throbber
FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
`Approved-23-JAN-2004
`
`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 273.36.
`
`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
`like sympathomimetic agents
`including
`amphetamine and methylphenidate, although the pharmacologic profile is not identical
`to that of sympathomimetic amines.
`
`At pharmacologically relevant concentrations, modafinil does not bind to most
`potentially
`relevant
`receptors
`for sleep/wake
`regulation,
`including
`those
`for
`norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, or
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`benzodiazepines. Modafinil also does 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 in
`several in vivo preclinical models capable of detecting enhanced dopaminergic activity.
`In vitro, modafinil binds to the dopamine reuptake site and causes an increase in
`extracellular dopamine, but no increase in dopamine release. In a preclinical model, the
`wakefulness induced by amphetamine, but not modafinil, is antagonized by the
`dopamine receptor antagonist haloperidol.
`
`Modafinil does not appear to be a direct or indirect α1-adrenergic agonist. Although
`modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor
`antagonist, prazosin, in assay systems known to be responsive to α-adrenergic
`agonists, modafinil has no activity. Modafinil does not display sympathomimetic activity
`in the rat vas deferens preparations (agonist-stimulated or electrically stimulated) nor
`does it increase the formation of the adrenergic receptor-mediated second messenger
`phosphatidyl inositol in in vitro models. Unlike sympathomimetic agents, modafinil does
`not reduce cataplexy in narcoleptic canines and has minimal effects on cardiovascular
`and hemodynamic parameters.
`
`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 wakefulness-promoting effects and increased locomotor activity in
`animals, in humans, PROVIGIL produces psychoactive and euphoric effects, alterations
`in mood, perception, thinking, and feelings typical of other CNS stimulants. Modafinil is
`reinforcing, as evidenced by its self-administration in monkeys previously trained to self-
`administer cocaine; modafinil was also partially discriminated as stimulant-like.
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`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
`humans). 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
`(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 and Distribution
`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.
`
`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 (1000:M; >25 times the Cmax of 40:M at steady state at
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`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
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`400 mg/day), modafinil has no effect on warfarin binding. Modafinil acid at
`the extent of warfarin binding, but
`these
`concentrations >500:M decreases
`concentrations are > 35 times those achieved therapeutically.
`
`Metabolism and Elimination
`The major route of elimination (~90%) is metabolism, primarily by the liver, with
`subsequent renal elimination of the metabolites. Urine alkalinization has no effect on
`the elimination of modafinil.
`
`ring
`through hydrolytic deamidation, S-oxidation, aromatic
`Metabolism occurs
`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 humans, 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).
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`Drug-Drug Interactions: 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).
`
`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).
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`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
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`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
`the elderly (See DOSAGE AND
`clearance of modafinil may be reduced
`in
`ADMINISTRATION).
`
`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 M and 3 F). 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).
`
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`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
`Approved-23-JAN-2004
`
`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 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.
`
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`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
`Approved-23-JAN-2004
`
`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.
`
`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).
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`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
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`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).
`
`Although PROVIGIL tended to be numerically superior to placebo on several of the
`other outcome measures, there were no consistent statistically significant differences
`between drug and placebo on these measures.
`
`Nighttime sleep measured with polysomnography was not affected by the use of
`PROVIGIL.
`
`The effectiveness of modafinil in long-term use (greater than 9 weeks) has not been
`systematically evaluated in placebo-controlled trials. The physician who elects to
`prescribe PROVIGIL tablets for an extended time in patients with narcolepsy should
`periodically re-evaluate long-term usefulness for the individual patient.
`
`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
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`
`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 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 200mg/day, PROVIGIL 400mg/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.
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`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
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`
`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.
`
`The effectiveness of modafinil in long-term use (greater than 12 weeks) has not been
`systematically evaluated in placebo-controlled trials. The physician who elects to
`prescribe PROVIGIL tablets for an extended time in patients with OSAHS should
`periodically reevaluate long-term usefulness for the individual patient.
`
`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 SWSD were randomized to receive PROVIGIL 200mg/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.
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`
`
`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).
`
`Daytime sleep measured with polysomnography was not affected by the use of
`PROVIGIL.
`
`The effectiveness of modafinil in long-term use (greater than 12 weeks) has not been
`systematically evaluated in placebo-controlled trials. The physician who elects to
`prescribe PROVIGIL for an extended time in patients with SWSD should periodically
`reevaluate long-term usefulness for the individual patient.
`
`Table 1. Average Baseline Sleep Latency and Change from Baseline at Final Visit
`(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)
`
`Disorder Measure
`
`
`
`
`
`12
`
`Placebo
`
`Baseline
`
`5.8
`6.0
`13.8
`2.0
`
`Change
`from
`Baseline
`-0.7
`-0.7
`-1.1
`0.3
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`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
`Approved-23-JAN-2004
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`
`
`Table 2. Clinical Global Impression of Change (CGI-C)
`(Percent of Patients Who Improved at Final Visit)
`Disorder
`PROVIGIL
`PROVIGIL
`Placebo
`200mg*
`400mg*
`64%
`72%
`Narcolepsy I
`58%
`60%
`Narcolepsy II
`61%
`68%
`OSAHS
`74%
`------
`SWSD
`*Significantly different than placebo for all trials (p<0.01)
`
`37%
`36%
`
`37%
`38%
`
`
`INDICATIONS AND USAGE
`PROVIGIL is indicated to improve wakefulness in 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.
`
`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.
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`
`CONTRAINDICATIONS
`PROVIGIL is contraindicated in patients with known hypersensitivity to modafinil.
`
`WARNINGS
`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.
`
`PRECAUTIONS
`Diagnosis of Sleep Disorders
`
`PROVIGIL should be used only in patients who have had a complete evaluation of their
`excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSAHS, and/or
`SWSD has been made in accordance with ICSD or DSM diagnostic criteria (See
`CLINICAL TRIALS Section). Such an evaluation usually consists of a complete history
`and physical examination, and it may be supplemented with testing in a laboratory
`setting. Some patients may have more than one sleep disorder contributing to their
`excessive sleepiness (e.g., OSAHS and SWSD coincident in the same patient).
`
`CPAP Use in Patients with OSAHS
`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.
`
`14
`
`

`

`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
`Approved-23-JAN-2004
`
`
`General
`Although modafinil has not been shown to produce functional impairment, any drug
`affecting the CNS may alter judgment, thinking or motor skills. Patients should be
`cautioned about operating an automobile or other hazardous machinery until they are
`reasonably certain that PROVIGIL therapy will not adversely affect their ability to
`engage in such activities.
`
`Patients Using Contraceptives
`The effectiveness of steroidal contraceptives may be reduced when used with
`PROVIGIL tablets and for one month after discontinuation of therapy (See Drug
`Interactions). Alternative or concomitant methods of contraception are recommended
`for patients treated with PROVIGIL tablets, and for one month after discontinuation of
`PROVIGIL.
`
`Cardiovascular System
`In clinical studies of PROVIGIL, signs and symptoms including chest pain, palpitations,
`dyspnea and transient ischemic T-wave changes on ECG were observed in three
`subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is
`recommended that PROVIGIL tablets not be used in patients with a history of left
`ventricular hypertrophy or in patients with mitral valve prolapse who have experienced
`the mitral valve prolapse syndrome when previously receiving CNS stimulants. Such
`signs may include but are not limited to ischemic ECG changes, chest pain, or
`arrhythmia.
`
`Modafinil has not been evaluated or used to any appreciable extent in patients with a
`recent history of myocardial infarction or unstable angina, and such patients should be
`treated with caution.
`
`Blood pressure monitoring in short-term (<3 months) controlled trials showed no
`clinically significant changes in mean systolic and diastolic blood pressure in patients
`
`
`15
`
`

`

`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
`Approved-23-JAN-2004
`
`receiving PROVIGIL as compared to placebo. However, a retrospective analysis of the
`use of antihypertensive medication in these studies showed that a greater proportion of
`patients on PROVIGIL required new or increased use of antihypertensive medications
`(2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger
`when only studies in OSAHS were included, with 3.4% of patients on PROVIGIL and
`1.1% of patients on placebo requiring such alterations in the use of antihypertensive
`medication. Increased monitoring of blood pressure may be appropriate in patients on
`PROVIGIL.
`
`Central Nervous System
`There have been reports of psychotic episodes associated with PROVIGIL use. One
`healthy male volunteer developed ideas of reference, paranoid delusions, and auditory
`hallucinations in association with multiple daily 600 mg doses of PROVIGIL and sleep
`deprivation. There was no evidence of psychosis 36 hours after drug discontinuation.
`Caution should be exercised when PROVIGIL is given to patients with a history of
`psychosis.
`
`Patients with Severe Renal Impairment
`In patients with severe renal impairment (mean creatinine clearance = 16.6 mL/min), a
`200 mg single dose of modafinil did not lead to increased exposure to modafinil but
`resulted in much higher exposure to the inactive metabolite, modafinil acid, than is seen
`in subjects with normal renal function. There is little information available about the
`safety of such levels of this metabolite (See CLINICAL PHARMACOLOGY).
`
`Patients with Severe Hepatic Impairment
`In patients with severe hepatic impairment, with or without cirrhosis (See CLINICAL
`PHARMACOLOGY), PROVIGIL should be administered at a reduced dose as the
`clearance of modafinil was decreased compared to that in normal subjects (See
`DOSAGE AND ADMINISTRATION).
`
`
`16
`
`

`

`FDA Approved Labeling Text for NDA 20-717/S-005 &S-008
`Approved-23-JAN-2004
`
`Elderly Patients
`To the extent that elderly patients may have diminished renal and/or hepatic function,
`dosage reductions should be considered (See DOSAGE AND ADMINISTRATION).
`
`Information for Patients
`Physicians are advised to discuss the following issues with patients for whom they
`prescribe PROVIGIL.
`
`PROVIGIL is indicated for patients who have abnormal levels of sleepiness. PROVIGIL
`has been shown to improve, but not eliminate this abnormal tendency to fall asleep.
`Therefore, patients should not alter their previous behavior with regard to potentially
`dangerous activities (e.g., driving, operating machinery) or other activities requiring
`appropriate levels of wakefulness, until and unless treatment with PROVIGIL has been
`shown to produce levels of wak

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