest number of adverse events was the CNS with 16 likely/possible.
`Eight of these 16 costart terms were either nervousness/anxietylagitation. The body system with the
`next most frequent mention was the gastrointestinal system, with nine likely/possible, four of these
`nine being dry mouth. The systems in diminishing order of frequency follow: cardiovascular with six
`events (four of the six being tachycardia); dermatologic with four events (all four being rashes of
`various sorts): endocrine/metabolic with four events: musculoskeletal with three events: and various
`miscellaneous events comprising five events (including two cases of increased sweating).
`
`WHO Adverse Reactions database up to July 1997, was reviewed as well. There appeared to be no
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`discernible pattern of events from this database and causation was difficult to establish. The only
`“new“ events listed that were not in the clinical study database included urinary incontinence,
`dyskinesia, m'alaise. hypertension, and tinnitus.
`
`Table III. AEs in Subjects Leading to Discontinuation from Study - By COSTART Terms
`
`
`
`
`CLINICAL STUDIES
`
`
`
`Modafinil (N = 2305)
`
`Placebo (N = ‘I 050)
`
`m «78 «7-7»
`
`37 «3-5)
`
`
`
`
`
`
`
` Anxiety222.222.2222 E
`
`IBE-
`
`
`CNS Stimulation
`
`Sleep Disorder
`22222222222222
`
`63 (2 7)
`22222.2, m
`402 «17-4)
`222.2,
`
`-«
`DIGESTIVE
`403 (1 7 5)
`1 03 (9.8)
`122 (2.4, m
`—m 7 «0-67»
`72 (2.2»
`Im—
`
`
`
`
`W. The most commonly observed AE's in modafinil-
`treated subjects (not seen at an equivalent incidence in placebo-treated subjects) were: headache.
`nausea, diarrhea. dry mouth, anorexia, nervousness. dizziness, rhinitis, and pharyngitis (See Table III,
`above). The most frequent A55 in modafinil-treated subjects compared to subiects on placebo were
`headache and nausea. AEs of clinical concern that resulted in discontinuation from study were
`primarily cardiovascular-related.
`
`(.2
`
`Wm Forty of 478 (8%) subjects dISCONtim-led
`due to AE's in the Phase 3 open label studies compared to 5% in the Phase 3 double blind studies.
`This small difference is likely due to the significantly longer duration of the open label trials (52 weeks
`vs. 9 weeks). AE's leading to discontinuation were similar in the double blind and open label studies.
`Seventeen of the 478 (4%) subjects in the open label studies discontinued because of development of
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`10
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`including nervousness (7 subjects), anxiety (4), depression (3) and cataplexy (2
`nervous system AEs:
`subjects). Other long term studies (1 year or longer) resulted in seven of ten subjects withdrawing or
`foeing discontinued due to the following AEs: salivation disorders, restless legs, nausea, anxiety and
`'internal tension.‘
`
`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/day range. Duration of treatment ranged from one month to
`.\ ten years. Eighty-one subjects received modafinil for 1 year or longer and 37 subjects received
`modafinil for at least 3 years. Sixty-seven subjects reported a total of 319 AEs: including irritability,
`sleep disorders, headaches, and gastric pain. Ten subjects withdrew because of the following AE’s:
`depression, gastric pain, asthenia, dyspnea, nervousness, cutaneous eruption, anorexia and ‘poor
`tolerance.‘ There were three serious AEs: myocardial infarction, cranial trauma and abdominal surgery
`for stenosis.
`
`"
`
`W The potential abuse liability of orally administered modafinil
`using methylphenidate as a reference agent was evaluated in a double-blind, placebo-controlled, 6x 6
`Latin square crossover, inpatient study. Each drug evaluation session was separated by two washout
`days. Doses were chosen on the basis of the results of a dose ranging study. Each subject received
`two doses of methylphenidate (45 mg and 90 mg), three doses of modafinil ( 200, 400 and 800 mg),
`and placebo in a randomized, double-blind manner. The study was conducted in male (n= 24; 30-46
`years old) and female (n=12; 30-40 years old) subjects with a history of polysubstance abuse that
`included cocaine. The treatment sequence for male subjects was different than the sequence for the
`female subjects. The criteria for evaluation included the Addiction Research Center Inventory (ARCI )
`subscales, Drug Rating questionnaires, Drug Identification questionnaires, Specific Drug Effect
`Questionnaire and functional and physiological measurements.
`
`0n the ARCI Amphetamine (Stimulant) Subscale in the male group, maximal response for modafinil 800
`mg was observed at 1 hour, which was greater than that of modafinil 200 mg, modafinil 400 mg and
`placebo. 0n the same Scale, the female group’s maximal responses for modafinil 200 mg and 800 mg
`were greater than that of placebo. 0n the ARCl Benzedrine (Stimulant) Subscale, the male subjects did
`not identify modafinil as an stimulant. Methylphenidate 90 mg was identified as an stimulant within 1
`hour after dosing.
`In contrast, the female subjects, identified modafinil 200 mg as an stimulant. The
`maximal response for modafinil 200 mg was observed at 1.5 hours and it was greater than that of
`modafinil 400 mg.
`
`On the important ARCI Morphine-Benzedrine (Euphoria) Subscale, in the male group modafinil 200 and
`modafinil 400 mg produced little difference from placebo. A dose-dependent effect for this measure
`was apparent for both methylphenidate and modafinil. As it was observed in the Amphetamine
`Subscale, the peak effect for modafinil 800 mg occurred within 1 hour. The response for modafinil
`800 mg fell between that of methylphenidate 45 mg and methylphenidate 90 mg.
`In the female
`group, the response for modafinil 800 mg was greater than both methylphenidate doses and modafinil
`400 mg.
`
`.
`(
`
`On the Sedation Subscale of the ARCI (Pentobarbital-Chlorpromazine-Alcohol Group). in males and
`females the maximal responses for all doses of methylphenidate and modafinil were similar to that of
`placebo. 0n the Dysphoria or Hallucinogenic Subscale (Lysergic Acid Diethylamide Group), both
`modafinil 800 mg and methylphenidate 90 mg produced similar dose-response curves in males. The
`response for methylphenidate 90 mg was greater than that of modafinil 800 mg.
`In females, the
`response for modafinil 800 mg was greater than that of methylphenidate 45 mg. The intensity of the
`
`,
`
`C LSD responses increased as the responses on the stimulant subscale decreased.
`
`The Drug Rating Questionnaire is a four-item questionnaire in which the subject indicates 'drug liking“.
`“drug disliking“ and if ‘felt the dmg’s effect' and whether ‘felt high'. To the question 'Feel the drug",
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`in males, both doses of methylphenidate and the 800 mg dose of modafinil were discriminated from
`placebo and the maximum effect for modafinil 800 mg which was achieved at one hour was
`intermediate to that of methylphenidate 45 mg and 90 mg.
`In the female group, the response observed-
`for modafinil 800 mg was greater than that of methylphenidate 45 mg and 90 mg and a dose-
`dependent effect was observed for modafinil and methylphenidate.
`
`.
`
`To the question 'Like the drug effect“, in males. a dose-dependent effect for this measure was
`apparent for both methylphenidate and modafinil and the response for modafinil 800 mg was similar to
`that of methylphenidate 90 mg; the maximal response was achieved in one hour.
`In the female group,
`the maximum responses for modafinil 200 and 400 mg were slightly higher than those of both doses of
`methylphenidate. The maximal response for modafinil 800 mg was higher than the response produced
`by methylphenidate 90 mg and occurred at 2.5 hours.
`
`To the question “Dislike the drug effect', in males, the response obtained for modafinil 800 mg was
`similar to that of methylphenidate 90 mg and the maximum responses for all modafinil doses were
`lower than those produced by both methylphenidate doses.
`In females, the responses for modafinil
`400 mg and 800 mg were similar to those of methylphenidate 45 and 90 mg respectively. To the
`question “Do you feel high', in males, a dose-dependent effect for this measure was apparent for both
`methylphenidate and modafinil. Both doses of methylphenidate and the 800 mg dose of modafinil
`produced statistically significant elevations compared to placebo. The response for modafinil 800 mg
`was intermediate to that of methylphenidate 45 mg and 90 mg and greater than modafinil 200 mg.
`In
`females, also a dose-dependent effect for this measure was apparent for both methylphenidate and
`modafinil and the response for modafinil 800 mg was greater than both methylphenidate doses and
`modafinil 200 and 400 mg.
`
`~'
`
`'
`
`In the drug identification questionnaire in males and females, the effects of both methylphenidate and
`modafinil were predominantly identified as stimulant-like, with positive identifications reported by the
`majority of subjects for methylphenidate (45 mg and 90 mg) and for modafinil (400 mg and 800 mg).
`
`In drug response questionnaire, male and female subjects reported “body feels different, changed",
`I“nervous“ and “stomach turning' following administration of methylphenidate and modafinil compared
`to placebo. Subjects also reported a ‘need to talk' following all active doses with the exception of
`modafinil 200 mg. Fewer male subjects reported feeling 'sleepy' or ‘relaxed' following modafinil
`dosing compared to placebo and methylphenidate.
`In females, modafinil 400 mg and 800 mg resulted
`in a greater number of reports of ‘full of energy' and modafinil 200 mg had increased reports of
`‘stomach turning" and modafinil 800 mg had increased reports of 'afraid'.
`In the same questionnaire,
`the observer’s evaluation differed from the male subjects in that there were more reports of ‘talking',
`'nervous' and 'anxious' and fewer reports of 'nodding' for methylphenidate and modafinil; and fewer
`reports of 'sIeepy' and greater responses of “active” occurred for modafinil compared to
`methylphenidate and placebo. The observer also reported for the female group a greater number of
`‘talking‘ responses and fewer ‘sleepy' and 'nodding' responses for methylphenidate and modafinil.
`More ‘active' responses were observed following administration of modafinil.
`
`Both methylphenidate and modafinil produced dose-dependent reductions in the number of observed
`and reported hours of sleep relative to placebo in male and female subjects. Also, mduction of appetite
`was assessed by caloric intake count.
`In both groups, all doses of methylphenidate and modafinil
`reduced caloric intake at the noon meal relative to placebo, and methylphenidate 90 mg and modafinil
`400 and 800 mg produch statistically significant reductions in combined caloric conwmption at the
`
`( ~
`
`noon and evening meals compared to placebo.
`
`In both groups a dose-dependent increase in supine and standing systolic and diastolic blood pressure;'
`and positive correlation between blood pressure and standing pulse rate was observed for
`methylphenidate and modafinil.
`
`a
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`It
`QHEMLSIEL Modafinil, registry number CAS-68693-11-8, is 2-[(diphenylmethyllsulfinvl}~‘acetamide.
`is also known by the code names CRL 40476 and CEP 1538.
`Its molecular formula is C,,H.,NO,S ; the
`molecular weight is 273.36. Modafinil (Provi
`ii) is a tablet with 1
`m
`ctive ingredient.
`The product contains talc. flmmm has
` .
`little stmctural similarity to any of the known CNS stimulants (e.g. cocaine, amphetamine,
`methamphetamine or pemolinel.
`
`12
`
` .
`
`Modafinil is white to off-white crystalline powder that is practically insoluble in water (1 O mg/lOO mL)
`and cyclohexane, slightly soluble in ethanol (1 mg/le and soluble in methanol (10 m lle. It is
` .
`
`sparingly to slightly soluble in methanol and acetone.
`
` .
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`W Modafinil is well-absorbed after oral administration. Peak
`plasma concentration occurs at 1-4 hours. Elimination half-life was 9 to 14 hours after a single oral
`dose of 200 or 400 mg. Both modafinil and modafinil acid exhibited linear pharmacokinetics over a
`dose range of 50-499 mg. Oral bioavailability of a 200 mg tablet relative to a micronized aqueous
`suspension was close to 100%. Apparent volume of distribution of modafinil was larger than the
`volume of total body water (0.6 ngl. Females (3596) appeared to excrete less modafinil acid in urine
`than males (51%). Clearance of modafinil in males decreased slightly (approximately 10-20%) as the
`age increased. Stereospecific pharmacokinetics of enantiomers have been demonstrated. The dextro-
`isomer was eliminated faster (100-140 mUmin) than the lava-isomer (35-50 lemin).
`
`Modafinil was extensively metabolized after oral dosing by deamination, oxidation, and aromatic ring
`hydroxylation. Total oral clearance of modafinil after a single dose was approximately 60 mL/min.
`Less than 10% of the dose was excreted in urine as parent drug. Modafinil acid accounted for 50-60%
`of the dose in males and 30-40% in females. Urinary excretion of modafinil sulfone was negligible.
`Renal clearance of modafinil accounts for 5-6% of plasma clearance, indicating that modafinil is
`primarily eliminated by liver metabolism. After a single dose of side-chain labeled “C—modafinil, 79.6
`t 5.9% and 1.0 :l: 0.3% of the dose was recovered in urine and feces, respectively, over an eleven
`day period.
`
`After multiple once daily 200, 400, and 600 mg dosing, apparent steady-state plasma levels were
`reached after 2-4 days of dosing. Elimination half-life after the last dose of multiple dose regimen was
`13-18 hours. Modafinil was moderately bound to plasma proteins (61-65%), primarily albumin.
`Food delayed absorption of modafinil (Tmax: 3.21 vs. 2.05 hours). However, AUC and elimination half-
`lives did not differ between fasted and fed conditions.
`In patients with renal impairment, elimination of
`modafinil acid was reduced after a single dose of 200 mg. Only 25% of the modafinil dose was
`excreted in urine as modafinil acid in patients with renal insufficiency. Forty-five percent of the
`modafinil dose was excreted as modafinil acid in the urine of healthy subjects.
`
`In a multiple dose study (200 mglday) for 8 days in patients with liver cirrhosis, patients exhibited high
`modafinil AUC and extended half-life, suggesting that the major elimination route of modafinil was
`liver.
`In a single-dose pharmacokinetics interaction study with methylphenidate and modafinil, no
`clinically important alterations in the pharmacokinetics profile of either drug was noted. A delay in oral
`absorption of modafinil was observed (Tmax of 2.9 vs. 1.9 hours).
`
`An open label, multiple dose, study in elderly male and female volunteers followed administration of
`300 mglday modafinil for 7 days. Plasma levels were determined on days 1 and 7. Maximum plasma
`concentrations after the first dose were much higher in healthy young volunteers. Plasma levels of
`modafinil obtained from day 7 were higher than those of day 1. This implied occurrence of
`accumulation after 7 days of daily dosing of 300 mg modafinil in elderly Subjects.
`
`The pharmacokinetics portions of the pivotal Phase III efficacy trials were designed to evaluate the
`steady state plasma trough levels of modafinil and its two metabolites, modafinil acid and modafinil
`sulfone. After daily dosing of 200 mg modafinil, plasma trough levels of modafinil and the two
`metabolites reached steady state by Week 3 and remained unchanged through Week 9. After daily
`doses of 400 mg modafinil, the plasma trough levels of modafinil at Week 9 were significantly lower
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`(approximately 20%) than those of Week 3. The two metabolites did not show this difference. Also,
`the plasma trough levels of modafinil sulfone were negatively correlated with age, suggesting
`metabolism of modafinil to modafinil sulfone might be slower in older patients. Also. plasma levels of
`modafinil Sulfone from female patients in the 400 mg group were higher than those of male patients at
`Weeks 3 and 6.
`'
`
`«WWW
`
`Marketing authorization in France was granted in 1992, although the product was not commercially
`available there until 1994.
`Initially, modafinil could only be obtained through restricted prescription,
`that is, it was only obtained from a public neurologist and dispensing hospital pharmacies.
`In
`November of 1995, the prescribing requirements were relaxed by the French Health Ministry in
`
`prescription be restricted to specialists and physicians working in departments of neurology and public
`or private sleep centers, with dispensing by retail pharmacists. General practitioners may renew
`prescriptions, provided that the specialist carries out a clinical assessment every year, and that a
`specialized evaluation (polysomnography followed by a Multiple Sleep Latency Test) be performed
`every 5 years. - filed a Multistate Application in October 1994 to: Belgium, Denmark, Greece,
` .
`Ireland, Italy, Netherlands, Portugal, Spain and the U.K. Obiections were raised by the member states
`and in October 1996, responses were submitted to the CPMP for evaluation. At the time of
`submission of the NDA, approval was pending in 13/14 European countries, France being the only
`European state where the drug has been approved.
`
` .
`( . A_ licensee submitted its_marketing application in May 1993. The application was
` .
`It was supplemented and resubmitted in
`rejected due to a lack of sufficient data to assess efficacy.
`August 1996, with approval endin . According to Cephalon, since the 1994 date of commercial
`I
`availability 01‘ modafinil inH has not issued any warning letters to the prescribing
` .
`
`physicians.
`
`Although modafinil’s duration of action, onset and offset of its subjective and other CNS related effects
`are virtually instantaneous. This implies existence of a close association between behavioral
`administration and onset of effect leading to reinforcement and heightened abuse potential.
`Comparable effects of the reference stimulants appear to develop more slowly, although the duration
`of effects is much longer.
`
`As a drug of abuse, methylphenidate has a history of abuse. When abused, the most common route of
`administration for amphetamine derivatives is intravenous, although it can be smoked, taken orally,
`transmucosally or intranasally. No studies examining alternative routes of modafinil administration
`(s.c., intradermally, im, po, or transderrnally) have been completed in humans. Animal studies indicate
`that modafinil is poorly absorbed by the oral and dermal routes, but was well absorbed following
`intratracheal inhalation or ocular application.
`
`Modafinil and its N-hydroxy analog, adrafinil, can be purchased without any restriction through the
`Internet. Both drugs are advertized as ‘smart dmgs' which promote vigilance and alertness. Modafinil
`is approximately ten-fold more expensive than adrafinil: Modafinil, Modiodal, 100 mg, $640 per 120
`tablets; Adrafinil, Olmifon, 300 mg, 322 per 40 tablets). Different routes of synthesis are described in
`the literature. Adrafanil is also commercially available in France and is indica
`i
`
`sleeping and attention deficit disorder .
` .
` .
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`There are no reports of abuse of modafinil (See 4.W31. The product
`has not been widely marketed throughout world. Currently, it is only marketed in France. Abuse of
`modafinil would be for similar reasons that other currently available CNS stimulants. such as
`amphetamine, methamphetamine, and dextroamphetamine are abused. Were modafinil marketed as a
`noncontrolled CNS active stimulant, the individual who abuses such drugs would likely prefer to use
`Pl‘IOVlGlLfl , for its noncontrolled status, rather than amphetamine, methamphetamine or
`methylphenidate, which are controlled under the CSA, and are therefore more difficult to acquire by
`individuals not registered with the Dmg Enforcement Administration.
`
`One currently accepted criterion for predicting abuse liability of a new drug relies upon measurements
`of measuring subjective and objective responses of 'drugaware" subjects to both new and reference
`drugs. Human drug abuse liability testing indicate that modafinil has an abuse potential that is greater
`than placebo and equal to or greater than methylphenidate in its peak effects. This property appears to
`be especially pronounced in female subjects. The abuse liability of oral modafinil was assessed relative
`to methylphenidate in CNS psychostimulant-experienced individuals. Both drugs are CNS stimulants
`with effects mediated primarily through dopamine reuptake inhibition sites. Modafinil, however, is less
`potent on a milligram to milligram basis than methylphenidate or amphetamine or methamphetamine,
`and is primarily active by the oral route.
`K
`
`-
`
`_
`
`,
`
`y
`
`Both modafinil and methylphenidate have typical CNS psychostimulant effects and as such each has
`the potential to be abused. The principal difference between the two drugs is that modafinil is not
`water very soluble and therefore is not likely to be abused by intravenous injection as the
`
`amphetamines and methylphenidate are abused at times. Modafinil also decomposes upon heating;
`
`therefore, modafinil is not likely to be abused by the smoking route. Similarities between modafinil and
`methylphenidate were found both for its physiologic effects and for subjective reports such as liking
`and other pleasant effects related to abuse liability. Modafinil was as well tolerated as
`methylphenidate in psychostimulant experienced subjects.
`
`At greater than therapeutic dose levels, modafinil has been recognized as amphetamine-like in
`behavioral studies [Addiction Research Center Inventory (ARClll in post-addict volunteers.
`In the other
`critical subscales of the ARCI, modafinil produced high scores on euphoria, stimulant, and
`hallucinogenic subscales; modafinil was compared in these double blind studies against placebo and
`methylphenidate as a positive control.
`
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`
`individuals may likely become dependent on modafinil, and suffer adverse consequences of modafinil
`overdosage if abused. Easy availability and ease of ad lib. administration by the oral route may be
`expected to contribute to risk of overdosage.
`
`PROVIGIL" presents the same risks to the public health as those resulting from administration of other
`orally active CNS stimulants which are readily available in hospitals, clinics, and at the retail level. Past
`outbreaks of diversion and abuse of amphetamine and its analogues have resulted in public health
`problems. Nonmedical and improper administration may more likely lead to overdosage and production
`\ .
`of dependence and tolerance as is seen with other CNS stimulants.
`
`A comparative evaluation of the dependence potentials of modafinil versus cocaine in primates is
`inferred from self-administration of drug following administration of cocaine as training drug. The self-
`administration paradigm is widely used to determine whether or not a drug can control behavior, that
`
`.
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`is, function as a positive reinforcer, and is used to ashes the abuse potential of the substance. Self-
`administration studies using nonhuman primates and rats have been shown to be a valid and reliable
`predictor of the potential of a substance to result in drug dependence Ii.e., addiction). There is a
`strong concordance between the types of drugs that serve as reinforcers in animals and the many illicit
`drugs associated with problems of dependence, addiction, and abuse in man (Johanson and Balster,
`1978; Griffiths er al., 1980; Woolverton and Nader, 1990). The reinforcing effects of modafinil were
`evaluated in rhesus monkeys experienced in self-administration of intravenous cocaine under a fixed
`ratio 10 schedule of reinforcement. Modafinil maintained FR 10 responding at rates that exceeded
`saline self-administration at one or more doses. Mofiafinil maintained FR 10 responding in all monkeys
`tested.
`
`The results from the study clearly demonstrated that modafinil can function as a positive reinforcer in
`monkeys trained to self-administer cocaine as their baseline drug. These results suggest that modafinil
`has the potential to be a drug of abuse in individuals with a history of stimulant abuse. However, one
`can not rule out the possibility that modafinil may become a drug of abuse in individuals who have no
`history of substance abuse.
`
`Discriminative stimulus properties of modafinil were analyzed in rats trained to discriminate cocaine
`(10.0 mg/kg, i.p. I from vehicle. Modafinil (250 rug/kg) Produced cocaine-appropriate responding in four
`out of six rats. Modafinil (250 mg/kg) also reduced response rates.
`
`
`
`Modafinil is not readily convertible to other controlled substances.
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`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
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`17
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`(A)
`
`The drug or other substance has a low potential for abuse relative to the dmgs or other
`
`which limit its abuse potential. Modafinil elicits many of the same pharmacological responses
`and adverse reactions as those of the classical psychostimulants.
`lts short duration of action
`and rapid onset further enhance the likelihood that modafinil would be abused. The physical
`properties of modafinil are likely to limit its actual abuse. Although modafinil was self-
`administered by primates when substituted for training drug cocaine, it was only partially
`discriminated as amphetamine-like by rats in drug discrimination studies.
`
`(B)
`
`The drug or other substance has a currently accepted medical use in treatment in the
`United States.
`
`Upon FDA approval of its currently pending new drug application, PROVlGlL" (modafinil) will be
`able to be marketed in the United States for treatment of narcolepsy.
`
`(C)
`
`Abuse of the drug or other substance may lead to limited physical dependence or
`psychological dependence relative to the drugs or other substances in Schedule III.
`
`The dependence capacity of modafinil can be inferred from preclinical data and an overall
`clinical pharmacology profile which relate its drug discriminative properties, reinforcing
`efficacy, and adverse events to other CNS stimulants. From preclinical studies, the
`
`stimulants (including cocaine, methylphenidate, amphetamine and methamphetamine).
`Modafinil is likely to be used to suppress a withdrawal syndrome upon withdrawal of other
`stimulants. Physical dependence, tolerance production and a withdrawal syndrome may result
`after abrupt discontinuation of modafinil following excessive use. The indication of a possible
`mild withdrawal syndrome from clinical trials, typified by tiredness, occurred upon
`discontinuing usage of modafinil.
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`18
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`Abel-Coindoz, C.; Vezin, H.; Daveloose, 0.; Roussel, 8.; Viret, J.; ‘Study by EPR of structural
`1 .
`modifications on liposomes induced by metabolites of modafinil,‘ Ann. Pharm. Fr., 51 (4): 197-204,
`1 993.
`
`Akaoka, H.; Roussel, 8.; Lin, J. 8.; Chouvet, G.; Jouvet, M.; “Effect of modafinil and
`2.
`amphetamine on the rat catecholaminergic neuron activity,“ Neurosci. Lett., 123(1): 20-2, 1 991.
`
`Besset, A.; Chetrit, M.; Carlander, 8.; Billiard, M., 'Use of modafinil in the treatment of
`3.
`narcolepsy: a long term follow-up study,’ Neurophysiol. Clin., 26(1): 60-6, 1996.
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`Bettendorff, L., Sallanon-Moulin, M.; Touret, M.; Wins, P.; Margineanu, l.; Schoffeniels, E.,
`4.
`'paradoxical sleep deprivation increases the content of glutamate and glutamine in rat cerebral cortex,"
`Sleep, 19(1): 65-71. 1996.
`
`5.
`
`Billiard. M., ‘Narcolepsy,' Rev-Prat, 46(20): 2428-34, 1996.
`
`Billiard, M.; Besset, A.; Montplaisir, J.; Laffont, F.; Goldenberg, F.; Weill, J.S.; Lubin, 8.;
`6.
`‘Modafinil: a double-blind multicentric study,‘ Sleep, 17 (8 Suppl): 3107-12, 1994.
`
`Bourdon, L.; Jacobs, L; Bateman, W.A.; Vallerand, A. L.; ‘Effect of modafinil on heat
`7.
`production and regulation of body temperatures in cold-exposed humans,‘ Aviat. Space Environ. Med.,
`65(11): 999-1004, 1994.
`
`Carceller, E.; Merlos, M.; Giral, M.; Almansa, C.; Bartroli, J. |.; Garcia-Rafanell, J.; Forn, J.,
`8.
`'Synthesis and structure-activity relationships of 1-acyl-4-[(2-methyl-3-pyridyl) cyanomethyllpiperazines
`as PAF antagonists.‘ J. Med. Chem., 36:2984-97, 1993.
`
`De Sereville, J. E.; Boer, C.; Rambert, F. A.; Duteil, J.; ‘Lack of pro-synaptic dopaminergic
`9.
`involvement in modafinil activity in anaesthetized mice: in vivo voltammetry studies,"
`Neuropharmacoloigy. 33(6): 755-61. 1994.
`
`Disdier, P.; Genton, P.; Milandre, C.; Bemard, P.M.; Millet, Y.; 'Fibrositis syndrome and
`10.
`narcolepsy," J. Rheumatol., 20(5): 888-9, 1993.
`
`Duteil, J.; Rambert, F. A.; Pesonnier, J.; Hennant, J. F.; Gombert, FL; Assous, E.; 'Central
`11.
`alpha 1-adrenergic stimulaiton in relation to the behavior stimulating effect of modafinil: studies with
`experimental animals,‘ Eur. J. Pharmacol., 180(1): 49-58, 1 990.
`
`Ferraro, L.; Tanganelli, 8.; O’Connor, WT; Antonelli, T.; Rambert, F., "The vigilance promoting
`12.
`dmg modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus
`of the awake rat: possible involvement of the serotonergic 5-HT3 receptor,‘ Neurosci. Lett., 220(1): 5-
`8. 1 996.
`
`Ferraro, L.; Tangenelli,‘s.; O'Connor, W. T.; Antonelli, T.; Rambert, F.; Fuxe,K., 'The vigilance
`13.
`promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement
`of GABAergic mechanism,‘ Eur. J. Pharmacol., 306(1-3): 33-9, 1996.
`
`Gold, L. H., Balster. R. L., 'Evaluation of the cocaine-like discriminative stimulus effects and
`14.
`reinforcing effects of modafinil,‘ Psychopharmacology-Berl., 126(4): 286-92, 1996.
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`
`19
`
`Griffiths, R. R.; Bigelow, G. E., and Henningfield, J. E., in Advances in Substance Abuse (Vol.
`15.
`1), JAI Press Inc., pp. 1-90, 1980..”
`
`Jasinski, D. R.; Johnson, R. 5.; and Henningfield, J. E.; "Abuse liability assessment in human
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`'
`
`Johansson, C. E. and Balster, R. I... 'A