CHSOCH2CNH2ONDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®1PROVIGIL (modafinil) TABLETS®DESCRIPTIONPROVIGIL (modafinil) is a wakefulness-promoting agent for oral administration. Modafinilis a racemic compound. The chemical name for modafinil is2-[(diphenylmethyl)sulfinyl]acetamide. The molecular formula is CHNOS and the15152molecular weight is 273.36.The chemical structure is:Modafinil is a white to off-white, crystalline powder that is practically insoluble in water andcyclohexane. It is sparingly to slightly soluble in methanol and acetone. PROVIGIL tabletscontain 100 mg or 200 mg of modafinil and the following inactive ingredients: lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, andtalc.CLINICAL PHARMACOLOGYMechanism of Action and PharmacologyThe precise mechanism(s) through which modafinil promotes wakefulness is unknown.Modafinil has wake-promoting actions like sympathomimetic agents includingamphetamine and methylphenidate, although the pharmacologic profile is not identical tothat of sympathomimetic amines.
`
`

`

`"
`-adrenergic agonist. Although1modafinil-induced wakefulness can be attenuated by the
`""
`-adrenergic receptor1antagonist, prazosin, in assay systems known to be responsive to
`""
`
`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®2At pharmacologically relevant concentrations, modafinil does not bind to most potentiallyrelevant receptors for sleep/wake regulation, including those for norepinephrine, serotonin,dopamine, GABA, adenosine, histamine-3, melatonin, or benzodiazepines. Modafinil alsodoes not inhibit the activities of MAO-B or phosphodiesterases II-V.Modafinil is not a direct- or indirect-acting dopamine receptor agonist and is inactive inseveral in vivo preclinical models capable of detecting enhanced dopaminergic activity.In vitro, modafinil binds to the dopamine reuptake site and causes an increase inextracellular dopamine, but no increase in dopamine release. In a preclinical model, thewakefulness induced by amphetamine, but not modafinil, is antagonized by the dopaminereceptor antagonist haloperidol.Modafinil does not appear to be a direct or indirect
`
`-adrenergic agonists,modafinil has no activity. Modafinil does not display sympathomimetic activity in the ratvas deferens preparations (agonist-stimulated or electrically stimulated) nor does itincrease the formation of the adrenergic receptor-mediated second messengerphosphatidyl inositol in in vitro models. Unlike sympathomimetic agents, modafinil doesnot reduce cataplexy in narcoleptic canines and has minimal effects on cardiovascular andhemodynamic parameters.In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamineincreased neuronal activation throughout the brain. Modafinil at an equivalentwakefulness-promoting dose selectively and prominently increased neuronal activation inmore discrete regions of the brain.The relationship of this finding in cats to the effects ofmodafinil in humans is unknown.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®3In addition to its wakefulness-promoting effects and increased locomotor activity inanimals, in humans, PROVIGIL produces psychoactive and euphoric effects, alterationsin mood, perception, and thinking, and feelings typical of other CNS stimulants. Modafinilis reinforcing, as evidenced by its self-administration in monkeys previously trained to selfadminister cocaine; modafinil was also partially discriminated as stimulant-like.The optical enantiomers of modafinil have similar pharmacological actions in animals. Theenantiomers have not been individually studied in humans. Two major metabolites ofmodafinil, modafinil acid and modafinil sulfone, do not appear to contribute to the CNS-activating properties of modafinil.PharmacokineticsModafinil is a racemic compound, whose enantiomers have different pharmacokinetics(e.g., the half-life of the l-isomer is approximately three times that of the d-isomer inhumans). The enantiomers do not interconvert. At steady state, total exposure to the l-isomer is approximately three times that for the d-isomer. The trough concentration (C) of circulating modafinil after once daily dosing consists of 90% of the l-isomer andminss10% of the d-isomer. The effective elimination half-life of modafinil after multiple doses isabout 15 hours. The enantiomers of modafinil exhibit linear kinetics upon multiple dosingof 200-600 mg/day once daily in healthy volunteers. Apparent steady states of totalmodafinil and l-(-)-modafinil are reached after 2-4 days of dosing.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®4Absorption and DistributionAbsorption of PROVIGIL tablets is rapid, with peak plasma concentrations occurring at2-4 hours. The bioavailability of PROVIGIL tablets is approximately equal to that of anaqueous suspension. The absolute oral bioavailability was not determined due to theaqueous insolubility (<1 mg/ml) of modafinil, which precluded intravenous administration.Food has no effect on overall PROVIGIL bioavailability; however, its absorption (t) maymaxbe delayed by approximately one hour if taken with food.Modafinil is well distributed in body tissue with an apparent volume of distribution (~0.9L/kg) larger than the volume of total body water (0.6 L/kg). In human plasma, in vitro,modafinil is moderately bound to plasma protein (~60%, mainly to albumin). At serumconcentrations obtained at steady state after doses of 200 mg/day, modafinil exhibits nodisplacement of protein binding of warfarin, diazepam, or propranolol. Even at much largerconcentrations (1000µM; >25 times the C of 40µM at steady state at 400 mg/day),maxmodafinil has no effect on warfarin binding. Modafinil acid at concentrations >500µMdecreases the extent of warfarin binding, but these concentrations are > 35 times thoseachieved therapeutically.Metabolism and EliminationThe major route of elimination (~90%) is metabolism, primarily by the liver, withsubsequent renal elimination of the metabolites. Urine alkalinization has no effect on theelimination of modafinil.Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ringhydroxylation, and glucuronide conjugation. Less than 10% of an administered dose isexcreted as the parent compound. In a clinical study using radiolabeled modafinil, a totalof 81% of the administered radioactivity was recovered in 11 days post-dose,predominantly in the urine (80% vs. 1.0% in the feces). The largest fraction of the drugin urine was modafinil acid, but at least six other metabolites were present in lower
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®5concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e.,modafinil acid and modafinil sulfone. In preclinical models, modafinil acid, modafinilsulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy modafinil, were inactive ordid not appear to mediate the arousal effects of modafinil.In humans, modafinil shows a possible induction effect on its own metabolism after chronicadministration of doses
`400 mg/day. Induction of hepatic metabolizing enzymes, mostimportantly cytochrome P (CYP) 3A4, has also been observed in vitro after incubation450of primary cultures of human hepatocytes with modafinil. (For further discussion of theeffects of modafinil on CYP enzyme activities see PRECAUTIONS, Drug Interactions).Drug-Drug Interactions: Because modafinil is a reversible inhibitor of the drug-metabolizing enzyme CYP2C19, co-administration of modafinil with drugs such asdiazepam, phenytoin, and propranolol, which are largely eliminated via that pathway, mayincrease the circulating levels of those compounds. In addition, in individuals deficient inthe enzyme CYP2D6 (i.e., 7-10% of the Caucasian population; similar or lower in otherpopulations), the levels of CYP2D6 substrates such as tricyclic antidepressants andselective serotonin reuptake inhibitors, which have ancillary routes of elimination throughCYP2C19, may be increased by co-administration of modafinil. Dose adjustments may benecessary for patients being treated with these and similar medications (seePRECAUTIONS, Drug Interactions).Chronic administration of modafinil may also cause modest induction of the metabolizingenzyme CYP3A4, thus reducing the levels of co-administered substrates for that enzymesystem, such as steroidal contraceptives, cyclosporine and to a lesser degree,theophylline. Dose adjustments may be necessary for patients being treated with theseand similar medications (see PRECAUTIONS, Drug Interactions).
`
`$
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®6An apparent concentration-related suppression of CYP2C9 activity was observed inhuman hepatocytes after exposure to modafinil in vitro. Although no other indication ofCYP2C9 suppression has been observed, the in vitro results suggest that there is potentialfor metabolic interaction between PROVIGIL and CYP2C9 substrates, such as warfarin orphenytoin (see PRECAUTIONS, Drug Interactions).Special PopulationsGender Effect: The pharmacokinetics of modafinil are not affected by gender.Age Effect: A slight decrease (
`
`0%) in oral clearance (CL/F) of modafinil was observedin a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53-72years), but the change was considered unlikely to be clinically significant. In a multipledose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67-87 years),the mean levels of modafinil in plasma were approximately two times those historicallyobtained in matched younger subjects. Due to potential effects from the multipleconcomitant medications with which most of the patients were being treated, the apparentdifference in modafinil pharmacokinetics may not be attributable solely to the effects ofaging. However, the results suggest that the clearance of modafinil may be reduced in theelderly. (See DOSAGE AND ADMINISTRATION).Race Effect: The influence of race on the pharmacokinetics of modafinil has not beenstudied.Renal Impairment: In a single dose 200 mg modafinil study, severe chronic renal failure(creatinine clearance
`
`- 2
`
`#
`
`20 ml/min) did not significantly influence the pharmacokinetics ofmodafinil, but exposure to modafinil acid (an inactive metabolite) was increased 9 fold(see PRECAUTIONS).
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®7Hepatic Impairment: Pharmacokinetics and metabolism were examined in patients withcirrhosis of the liver (6 M and 3 F). Three patients had stage B or B+ cirrhosis (per theChild criteria) and 6 patients had stage C or C+ cirrhosis. Clinically 8 of 9 patients wereicteric and all had ascites. In these patients, the oral clearance of modafinil was decreasedby about 60% and the steady state concentration was doubled compared to normalpatients. The dose of PROVIGIL should be reduced in patients with severe hepaticimpairment (see PRECAUTIONS and DOSAGE and ADMINISTRATION).CLINICAL TRIALSThe effectiveness of PROVIGIL in reducing the excessive daytime sleepiness (EDS)associated with narcolepsy was established in two US 9-week, multicenter,placebo-controlled, two-dose (200 mg per day and 400 mg per day) parallel-group,double-blind studies of outpatients who met the ICD-9 and American Sleep DisordersAssociation criteria for narcolepsy (which are also consistent with the American PsychiatricAssociation DSM-IV criteria). These criteria include either 1) recurrent daytime naps orlapses into sleep that occur almost daily for at least three months, plus sudden bilateralloss of postural muscle tone in association with intense emotion (cataplexy) or 2) acomplaint of excessive sleepiness or sudden muscle weakness with associated features:sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleepepisode; and polysomnography demonstrating one of the following: sleep latency lessthan 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes. Inaddition, for entry into these studies, all patients were required to have objectivelydocumented excessive daytime sleepiness, a Multiple Sleep Latency Test (MSLT) with twoor more sleep onset REM periods, and the absence of any other clinically significant activemedical or psychiatric disorder. The MSLT, an objective daytime polysomnographic assessment of the patient’s ability to fall asleep in an unstimulating environment, measures
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®8latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervalsfollowing nocturnal polysomnography. For each test session, the subject was told to liequietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleepoccurred or 15 minutes after sleep onset.In both studies, the primary measures of effectiveness were 1) sleep latency, as assessedby the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overalldisease status, as measured by the Clinical Global Impression of Change (CGI-C). Fora successful trial, both measures had to show significant improvement.The MWT measures latency (in minutes) to sleep onset averaged over 4 test sessions at2 hour intervals following nocturnal polysomnography. For each test session, the subjectwas asked to attempt to remain awake without using extraordinary measures. Each testsession was terminated after 20 minutes if no sleep occurred or 10 minutes after sleeponset. The CGI-C is a 7-point scale, centered at No Change, and ranging from Very MuchWorse to Very Much Improved. Patients were rated by evaluators who had no access toany data about the patients other than a measure of their baseline severity. Evaluatorswere not given any specific guidance about the criteria they were to apply when ratingpatients.Other assessments of effect included the Multiple Sleep Latency Test (MSLT), EpworthSleepiness Scale (ESS; a series of questions designed to assess the degree of sleepinessin everyday situations) the Steer Clear Performance Test (SCPT; a computer-basedevaluation of a patient’s ability to avoid hitting obstacles in a simulated driving situation),standard nocturnal polysomnography, and patient’s daily sleep log. Patients were alsoassessed with the Quality of Life in Narcolepsy (QOLIN) scale, which contains thevalidated SF-36 health questionnaire.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®9Both studies demonstrated improvement in objective and subjective measures of excessdaytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patientstreated with either dose of PROVIGIL showed a statistically significantly enhanced abilityto remain awake on the MWT (all p values <0.001), at weeks 3,6,9, and endpoint compared to placebo and a statistically significantly greater global improvement, as ratedon the CGI-C scale (all p values <0.05).The average sleep latencies (in minutes) on the MWT at endpoint in the 2 controlled trialsare shown in the table below:Table 1. MWT Average Sleep Latency at EndpointAverage Sleep Latency at EndpointPROVIGILPlacebo200 mg*400 mg*Trial 15.078.188.90Trial 25.358.287.86 * significantly different from placebo for both trials (p<0.001)The percentages of patients who showed any degree of improvement on the CGI-C in thetwo clinical trials are shown in the table below:Table 2. Clinical Global Impression of Change (CGI-C)Percent of Patients Who Improved at EndpointPROVIGILPlacebo200 mg*400 mg*Trial 137%64%72%Trial 238%58%60% * significantly different from placebo for both trials (Trial 1: p<0.001; Trial 2: p<0.01)
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®10Similar statistically significant treatment-related improvements were seen on othermeasures of impairment in narcolepsy, including a decrease in the propensity to fall asleepon the MSLT (p<0.001 for each dose in comparison to placebo) and a statisticallysignificant lessening of patient-assessed level of daytime sleepiness on the ESS (P<0.001for each dose in comparison to placebo).Although PROVIGIL tended to be numerically superior to placebo on several of the otheroutcome measures, there were no consistent statistically significant differences betweendrug and placebo on these measures.Nighttime sleep measured with nocturnal polysomnography was not affected by the useof PROVIGIL.The effectiveness of modafinil in long-term use (greater than 9 weeks) has not beensystematically evaluated in placebo-controlled trials. The physician who elects to prescribePROVIGIL tablets for an extended time should periodically re-evaluate long-termusefulness for the individual patient.INDICATIONS AND USAGEPROVIGIL is indicated to improve wakefulness in patients with excessive daytimesleepiness associated with narcolepsy.CONTRAINDICATIONSPROVIGIL is contraindicated in patients with known hypersensitivity to modafinil.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®11PRECAUTIONSGeneralAlthough modafinil has not been shown to produce functional impairment, any drugaffecting the CNS may alter judgment, thinking or motor skills. Patients should becautioned about operating an automobile or other hazardous machinery until they arereasonably certain that PROVIGIL therapy will not adversely affect their ability to engagein such activities.Cardiovascular SystemIn clinical studies of PROVIGIL, signs and symptoms including chest pain, palpitations,dyspnea and transient ischemic T-wave changes on ECG were observed in three subjectsin association with mitral valve prolapse or left ventricular hypertrophy. It is recommendedthat PROVIGIL tablets not be used in patients with a history of left ventricular hypertrophyor ischemic ECG changes, chest pain, arrhythmia or other clinically significantmanifestations of mitral valve prolapse in association with CNS stimulant use.Modafinil has not been evaluated or used to any appreciable extent in patients with arecent history of myocardial infarction or unstable angina, and such patients should betreated with caution.Modafinil has not been systematically evaluated in patients with hypertension. Periodicmonitoring of hypertensive patients may be appropriate.Central Nervous SystemOne healthy male volunteer developed ideas of reference, paranoid delusions, andauditory hallucinations in association with multiple daily 600 mg doses of PROVIGIL andsleep deprivation. There was no evidence of psychosis 36 hours after drugdiscontinuation. Caution should be exercised when PROVIGIL is given to patients with ahistory of psychosis.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®12Patients with Severe Renal ImpairmentIn patients with severe renal impairment (mean creatinine clearance = 16.6 mL/min), a200 mg single dose of modafinil did not lead to increased exposure to modafinil butresulted in much higher exposure to the inactive metabolite, modafinil acid, than is seenin subjects with normal renal function. There is little information available about the safetyof such levels of this metabolite (see CLINICAL PHARMACOLOGY).Patients with Severe Hepatic ImpairmentIn patients with severe hepatic impairment, with or without cirrhosis (see CLINICALPHARMACOLOGY), PROVIGIL should be administered at a reduced dose as theclearance of modafinil was decreased compared to that in normal subjects (see DOSAGEand ADMINISTRATION).Elderly PatientsTo the extent that elderly patients may have diminished renal and/or hepatic function,dosage reductions should be considered (see DOSAGE and ADMINISTRATION).Patients Using ContraceptivesThe effectiveness of steroidal contraceptives may be reduced when used with PROVIGILtablets and for one month after discontinuation of therapy (See Potential Interactions withDrugs That Inhibit or are Metabolized by Cytochrome P-450 Isoenzymes and Other HepaticEnzymes). Alternative or concomitant methods of contraception are recommended forpatients treated with PROVIGIL tablets, and for one month after discontinuation ofPROVIGIL.Information for PatientsPhysicians are advised to discuss the following issues with patients for whom theyprescribe PROVIGIL tablets.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®13PregnancyAnimal studies to assess the effects of modafinil on reproduction and the developing fetuswere not conducted at adequately high doses or according to guidelines which wouldensure a comprehensive evaluation of the potential of modafinil to adversely affect fertility,or cause embryolethality or teratogenicity (see Impairment of Fertility and Pregnancy).Patients should be advised to notify their physician if they become pregnant or intend tobecome pregnant during therapy. Patients should be cautioned regarding the potentialincreased risk of pregnancy when using steroidal contraceptives (including depot orimplantable contraceptives) with PROVIGIL tablets and for one month after discontinuationof therapy.NursingPatients should be advised to notify their physician if they are breast feeding an infant.Concomitant MedicationPatients should be advised to inform their physician if they are taking, or plan to take, anyprescription or over-the-counter drugs, because of the potential for interactions betweenPROVIGIL tablets and other drugs.AlcoholPatients should be advised that the use of PROVIGIL in combination with alcohol has notbeen studied. Patients should be advised that it is prudent to avoid alcohol while takingPROVIGIL tablets.Allergic ReactionsPatients should be advised to notify their physician if they develop a rash, hives, or arelated allergic phenomenon.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®14Drug InteractionsCNS Active DrugsMethylphenidate - In a single-dose study in healthy volunteers, coadministration ofmodafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterationsin the pharmacokinetics of either drug. However, the absorption of PROVIGIL may bedelayed by approximately one hour when coadministered with methylphenidate.Clomipramine - The coadministration of a single dose of clomipramine (50 mg) on the firstof three days of treatment with modafinil (200 mg/day) in healthy volunteers did not showan effect on the pharmacokinetics of either drug. However, one incident of increasedlevels of clomipramine and its active metabolite desmethylclomipramine has been reportedin a patient with narcolepsy during treatment with modafinil (See Potential Interactions withDrugs That Inhibit or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes).Triazolam - In a single-dose pharmacodynamic study with PROVIGIL in healthy volunteers(50, 100 or 200 mg) and triazolam (0.25 mg), no clinically important alterations in thesafety profile of modafinil or triazolam were noted.Monoamine Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidaseinhibitors have not been performed. Therefore, caution should be used whenconcomitantly administering MAO inhibitors and modafinil.Potential Interactions with Drugs That Inhibit , Induce, or are Metabolized by CytochromeP-450 Isoenzymes and Other Hepatic EnzymesIn a controlled study in patients with narcolepsy, chronic dosing of PROVIGIL at 400mg/day once daily resulted in a ~20% mean decrease in modafinil plasma troughconcentrations by week 9, relative to those at week 3 suggesting that chronicadministration of PROVIGIL might have caused induction of its metabolism. In addition,
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®15coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital,rifampin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the levelsof modafinil due to the partial involvement of that enzyme in the metabolic elimination ofthe compound.In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightlyinduce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Althoughinduction results based on in vitro experiments are not necessarily predictive of responsein vivo, caution needs to be exercised when PROVIGIL is coadministered with drugs thatdepend on these three enzymes for their clearance. Specifically, lower blood levels ofsuch drugs could result. In the case of CYP1A2 and CYP2B6, no other evidence ofenzyme induction has been observed. A modest induction of CYP3A4 by modafinil hasbeen indicated by other results, hence the clearance of CYP3A4 substrates such ascyclosporine or steroidal contraceptives and to a lesser degree, theophylline may beincreased. One case of an interaction between modafinil and cyclosporine has beenreported in a 41 year old woman who had undergone an organ transplant. After one monthof administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by50%. The interaction was postulated to be due to the increased metabolism ofcyclosporine, since no other factor expected to affect the disposition of the drug hadchanged.The exposure of human hepatocytes to modafinil in vitro produced an apparentconcentration-related suppression of expression of CYP2C9 activity. The clinicalrelevance of this finding is unclear, since no other indication of CYP2C9 suppression hasbeen observed. However, monitoring of prothrombin times is suggested as a precautionfor the first several months of coadministration of PROVIGIL and warfarin, a CYP2C9substrate, and thereafter whenever PROVIGIL dosing is changed. In addition, patientsreceiving PROVIGIL and phenytoin, a CYP2C9 substrate, concomitantly should bemonitored for signs of phenytoin toxicity.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®16In vitro studies using human liver microsomes showed that modafinil has little or nocapacity to inhibit the major CYP enzymes except for CYP2C19, which is reversiblyinhibited at pharmacologically relevant concentrations of modafinil. Drugs that are largelyeliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin or S-mephenytoin may have prolonged elimination upon coadministration with PROVIGIL andmay require dosage reduction. In addition, CYP2C19 provides an ancillary pathway for the metabolism of certain tricyclicantidepressants (e.g., clomipramine and desipramine) that are primarily metabolized byCYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poormetabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in otherpopulations), the amount of metabolism by CYP2C19 may be substantially increased.PROVIGIL may cause elevation of the levels of the tricyclics in this subset of patients.Physicians should be aware that a reduction in the dose of tricyclic agents might beneeded in these patients.Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisCarcinogenicity studies were conducted in which modafinil was administered in the dietto mice for 78 weeks and to rats for 104 weeks at doses of 6, 30 and 60 mg/kg/day. Thehighest dose studied represents 1.5 times (mouse) or 3 times (rat) greater than themaximum recommended human daily dose of 200 mg on a mg/mbasis. There was no2 evidence of tumorigenesis associated with modafinil administration in these studies, butbecause the mouse study used an inadequate high dose that was not representative of amaximum tolerated dose, the carcinogenic potential of modafinil has not been fullyevaluated.MutagenesisThere was no evidence of mutagenic or clastogenic potential of modafinil in a series ofassays. It was not mutagenic in the in vitro Ames bacterial reverse mutation test, the in
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®17vitro mouse lymphoma/TK locus assay in the presence or absence of metabolic activation;and it was not clastogenic in the in vitro human lymphocyte chromosomal aberration assayin the presence or absence of metabolic activation, or in two in vivo mouse bone marrowmicronucleus assays. Modafinil did not increase unscheduled DNA synthesis in rathepatocytes. In a cell transformation assay in BALB/3T3 mouse embryo cells, modafinildid not cause an increase in the frequency of transformed foci in the presence or absenceof metabolic activation.Impairment of FertilityWhen modafinil was administered orally to male and female rats prior to and throughoutmating and gestation at doses up to 100 mg/kg/day (4.8 times the maximum recommendeddaily dose of 200 mg on a mg/m basis) no effects on fertility were seen. The study to2evaluate these effects, however, did not use sufficiently high doses or large enoughsample size to adequately assess effects on fertility.PregnancyPregnancy Category C: Embryotoxicity was observed in the absence of maternal toxicitywhen rats received oral modafinil throughout the period of organogenesis. At a dose of200 mg/kg/day (10 times the maximum recommended daily human dose of 200 mg on amg/m basis) there was an increase in resorption, hydronephrosis, and skeletal variations.2The no-effect dose for these effects was 100 mg/kg/day (5 times the maximumrecommended daily human dose on a mg/m basis). When rabbits received oral modafinil2throughout organogenesis at doses up to 100 mg/kg/day (10 times the maximumrecommended daily human dose on a mg/m basis), no embryotoxicity was seen. Neither2of these studies, however, used optimal doses for the evaluation of embryotoxicity.Although a threshold dose for embryotoxicity has been identified, the full spectrum ofpotential toxic effects on the fetus has not been characterized. When rats were dosedthroughout gestation and lactation at doses up to 200 mg/kg/day, no developmental toxicitywas noted post-natally in the offspring. There are no adequate and well-controlled trials
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®18with modafinil in pregnant women and this drug should be used during pregnancy only ifthe potential benefit outweighs the potential risk.
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®19Labor and DeliveryThe effect of modafinil on labor and delivery in humans has not been systematicallyinvestigated. Seven normal births occurred in patients who had received modafinil duringpregnancy. One patient gave birth 3 weeks earlier than the expected range of deliverydates (estimated using ultrasound) to a healthy male infant. One woman with a history ofspontaneous abortions suffered a spontaneous abortion while being treated with modafinil.Nursing MothersIt is not known whether modafinil or its metabolites are excreted in human milk. Becausemany drugs are excreted in human milk, caution should be exercised when PROVIGILtablets are administered to a nursing woman.PEDIATRIC USESafety and effectiveness in individuals below 16 years of age have not been established.GERIATRIC USESafety and effectiveness in individuals above 65 years of age have not been established.Experience in a limited number of patients (15) who were greater than 65 years of age inUS clinical trials showed an incidence of adverse experiences similar to other age groups.ADVERSE REACTIONSModafinil has been evaluated for safety in over 2200 subjects, of whom more than 900subjects with narcolepsy or narcolepsy/hypersomnia were given at least one dose ofmodafinil. Modafinil has been found to be generally well-tolerated. In controlled clinicaltrials, most adverse experiences were mild to moderate.The most commonly observed adverse events (
`
`%) associated with the use of modafinilmore frequently than placebo-treated patients in controlled US and foreign studies wereheadache, infection, nausea, nervousness, anxiety, and insomnia.
`
`$ 5
`
`

`

`NDA 20-717Provigil (modafinil) – FDA Approved Draft Labeling 12/98®20In US placebo-controlled Phase 3 clinical trials, 5% of the 369 patients who receivedPROVIGIL discontinued due to an adverse experience. The most frequent (
`%) reasonsfor discontinuation that occurred at a higher rate for PROVIGIL than placebo patients wereheadache (1%), nausea (1%), depression (1%) and nervousness (1%). In foreign,controlled clinical trials, reasons for discontinuation were similar to those in US trials. Ina Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history ofsyncopal episodes experienced a 9 second episode of asystole while sleeping after 27days of modafinil treatment (300 mg/day in divided doses). Incidence in Controlled TrialsThe following table presents the adv