`
`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
`
`PROVIGIL® (modafinil) Tablets [C-IV] Rx Only
`
`DESCRIPTION
`PROVIGIL (modafinil) is a wakefulness-promoting agent for oral administration. Modafinil is a
`racemic compound. The chemical name for modafinil is 2-[(diphenylmethyl)sulfinyl]acetamide.
`The molecular formula is C15H15NO2S and the molecular weight is 273.35.
`
`The chemical structure is:
`
`
`O
`CH S
`
`O
`CH2 C NH2
`
`
`Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and
`cyclohexane. It is sparingly to slightly soluble in methanol and acetone. PROVIGIL tablets
`contain 100 mg or 200 mg of modafinil and the following inactive ingredients: lactose,
`microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and
`magnesium stearate.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action and Pharmacology
`The precise mechanism(s) through which modafinil promotes wakefulness is unknown.
`Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine and
`methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic
`amines.
`
`Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin,
`dopamine, GABA, adenosine, histamine-3, melatonin, and benzodiazepines. Modafinil also does
`not inhibit the activities of MAO-B or phosphodiesterases II-V.
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`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
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`Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist
`prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive
`to α-adrenergic agonists, such as the rat vas deferens preparation.
`
`Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro,
`modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has
`been associated in vivo with increased extracellular dopamine levels in some brain regions of
`animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil
`lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the
`wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the
`dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a
`dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor
`activity induced by modafinil.
`
`In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamine increased
`neuronal activation throughout the brain. Modafinil at an equivalent wakefulness-promoting
`dose selectively and prominently increased neuronal activation in more discrete regions of the
`brain. The relationship of this finding in cats to the effects of modafinil in humans is unknown.
`
`In addition to its wake-promoting effects and ability to increase locomotor activity in animals,
`modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking,
`and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as
`evidenced by its self-administration in monkeys previously trained to self-administer cocaine.
`Modafinil was also partially discriminated as stimulant-like.
`
`The optical enantiomers of modafinil have similar pharmacological actions in animals. Two
`major metabolites of modafinil, modafinil acid and modafinil sulfone, do not appear to
`contribute to the CNS-activating properties of modafinil.
`
`Pharmacokinetics
`Modafinil 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 in adult humans). The
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`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
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`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 (Cminss) of circulating modafinil after
`once daily dosing consists of 90% of the l-isomer and 10% of the d-isomer. The effective
`elimination half-life of modafinil after multiple doses is about 15 hours. The enantiomers of
`modafinil exhibit linear kinetics upon multiple dosing of 200-600 mg/day once daily in healthy
`volunteers. Apparent steady states of total modafinil and l-(-)-modafinil are reached after 2-4
`days of dosing.
`
`Absorption
`Absorption of PROVIGIL tablets is rapid, with peak plasma concentrations occurring at 2-4
`hours. The bioavailability of PROVIGIL tablets is approximately equal to that of an aqueous
`suspension. The absolute oral bioavailability was not determined due to the aqueous insolubility
`(<1 mg/mL) of modafinil, which precluded intravenous administration. Food has no effect on
`overall PROVIGIL bioavailability; however, its absorption (tmax) may be delayed by
`approximately one hour if taken with food.
`
`Distribution
`Modafinil is well distributed in body tissue with an apparent volume of distribution (~0.9 L/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 serum concentrations
`obtained at steady state after doses of 200 mg/day, modafinil exhibits no displacement of protein
`binding of warfarin, diazepam or propranolol. Even at much larger concentrations (1000µM; >
`25 times the Cmax of 40µM at steady state at 400 mg/day), modafinil has no effect on warfarin
`binding. Modafinil acid at concentrations >500µM decreases the extent of warfarin binding, but
`these concentrations are >35 times those achieved therapeutically.
`
`Metabolism and Elimination
`The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent
`renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of
`modafinil.
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`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
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`Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation,
`and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent
`compound. In a clinical study using radiolabeled modafinil, a total of 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 drug in urine was modafinil acid but at least six other
`metabolites were present in lower concentrations. Only two metabolites reach appreciable
`concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models,
`modafinil acid, modafinil sulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy
`modafinil, were inactive or did not appear to mediate the arousal effects of modafinil.
`
`In adults, decreases in trough levels of modafinil have sometimes been observed after multiple
`weeks of dosing, suggesting auto-induction, but the magnitude of the decreases and the
`inconsistency of their occurrence suggest that their clinical significance is minimal. Significant
`accumulation of modafinil sulfone has been observed after multiple doses due to its long
`elimination half-life of 40 hours. Induction of metabolizing enzymes, most importantly
`cytochrome P-450 (CYP) 3A4, has also been observed in vitro after incubation of primary
`cultures of human hepatocytes with modafinil and in vivo after extended administration of
`modafinil at 400 mg/day. (For further discussion of the effects of modafinil on CYP enzyme
`activities, see PRECAUTIONS, Drug Interactions.)
`
`Drug-Drug Interactions: Based on in vitro data, modafinil is metabolized partially by the 3A
`isoform subfamily of hepatic cytochrome P450 (CYP3A4). In addition, modafinil has the
`potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2.
`Because modafinil and modafinil sulfone are reversible inhibitors of the drug-metabolizing
`enzyme CYP2C19, co-administration of modafinil with drugs such as diazepam, phenytoin and
`propranolol, which are largely eliminated via that pathway, may increase the circulating levels of
`those compounds. In addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% of
`the Caucasian population; similar or lower in other populations), the levels of CYP2D6
`substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which
`have ancillary routes of elimination through CYP2C19, may be increased by co-administration
`of modafinil. Dose adjustments may be necessary for patients being treated with these and
`similar medications (See PRECAUTIONS, Drug Interactions). An in vitro study
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`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
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`demonstrated that armodafinil (one of the enantiomers of modafinil) is a substrate of P-
`glycoprotein.
`
`Coadministration of modafinil with other CNS active drugs such as methylphenidate and
`dextroamphetamine did not significantly alter the pharmacokinetics of either drug.
`
`Chronic administration of modafinil 400 mg was found to decrease the systemic exposure to two
`CYP3A4 substrates, ethinyl estradiol and triazolam, after oral administration suggesting that
`CYP3A4 had been induced. Chronic administration of modafinil can increase the elimination of
`substrates of CYP3A4. Dose adjustments may be necessary for patients being treated with these
`and similar medications (See PRECAUTIONS, Drug Interactions).
`
`An apparent concentration-related suppression of CYP2C9 activity was observed in human
`hepatocytes after exposure to modafinil in vitro suggesting that there is a potential for a
`metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin,
`phenytoin). However, in an interaction study in healthy volunteers, chronic modafinil treatment
`did not show a significant effect on the pharmacokinetics of warfarin when compared to placebo.
`(See PRECAUTIONS, Drug Interactions, Other Drugs, Warfarin).
`
`Special Populations
`Gender Effect: The pharmacokinetics of modafinil are not affected by gender.
`
`Age Effect: A slight decrease (~20%) in the oral clearance (CL/F) of modafinil was observed in
`a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53 – 72 years),
`but the change was considered not likely to be clinically significant. In a multiple dose 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 historically obtained in matched
`younger subjects. Due to potential effects from the multiple concomitant medications with which
`most of the patients were being treated, the apparent difference in modafinil pharmacokinetics
`may not be attributable solely to the effects of aging. However, the results suggest that the
`clearance of modafinil may be reduced in the elderly (See DOSAGE AND
`ADMINISTRATION).
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`FDA Approved Labeling dated August 17, 2007
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`Race Effect: The influence of race on the pharmacokinetics of modafinil has not been studied.
`
`Renal Impairment: In a single dose 200 mg modafinil study, severe chronic renal failure
`(creatinine clearance ≤ 20 mL/min) did not significantly influence the pharmacokinetics of
`modafinil, but exposure to modafinil acid (an inactive metabolite) was increased 9-fold (See
`PRECAUTIONS).
`
`Hepatic Impairment: Pharmacokinetics and metabolism were examined in patients with cirrhosis
`of the liver (6 males and 3 females). Three patients had stage B or B+ cirrhosis (per the Child
`criteria) and 6 patients had stage C or C+ cirrhosis. Clinically 8 of 9 patients were icteric and all
`had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and
`the steady state concentration was doubled compared to normal patients. The dose of PROVIGIL
`should be reduced in patients with severe hepatic impairment (See PRECAUTIONS and
`DOSAGE AND ADMINISTRATION).
`
`CLINICAL TRIALS
`The effectiveness of PROVIGIL in reducing excessive sleepiness has been established in the
`following sleep disorders: narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS),
`and shift work sleep disorder (SWSD).
`
`Narcolepsy
`The effectiveness of PROVIGIL in reducing the excessive sleepiness (ES) 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 Disorders Association criteria for narcolepsy (which are also
`consistent with the American Psychiatric Association DSM-IV criteria). These criteria include
`either 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three
`months, plus sudden bilateral loss of postural muscle tone in association with intense emotion
`(cataplexy) or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated
`features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep
`episode; and polysomnography demonstrating one of the following: sleep latency less than 10
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`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
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`minutes or rapid eye movement (REM) sleep latency less than 20 minutes. In addition, for entry
`into these studies, all patients were required to have objectively documented excessive daytime
`sleepiness, a Multiple Sleep Latency Test (MSLT) with two or more sleep onset REM periods,
`and the absence of any other clinically significant active medical or psychiatric disorder. The
`MSLT, an objective daytime polysomnographic assessment of the patient’s ability to fall asleep
`in an unstimulating environment, measures latency (in minutes) to sleep onset averaged over 4
`test sessions at 2-hour intervals following nocturnal polysomnography. For each test session, the
`subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20
`minutes if no sleep occurred or 15 minutes after sleep onset.
`
`In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the
`Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall disease
`status, as measured by the Clinical Global Impression of Change (CGI-C). For a successful trial,
`both measures had to show significant improvement.
`
`The MWT measures latency (in minutes) to sleep onset averaged over 4 test sessions at 2 hour
`intervals following nocturnal polysomnography. For each test session, the subject was asked to
`attempt to remain awake without using extraordinary measures. Each test session was
`terminated after 20 minutes if no sleep occurred or 10 minutes after sleep onset. The CGI-C is a
`7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much
`Improved. Patients were rated by evaluators who had no access to any data about the patients
`other than a measure of their baseline severity. Evaluators were not given any specific guidance
`about the criteria they were to apply when rating patients.
`
`Other assessments of effect included the Multiple Sleep Latency Test (MSLT), Epworth
`Sleepiness Scale (ESS; a series of questions designed to assess the degree of sleepiness in
`everyday situations) the Steer Clear Performance Test (SCPT; a computer-based evaluation 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 also assessed with the Quality of
`Life in Narcolepsy (QOLIN) scale, which contains the validated SF-36 health questionnaire.
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`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
`
`Both studies demonstrated improvement in objective and subjective measures of excessive
`daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patients treated
`with either dose of PROVIGIL showed a statistically significantly enhanced ability to remain
`awake on the MWT (all p values <0.001) at weeks 3, 6, 9, and final visit compared to placebo
`and a statistically significantly greater global improvement, as rated on the CGI-C scale (all p
`values <0.05).
`
`The average sleep latencies (in minutes) on the MWT at baseline for the 2 controlled trials are
`shown in Table 1 below, along with the average change from baseline on the MWT at final visit.
`
`The percentages of patients who showed any degree of improvement on the CGI-C in the two
`clinical trials are shown in Table 2 below.
`
`Similar statistically significant treatment-related improvements were seen on other measures of
`impairment in narcolepsy, including a patient assessed level of daytime sleepiness on the ESS
`(p<0.001 for each dose in comparison to placebo).
`
`Nighttime sleep measured with polysomnography was not affected by the use of PROVIGIL.
`
`Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)
`The effectiveness of PROVIGIL in reducing the excessive sleepiness associated with OSAHS
`was established in two clinical trials. In both studies, patients were enrolled who met the
`International Classification of Sleep Disorders (ICSD) criteria for OSAHS (which are also
`consistent with the American Psychiatric Association DSM-IV criteria). These criteria include
`either, 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during
`sleep, and associated features such as loud snoring, morning headaches and dry mouth upon
`awakening; or 2) excessive sleepiness or insomnia and polysomnography demonstrating one of
`the following: more than five obstructive apneas, each greater than 10 seconds in duration, per
`hour of sleep and one or more of the following: frequent arousals from sleep associated with the
`apneas, bradytachycardia, and arterial oxygen desaturation in association with the apneas. In
`addition, for entry into these studies, all patients were required to have excessive sleepiness as
`demonstrated by a score ≥10 on the Epworth Sleepiness Scale, despite treatment with continuous
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`positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of
`apnea/hypopnea was required along with documentation of CPAP use.
`
`In the first study, a 12-week multicenter placebo-controlled trial, a total of 327 patients were
`randomized to receive PROVIGIL 200 mg/day, PROVIGIL 400 mg/day, or matching placebo.
`The majority of patients (80%) were fully compliant with CPAP, defined as CPAP use > 4
`hours/night on > 70% nights. The remainder were partially CPAP compliant, defined as CPAP
`use < 4 hours/night on >30% nights. CPAP use continued throughout the study. The primary
`measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness
`Test (MWT) and 2) the change in the patient’s overall disease status, as measured by the Clinical
`Global Impression of Change (CGI-C) at week 12 or the final visit. (See CLINICAL TRIALS,
`Narcolepsy section above for a description of these tests.)
`
`Patients treated with PROVIGIL showed a statistically significant improvement in the ability to
`remain awake compared to placebo-treated patients as measured by the MWT (p<0.001) at
`endpoint [Table 1]. PROVIGIL-treated patients also showed a statistically significant
`improvement in clinical condition as rated by the CGI-C scale (p<0.001) [Table 2]. The two
`doses of PROVIGIL performed similarly.
`
`In the second study, a 4-week multicenter placebo-controlled trial, 157 patients were randomized
`to either PROVIGIL 400 mg/day or placebo. Documentation of regular CPAP use (at least 4
`hours/night on 70% of nights) was required for all patients. The primary outcome measure was
`the change from baseline on the ESS at week 4 or final visit. The baseline ESS scores for the
`PROVIGIL and placebo groups were 14.2 and 14.4, respectively. At week 4, the ESS was
`reduced by 4.6 in the PROVIGIL group and by 2.0 in the placebo group, a difference that was
`statistically significant (p<0.0001).
`
`Nighttime sleep measured with polysomnography was not affected by the use of PROVIGIL.
`
`Shift Work Sleep Disorder (SWSD)
`The effectiveness of PROVIGIL for the excessive sleepiness associated with SWSD was
`demonstrated in a 12-week placebo-controlled clinical trial. A total of 209 patients with chronic
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`FDA Approved Labeling dated August 17, 2007
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`SWSD were randomized to receive PROVIGIL 200 mg/day or placebo. All patients met the
`International Classification of Sleep Disorders (ICSD-10) criteria for chronic SWSD (which are
`consistent with the American Psychiatric Association DSM-IV criteria for Circadian Rhythm
`Sleep Disorder: Shift Work Type). These criteria include 1) either: a) a primary complaint of
`excessive sleepiness or insomnia which is temporally associated with a work period (usually
`night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT
`demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity);
`and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do
`not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g.,
`time zone change [jet lag] syndrome).
`
`It should be noted that not all patients with a complaint of sleepiness who are also engaged in
`shift work meet the criteria for the diagnosis of SWSD. In the clinical trial, only patients who
`were symptomatic for at least 3 months were enrolled.
`
`Enrolled patients were also required to work a minimum of 5 night shifts per month, have
`excessive sleepiness at the time of their night shifts (MSLT score < 6 minutes), and have daytime
`insomnia documented by a daytime polysomnogram (PSG).
`
`The primary measures of effectiveness were 1) sleep latency, as assessed by the Multiple Sleep
`Latency Test (MSLT) performed during a simulated night shift at week 12 or the final visit and
`2) the change in the patient’s overall disease status, as measured by the Clinical Global
`Impression of Change (CGI-C) at week 12 or the final visit. Patients treated with PROVIGIL
`showed a statistically significant prolongation in the time to sleep onset compared to placebo-
`treated patients, as measured by the nighttime MSLT [Table 1] (p<0.05). Improvement on the
`CGI-C was also observed to be statistically significant (p<0.001). (See CLINICAL TRIALS,
`Narcolepsy section above for a description of these tests.)
`
`Daytime sleep measured with polysomnography was not affected by the use of PROVIGIL.
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`Disorder
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`Measure
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`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
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`Table 1. Average Baseline Sleep Latency and Change from Baseline at Final Visit in Adults
`(MWT and MSLT in minutes)
`PROVIGIL
`PROVIGIL
`200 mg *
`400 mg*
`Baseline
`Change
`Baseline
`Change
`from
`from
`Baseline
`Baseline
`6.6
`2.3
`2.3
`5.8
`Narcolepsy I MWT
`5.9
`2.2
`2.0
`6.1
`Narcolepsy II MWT
`13.6
`1.6
`1.5
`13.1
`MWT
`OSAHS
`-
`1.7
`-
`2.1
`MSLT
`SWSD
`*Significantly different than placebo for all trials (p<0.01 for all trials but SWSD, which was p<0.05)
`
`
`Placebo
`
`Baseline
`
`5.8
`6.0
`13.8
`2.0
`
`Change
`from
`Baseline
`-0.7
`-0.7
`-1.1
`0.3
`
`Disorder
`
`Table 2. Clinical Global Impression of Change (CGI-C) (Percent of
`Adult Patients Who Improved at Final Visit)
`PROVIGIL
`PROVIGIL
`200 mg*
`400 mg*
`64%
`72%
`Narcolepsy I
`58%
`60%
`Narcolepsy II
`61%
`68%
`OSAHS
`74%
`------
`SWSD
`*Significantly different than placebo for all trials (p<0.01)
`
`Placebo
`
`37%
`38%
`37%
`36%
`
`
`INDICATIONS AND USAGE
`PROVIGIL is indicated to improve wakefulness in adult patients with excessive sleepiness
`associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep
`disorder.
`
`In OSAHS, PROVIGIL is indicated as an adjunct to standard treatment(s) for the underlying
`obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a
`patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior
`to initiating PROVIGIL. If PROVIGIL is used adjunctively with CPAP, the encouragement of
`and periodic assessment of CPAP compliance is necessary.
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`In all cases, careful attention to the diagnosis and treatment of the underlying sleep disorder(s) is
`of utmost importance. Prescribers should be aware that some patients may have more than one
`sleep disorder contributing to their excessive sleepiness.
`
`The effectiveness of modafinil in long-term use (greater than 9 weeks in Narcolepsy clinical
`trials and 12 weeks in OSAHS and SWSD clinical trials) has not been systematically evaluated
`in placebo-controlled trials. The physician who elects to prescribe PROVIGIL for an extended
`time in patients with Narcolepsy, OSAHS, or SWSD should periodically reevaluate long-term
`usefulness for the individual patient.
`
`CONTRAINDICATIONS
`PROVIGIL is contraindicated in patients with known hypersensitivity to modafinil, armodafinil
`or its inactive ingredients.
`
`WARNINGS
`Serious Rash, including Stevens-Johnson Syndrome
`Serious rash requiring hospitalization and discontinuation of treatment has been reported
`in adults and children in association with the use of modafinil.
`
`Modafinil is not approved for use in pediatric patients for any indication.
`
`In clinical trials of modafinil, the incidence of rash resulting in discontinuation was
`approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes
`included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-
`organ hypersensitivity reaction. Several of the cases were associated with fever and other
`abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in
`discontinuation was 13 days. No such cases were observed among 380 pediatric patients
`who received placebo. No serious skin rashes have been reported in adult clinical trials (0
`per 4,264) of modafinil.
`
`Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis
`(TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been
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`reported in adults and children in worldwide post-marketing experience. The reporting
`rate of TEN and SJS associated with modafinil use, which is generally accepted to be an
`underestimate due to underreporting, exceeds the background incidence rate. Estimates of
`the background incidence rate for these serious skin reactions in the general population
`range between 1 to 2 cases per million-person years.
`
`There are no factors that are known to predict the risk of occurrence or the severity of rash
`associated with modafinil. Nearly all cases of serious rash associated with modafinil
`occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been
`reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy
`cannot be relied upon as a means to predict the potential risk heralded by the first
`appearance of a rash.
`
`Although benign rashes also occur with modafinil, it is not possible to reliably predict
`which rashes will prove to be serious. Accordingly, modafinil should ordinarily be
`discontinued at the first sign of rash, unless the rash is clearly not drug-related.
`Discontinuation of treatment may not prevent a rash from becoming life-threatening or
`permanently disabling or disfiguring.
`
`Angioedema and Anaphylactoid Reactions
`One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and
`bronchospasm), were observed among 1,595 patients treated with armodafinil, the R enantiomer
`of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical
`trials. However, angioedema has been reported in postmarketing experience with modafinil.
`Patients should be advised to discontinue therapy and immediately report to their physician any
`signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips,
`tongue or larynx; difficulty in swallowing or breathing; hoarseness).
`
`Multi-organ Hypersensitivity Reactions
`Multi-organ hypersensitivity reactions, including at least one fatality in postmarketing
`experience, have occurred in close temporal association (median time to detection 13 days: range
`4-33) to the initiation of modafinil.
`
`
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`13
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`

`

`
`
`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
`
`
`Although there have been a limited number of reports, multi-organ hypersensitivity reactions
`may result in hospitalization or be life-threatening. There are no factors that are known to
`predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions associated
`with modafinil. Signs and symptoms of this disorder were diverse; however, patients typically,
`although not exclusively, presented with fever and rash associated with other organ system
`involvement. Other associated manifestations included myocarditis, hepatitis, liver function test
`abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia),
`pruritis, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other
`organ system symptoms and signs, not noted here, may occur.
`
`If a multi-organ hypersensitivity reaction is suspected, PROVIGIL should be discontinued.
`Although there are no case reports to indicate cross-sensitivity with other drugs that produce this
`syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate
`this to be a possibility.
`
`Persistent Sleepiness
`Patients with abnormal levels of sleepiness who take PROVIGIL should be advised that their
`level of wakefulness may not return to normal. Patients with excessive sleepiness, including
`those taking PROVIGIL, should be frequently reassessed for their degree of sleepiness and, if
`appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers
`should also be aware that patients may not acknowledge sleepiness or drowsiness until directly
`questioned about drowsiness or sleepiness during specific activities.
`
`Psychiatric Symptoms
`Psychiatric adverse experiences have been reported in patients treated with modafinil.
`Postmarketing adverse events associated with the use of modafinil have included mania,
`delusions, hallucinations, and suicidal ideation, some resulting in hospitalization. Many, but not
`all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of
`reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600
`mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after
`drug discontinuation.
`
`
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`14
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`

`
`
`NDA 20-717 PROVIGIL® (modafinil) Tablets
`FDA Approved Labeling dated August 17, 2007
`
`
`In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment
`discontinuation (at a frequency >0.3%) and reported more often in patients treated with
`modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%),
`insomnia (<1%), confusion (<1%), agitation(<1%), and depression (<1%). Caution should be
`exercised when PROVIGIL is given to patients with a history of psychosis, depression, or mania.
`Consideration should be given to the possible emergence or exacerbation of psychiatric
`symptoms in patients treated with PROVIGIL. If psychiatric symptoms develop in association
`with PROVIGIL administration, consider discontinuing PROVIGIL.
`
`PRECAUTIONS
`Diagnosis of Sleep Disorders
`
`PROVIGIL should be used only in patients who have had a complete