CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER: 020717
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`FINAL PRINTED LABELING
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` NDA 20-717 1
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`PROVIGIL® (modafinil) TABLETS
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`DESCRIPTION
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`PROVIGIL (modafinil) is a wakefulness-promoting agent for oral administration. Modafinil
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`is
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`a
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`racemic
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`compound.
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`The
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`chemical
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`name
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`for
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`modafinil
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`is
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`2-[(diphenylmethyl)sulfinyl]acetamide. The molecular formula is C15H15N028 and the
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`molecular weight is 273.36.
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`The chemical structure is:
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`©iili
`CW
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`CH—S-CHg—C—NHZ
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`Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and
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`cyclohexane.
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`It is sparingly to slightly soluble in methanol and acetone. PROVIGIL tablets
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`contain 100 mg or 200 mg of modafinil and the following inactive ingredients: lactose, corn
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`starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, and
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`talc.
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`CLINICAL PHARMACOLOGY
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`Mechanism of Action and Pharmacology
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`The precise mechanism(s) through which modafinil promotes wakefulness is unknown.
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`Modafinil has wake-promoting actions
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`like
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`sympathomimetic
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`agents including
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`amphetamine and methylphenidate, although the phar'rnacologic profile is not identical to
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`that of sympathomimetic amines.
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`NDA 20-717
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`At pharmacologically relevant concentrations, modafinil does not bind to most potentially
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`relevant receptors for sleep/wake regulation, including those for norepinephrine, serotonin,
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`dopamine, GABA, adenosine, histamine-3, melatonin, or benzodiazepines. Modafinil also
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`does not inhibit the activities of MAO-B or phosphodiesterases ll-V.
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`Modafinil is not a direct- or indirect-acting dopamine receptor agonist and is inactive in
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`several in vivo preclinical models capable of detecting enhanced dopaminergic activity.
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`In vitro, modafinil binds to the dopamine reuptake site and causes an increase in
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`extracellular dopamine, but no increase in dopamine release.
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`In a preclinical model, the
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`wakefulness induced by amphetamine, but not modafinil, is antagonized by the dopamine
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`receptor antagonist haloperidol.
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`Modafinil does not appear to be a direct or indirect 0(1-adrenergic agonist. Although
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`modafinil-induced wakefulness can be attenuated by the (nu-adrenergic receptor
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`antagonist, prazosin, in assay systems known to be responsive to a-adrenergic agonists,
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`modafinil has no activity. Modafinil does not display sympathomimetic activity in the rat
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`vas deferens preparations (agonist-stimulated or electrically stimulated) nor does it
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`increase the formation of
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`the adrenergic receptor-mediated second messenger
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`phosphatidyl inositol in in vitro models. Unlike sympathomimetic agents, modafinil does
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`not reduce cataplexy in narcoleptic canines and has minimal effects on cardiovascular and
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`hemodynamic parameters.
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`In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamine
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`increased neuronal activation throughout
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`the brain. Modafinil at an equivalent
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`wakefulness—promoting dose selectively and prominently increased neuronal activation in
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`more discrete regions of the brain.The relationship of this finding in cats to the effects of
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`modafinil in humans is unknown.
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`NDA 20-717
`Provigil® (modafinil) - FDA Approved Draft Labeling 12/98
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`In addition to its wakefulness-promoting effects and increased locomotor activity in
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`animals, in humans, PROVIGIL produces psychoactive and euphoric effects, alterations
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`in mood, perception, and thinking, and feelings typical of other CNS stimulants. Modafinil
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`is reinforcing, as evidenced by its self-administration in monkeys previously trained to self
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`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. The
`enantiomers have not been individually studied in humans. Two major metabolites of
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`modafinil, modafinil acid and modafinil sulfone, do not appear to contribute to the CNS-
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`activating properties of modafinil.
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`Pharmacokinetics
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`Modafinil is a racemic compound, whose enantiomers have different pharrnacokinetics
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`(e.g., the half-life of the /-isomer is approximately three times that of the d-isomer in
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`humans). The enantiomers do not interconvert. At steady state, total exposure to the [-
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`isomer is approximately three times that for the d-isomer. The trough concentration
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`(Cminsslgiiof 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
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`about 15 hours. The enantiomers of modafinil exhibit linear kinetics upon multiple dosing
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`of 200-600 mg/day once daily in healthy volunteers. Apparent steady states of total
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`modafinil and I-(-)-modafinil are reached after 2-4 days of dosing.
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`NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`Absorption and Distribution
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`Absorption of PROVIGIL tablets is rapid, with peak plasma concentrations occurring at
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`2-4 hours. The bioavailability of PROVIGIL tablets is approximately equal to that of an
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`aqueous suspension. The absolute oral bioavailability was not determined due to the
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`aqueous insolubility (<1 mg/ml) of modafinil, which precluded intravenous administration.
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`Food has no effect on overall PROVlGlL bioavailability; however, its absorption (tmax) may
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`be delayed by approximately one hour if taken with food.
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`Modafinil is well distributed in body tissue with an apparent volume of distribution (~09
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`L/kg) larger than the volume of total body water (0.6 L/kg).
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`In human plasma, in vitro,
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`modafinil is moderately bound to plasma protein (~60°/o, mainly to albumin). At serum
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`concentrations obtained at steady state after doses of 200 mg/day, modafinil exhibits no
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`displacement of protein binding of warfarin, diazepam, or propranolol. Even at much larger
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`concentrations (1000pM; >25 times the Cmax of 40uM at steady state at 400 mg/day),
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`modafinil has no effect on warfarin binding. Modafinil acid at concentrations >500pM
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`decreases the extent of warfarin binding, but these concentrations are > 35 times those
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`achieved therapeutically.
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`Metabolism and Elimination
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`The major route of elimination (~90°/o)
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`is metabolism, primarily by the liver, with
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`subsequent renal elimination of the metabolites. Un'ne alkalinization has no effect on the
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`elimination of modafinil.
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`Metabolism occurs
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`through hydrolytic deamidation,
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`S—oxidation,
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`aromatic
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`ring
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`hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is
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`excreted as the parent compound.
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`In a clinical study using radiolabeled modafinil, a total
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`of 81% of
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`the administered radioactivity was recovered in 11 days post-dose,
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`predominantly in the urine (80% vs. 1.0% in the feces). The largest fraction of the drug
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`in urine was modafinil acid, but at least six other metabolites were present in lower
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`4
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`NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e.,
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`modafinil acid and modafinil sulfone.
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`In preclinical models, modafinil acid, modafinil
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`sulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy modafinil, were inactive or
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`did not appear to mediate the arousal effects of modafinil.
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`In humans, modafinil shows a possible induction effect on its own metabolism after chronic
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`administration of doses 2 400 mg/day.
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`Induction of hepatic metabolizing enzymes, most
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`importantly cytochrome P450 (CYP) 3A4, has also been observed in vitro after incubation
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`of primary cultures of human hepatocytes with modafinil.
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`(For further discussion of the
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`effects of modafinil on CYP enzyme activities see PRECAUTIONS, Drug Interactions).
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`Drug-Drug Interactions: Because modafinil
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`is a reversible inhibitor of the drug-
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`metabolizing enzyme CYPZC19, co-administration of modafinil with drugs such as
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`diazepam, phenytoin, and propranolol, which are largely eliminated via that pathway, may
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`increase the circulating levels of those compounds.
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`In addition, in individuals deficient in
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`the enzyme CYP2D6 (i.e., 7-10% of the Caucasian population; similar or lower in other
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`populations), the levels of CYP2D6 substrates such as tricyclic antidepressants and
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`selective serotonin reuptake inhibitors, which have ancillary routes of elimination through
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`CYPZC19, may be increased by co-administration of modafinil. Dose adjustments may be
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`necessary for patients being treated with these and similar medications
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`(see
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`PRECAUTIONS, Drug Interactions).
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`Chronic administration of modafinil may also cause modest induction of the metabolizing
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`enzyme CYP3A4, thus reducing the levels of co-administered substrates for that enzyme
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`system, such as steroidal contraceptives, cyclospon‘ne and to a lesser degree,
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`theophylline. Dose_adjustments may be necessary for patients being treated with these
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`and similar medications (see PRECAUTIONS, Drug Interactions).
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`NDA 20-717
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`An apparent concentration-related suppression of CYPZCQ activity was observed in
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`human hepatocytes after exposure to modafinil in vitro. Although no other indication of
`CYP2C9 suppression has been observed, the in vitro results suggest that there is potential
`for metabolic interaction between PROVIGIL and CYP2C9 substrates, such as warfan'n or
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`phenytoin (see PRECAUTIONS, Drug Interactions).
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`Special Populations
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`Gender Effect: The pharmacokinetics of modafinil are not affected by gender.
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`Age Effect: A slight decrease (~20%) in oral clearance (CL/F) of modafinil was observed
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`in a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53-72
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`years), but the change was considered unlikely to be clinically significant.
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`In a multiple
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`dose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67-87 years),
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`the mean levels of modafinil in plasma were approximately two times those historically
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`obtained in matched younger subjects. Due to potential effects from the multiple
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`concomitant medications with which most of the patients were being treated, the apparent
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`difference in modafinil pharmacokinetics may not be attributable solely to the effects of
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`aging. However, the results suggest that the clearance of modafinil may be reduced in the
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`elderly. (See DOSAGE AND ADMINISTRATION).
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`Race Effect: The influence of race on the pharmacokinetics of modafinil has not been
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`studied.
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`Renal Impairment:
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`In a single dose 200 mg modafinil study, severe chronic renal failure
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`(creatinine clearance 5 20 ml/min) did not significantly influence the pharmacokinetics of
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`modafinil, but exposure to modafinil acid (an inactive metabolite) was increased 9 fold
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`(see PRECAUTIONS).
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`NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`Hepatic Impairment: Pharmacokinetics and metabolism were examined in patients with
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`cirrhosis of the liver (6 M and 3 F). Three patients had stage B or B+ cirrhosis (per the
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`Child criteria) and 6 patients had stage C or C+ cirrhosis. Clinically 8 of 9 patients were
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`icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased
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`by about 60% and the steady state concentration was doubled compared to normal
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`patients. The dose of PROVIGIL should be reduced in patients with severe hepatic
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`impalrrnent (see PRECAUTIONS and DOSAGE and ADMINISTRATION).
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`CLINICAL TRIALS
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`The effectiveness of PROVIGIL in reducing the excessive daytime sleepiness (EDS)
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`associated with narcolepsy was established in
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`two US 9-week, multicenter,
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`placebo-controlled,
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`two-dose (200 mg per day and 400 mg per day) parallel-group,
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`double-blind studies of outpatients who met the lCD-9 and American Sleep Disorders
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`Association criteria for narcolepsy (which are also consistent with the American Psychiatric
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`Association DSM-IV criteria). These criteria include either 1) recurrent daytime naps or
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`lapses into sleep that occur almost daily for at least three months, plus sudden bilateral
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`loss of postural muscle tone in association with intense emotion (cataplexy) or 2) a
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`complaint of excessive sleepiness or sudden muscle weakness with associated features:
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`sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep
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`episode; and polysomnography demonstrating one of the following: sleep latency less
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`than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes.
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`In
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`addition, for entry into these studies, all patients were required to have objectively
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`documented excessive daytime sleepiness, a Multiple Sleep Latency Test (MSLT) with two
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`or more sleep onset REM periods, and the absence of any other clinically significant active
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`medical or psychiatric disorder. The MSLT, an objective daytime polysomnographic
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`assessment of the patients ability to fall asleep in an unstimulating environment, measures
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` NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labe|ing 12/98
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`latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals
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`following nocturnal polysomnography. For each test session, the subject was told to lie
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`quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep
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`occurred or 15 minutes after sleep onset.
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`In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed
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`by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall
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`disease status, as measured by the Clinical Global Impression of Change (CGl-C). For
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`a successful trial, both measures had to show significant improvement.
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`The MWT measures latency (in minutes) to sleep onset averaged over 4 test sessions at
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`2 hour intervals following noctumal polysomnography. For each test session, the subject
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`was asked to attempt to remain awake without using extraordinary measures. Each test
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`session was terminated after 20 minutes if no sleep occurred or 10 minutes after sleep
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`onset. The CGl-C is a 7-point scale, centered at No Change, and ranging from Very Much
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`Worse to Very Much Improved. Patients were rated by evaluators who had no access to
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`any data about the patients other than a measure of their baseline severity. Evaluators
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`were not given any specific guidance about the criteria they were to apply when rating
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`patients.
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`Other assessments of effect included the Multiple Sleep Latency Test (MSLT), Epworth
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`Sleepiness Scale (ESS; a series of questions designed to assess the degree of sleepiness
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`in everyday situations) the Steer Clear Performance Test (SCPT; a computer-based
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`evaluation of a patient’s ability to avoid hitting obstacles in a simulated driving situation),
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`standard nocturnal polysomnography, and patients daily sleep log. Patients were also
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`assessed with the Quality of Life in Narcolepsy (QOLIN) scale, which contains the
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`validated SF-36 health questionnaire.
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`NDA 20-717
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`
`
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`Both studies demonstrated improvement in objective and subjective measures of excess
`daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. §§§§Patients
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`treated with either dose of PROVIGIL showed a statistically significantly enhanced ability
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`to remain awake on the MWT (all p values_<0.001), at weeks 3,6,9, and endpoint
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`compared to placebo and a statistically significantly greater global improvement, as rated
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`on the CGl-C scale (all p values <0.05).
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`The average sleep latencies (in minutes) on the MWT at endpoint in the 2 controlled trials
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`are shown in the table below:
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`Table 1. MWT Averaoe Slee Latenc at End oint
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`PROVlGlL
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`Placebo
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`200 mg*
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`400 mg*
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`
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`‘ significantly different from placebo for both trials (p<0.001)
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`The percentages of patients who showed any degree of improvement on the CGl-C in the
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`two clinical trials are shown in the table below:
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`Table 2. Clinical Global lm-ression of Cha oe CGl-C
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`Placebo
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`PROVIGIL
`200 mg*
`400 mg*
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`‘
`‘
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`
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`" significantly different from placebo for both trials (Trial 1: p<0.001;na| 2: p0.01)
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` NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`Similar statistically significant treatment-related improvements were seen on other
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`measures of impairment in narcolepsy, including a decrease in the propensity to fall asleep
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`on the MSLT (p<0.001 for each dose in comparison to placebo) and a statistically
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`significant lessening of patient-assessed level of daytime sleepiness on the E88 (P<0.001
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`for each dose in comparison to placebo),
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`Although PROVIGIL tended to be numerically superior to placebo on several of the other
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`outcome measures, there were no consistent statistically significant differences between
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`drug and placebo on these measures.
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`Nighttime sleep measured with nocturnal polysomnography was not affected by the use
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`of PROVIGIL.
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`The effectiveness of modafinil in long-term use (greater than 9 weeks) has not been
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`systematically evaluated in placebo-controlled trials. The physician who elects to prescribe
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`PROVIGIL tablets for an extended time should periodically re-evaluate long-tenn
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`usefulness for the individual patient.
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`INDICATIONS AND USAGE
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`PROVIGIL is indicated to improve wakefulness in patients with excessive daytime
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`sleepiness associated with narcolepsy.
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`CONTRAINDICATIONS
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`PROVIGIL is contraindicated in patients with known hypersensitivity to modafinil.
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`NDA 20-717
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`PRECAUTIONS
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`General
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`Although modafinil has not been shown to produce functional
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`impairment, any drug
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`affecting the CNS may alter judgment,
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`thinking or motor skills. Patients should be
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`cautioned about operating an automobile or other hazardous machinery until they are
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`reasonably certain that PROVIGIL therapy will not adversely affect their ability to engage
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`in such activities.
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`Cardiovascular System
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`In clinical studies of PROVIGIL, signs and symptoms including chest pain, palpitations,
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`dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects
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`in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended
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`that PROVIGIL tablets not be used in patients with a history of left ventricular hypertrophy
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`or
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`ischemic ECG changes, chest pain, arrhythmia or other clinically significant
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`manifestations of mitral valve prolapse in association with CNS stimulant use.
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`Modafinil has not been evaluated or used to any appreciable extent in patients with a
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`recent history of myocardial infarction or unstable angina, and such patients should be
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`treated with caution.
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`Modafinil has not been systematically evaluated in patients with hypertension. Periodic
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`monitoring of hypertensive patients may be appropriate.
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`Central Nervous System
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`One healthy male volunteer developed ideas of reference, paranoid delusions, and
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`auditory hallucinations in association with multiple daily 600 mg doses of PROVIGIL and
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`sleep deprivation. There was no evidence of psychosis 36 hours after drug
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`discontinuation. Caution should be exercised when PROVIGIL is given to patients with a
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`history of psychosis.
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`NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`Patients with Severe Renal Impairment
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`In patients with severe renal impairment (mean creatinine clearance = 16.6 mLJmin), a
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`200 mg single dose of modafinil did not lead to increased exposure to modafinil but
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`resulted in much higher exposure to the inactive metabolite, modafinil acid, than is seen
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`in subjects with normal renal function. There is little information available about the safety
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`of such levels of this metabolite (see CLINICAL PHARMACOLOGY).
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`Patients with Severe Hepatic Impairment
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`In patients with severe hepatic impairment, with or without cirrhosis (see CLINICAL
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`PHARMACOLOGY), PROVIGIL should be administered at a reduced dose as the
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`clearance of modafinil was decreased compared to that in normal subjects (see DOSAGE
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`and ADMINISTRATION).
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`Elderly Patients
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`To the extent that elderly patients may have diminished renal and/or hepatic function,
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`dosage reductions should be considered (see DOSAGE and ADMINISTRA110N).
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`Patients Using Contraceptives
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`The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL
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`tablets and for one month after discontinuation of therapy (See Potential Interactions with
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`Drugs That Inhibit or are Metabolized by Cytochrome P-450 lsoenzymes and Other Hepatic
`
`Enzymes). Alternative or concomitant methods of contraception are recommended for
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`patients treated with PROVIGIL tablets, and for one month after discontinuation of
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`PROVIGIL.
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`Information for Patients
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`Physicians are advised to discuss the following issues with patients for whom they
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`prescribe PROVIGIL tablets.
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`12
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`NDA 20-717
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`Provigi|® (modafinil) - FDA Approved Draft Labeling 12/98
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`Pregnancy
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`Animal studies to assess the effects of modafinil on reproduction and the developing fetus
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`were not conducted at adequately high doses or according to guidelines which would
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`ensure a comprehensive evaluation of the potential of modafinil to adversely affect fertility,
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`or cause embryolethality or teratogenicity (see Impairment of Fertility and Pregnancy).
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`Patients should be advised to notify their physician if they become pregnant or intend to
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`become pregnant during therapy. Patients should be cautioned regarding the potential
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`increased risk of pregnancy when using steroidal contraceptives (including depot or
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`implantable contraceptives) with PROVIGIL tablets and for one month after discontinuation
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`of therapy.
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`Nursing
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`Patients should be advised to notify their physician if they are breast feeding an infant.
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`Concomitant Medication
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`Patients should be advised to inform their physician if they are taking, or plan to take, any
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`prescription or over-the-counter drugs, because of the potential for interactions between
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`PROVIGIL tablets and other drugs.
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`Alcohol
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`Patients should be advised that the use of PROVIGlL in combination with alcohol has not
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`been studied. Patients should be advised that it is prudent to avoid alcohol while taking
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`PROVIGIL tablets.
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`Allergic Reactions
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`Patients should be advised to notify their physician if they develop a rash, hives, or a
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`related allergic phenomenon.
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`NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`Drug Interactions
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`CNS Active Drugs
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`Methylphenidate -
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`In a single-dose study in healthy volunteers, coadministration of
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`modafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterations
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`in the pharmacokinetics of either drug. However, the absorption of PROVIGIL may be
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`delayed by approximately one hour when coadministered with methylphenidate.
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`Clomipramine — The coadministration of a single dose of clomipramine (50 mg) on the first
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`of three days of treatment with modafinil (200 mg/day) in healthy volunteers did not show
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`an effect on the pharmacokinetics of either drug. However, one incident of increased
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`levels of Clomipramine and its active metabolite desmethylclomipramine has been reported
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`in a patient with narcolepsy during treatment with modafinil (See Potential Interactions with
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`Drugs That Inhibit or are Metabolized by Cytochrome P—450 Isoenzymes and Other
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`Hepatic Enzymes).
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`Tn'azolam - In a single-dose pharrnacodynamic study with PROVIGIL in healthy volunteers
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`(50, 100 or 200 mg) and triazolam (0.25 mg), no clinically important alterations in the
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`safety profile of modafinil or triazolam were noted.
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`Mo‘noamine Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidase
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`inhibitors have not been performed.
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`Therefore, caution should be used when
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`concomitantly administering MAO inhibitors and modafinil.
`
`Potential Interactions with Drugs That Inhibit, Induce, or are Metabolized by Cytochrome
`
`P-450 Isoenzymes and Other Hepatic Enzymes
`
`in a controlled study in patients with narcolepsy, chronic dosing of PROVIGIL at 400
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`mg/day once daily resulted in a ~20% mean decrease in modafinil plasma trough
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`concentrations by week 9,
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`relative to those at wee suggesting that chronic
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`administration of PROVIGIL might have caused induction of its metabolism.
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`In addition,
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`14
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`NDA 20-717
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`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital,
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`n'fampin) orinhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the levels
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`of modafinil due to the partial involvement of that enzyme in the metabolic elimination of
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`the compound.
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`In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly
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`induce CYP1A2, CYPZBS and CYP3A4 in a concentration-dependent manner. Although
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`induction results based on in vitro experiments are not necessarily predictive of response
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`in vivo, caution needs to be exercised when PROVIGIL is coadministered with drugs that
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`depend on these three enzymes for their clearance. Specifically, lower blood levels of
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`such drugs could result.
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`In the case of CYP1A2 and CYPZBS, no other evidence of
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`enzyme induction has been observed. A modest induction of CYP3A4 by modafinil has
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`been indicated by other results, hence the clearance of CYP3A4 substrates such as
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`cyclosporine or steroidal contraceptives and to a lesser degree, theophylline may be
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`increased. One case of an interaction between modafinil and cyclospon‘ne has been
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`reported in a 41 year old woman who had_undergone an organ transplant. After one month
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`of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by
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`50%. The interaction was postulated to be due to the increased metabolism of
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`cyclosporine, since no other factor expected to affect the disposition of the drug had
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`changed.
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`The exposure of human hepatocytes to modafinil
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`in vitro produced an apparent
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`concentration—related suppression of expression of CYP2C9 activity. The clinical
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`relevance of this finding is unclear, since no other indication of CYP2C9 suppression has
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`been observed. However, monitoring of prothrombin times is suggested as a precaution
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`for the first several months of coadministration of PROVIGIL and warfan'n, a CYP2C9
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`substrate, and thereafter whenever PROVIGIL dosing is changed.
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`In addition, patients
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`receiving PROVIGIL and phenytoin, a CYP2C9 substrate, concomitantly should be
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`monitored for signs of phenytoin toxicity.
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`
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`

`

`NDA 20-717
`
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
`
`In vitro studies using human liver microsomes showed that modafinil has little or no
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`capacity to inhibit the major CYP enzymes except for CYP2C19, which is reversibly
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`inhibited at pharrnacologically relevant concentrations of modafinil. Drugs that are largely
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`eliminated via CYPZC19 metabolism, such as diazepam, propranolol, phenytoin or S-
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`mephenytoin may have prolonged elimination upon coadministration with PROVIGIL and
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`may require dosage reduction.
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`In addition, CYP2C19 provides an ancillary pathway for the metabolism of certain tricyclic
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`antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by
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`CYP2D6.
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`ln tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor
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`metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other
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`populations), the amount of metabolism by CYPZC19 may be substantially increased.
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`PROVIGIL may cause elevation of the levels of the tricyclics in this subset of patients.
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`Physicians should be aware that a reduction in the dose of tricyclic agents might be
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`needed in these patients.
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Carcinogenesis
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`Carcinogenicity studies were conducted in which modafinil was administered in the diet
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`to mice for 78 weeks and to rats for 104 weeks at doses of 6, 30 and 60 mg/kg/day. The
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`highest dose studied represents 1.5 times (mouse) or 3 times (rat) greater than the
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`maximum recommended human daily dose of 200 mg on a mg/m2 basis. There was no
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`evidence of tumorigenesis associated with modafinil administration in these studies, but
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`because the mouse study used an inadequate high dose that was not representative of a
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`maximum tolerated dose, the carcinogenic potential of modafinil has not been fully
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`evaluated.
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`Mutagenesis
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`There was no evidence of mutagenic or clastogenic potential of modafinil in a series of
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`assays.
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`It was not mutagenic in the in vitro Ames bacten'al reverse mutation test, the in
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`16
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`
`
`NDA 20-717
`
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`vitro mouse lymphoma/TK locus assay in the presence or absence of metabolic activation;
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`and it was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay
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`in the presence or absence of metabolic activation, or in two in vivo mouse bone marrow
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`micronucleus assays. Modafinil did not increase unscheduled DNA synthesis in rat
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`hepatocytes.
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`In a cell transformation assay in BALE/3T3 mouse embryo cells, modafinil
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`did not cause an increase in the frequency of transformed foci in the presence or absence
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`of metabolic activation.
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`Impairment of Fertility
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`When modafinil was administered orally to male and female rats prior to and throughout
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`mating and gestation at doses up to 100 mg/kg/day (4.8 times the maximum recommended
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`daily dose of 200 mg on a mg/m2 basis) no effects on fertility were seen. The study to
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`evaluate these effects, however, did not use sufficiently high doses or large enough
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`sample size to adequately assess effects on fertility.
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`Pregnancy
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`Pregnancy Category C: Embryotoxicity was observed in the absence of maternal toxicity
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`when rats received oral modafinil throughout the period of organogenesis. At a dose of
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`200 mg/kg/day (10 times the maximum recommended daily human dose of 200 mg on a
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`mglm2 basis) there was an increase in resorption, hydronephrosis, and skeletal variations.
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`The no-effect dose for these effects was 100 mg/kg/day (5 times the maximum
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`recommended daily human dose on a mg/m2 basis). When rabbits received oral modafinil
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`throughout organogenesis at doses up to 100 mg/kg/day (10 times the maximum
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`recommended daily human dose on a mg/m2 basis), no embryotoxicity was seen. Neither
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`of these studies, however, used optimal doses for the evaluation of embryotoxicity.
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`Although a threshold dose for embryotoxicity has been identified, the full spectrum of
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`potential toxic effects on the fetus has not been characterized. When rats were dosed
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`throughout gestation and lactation at doses up to 200 mg/kg/day, no developmental toxicity
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`was noted post=natally in the offspring. There are no adequate and well-controlled trials
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`17
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`

`

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

`NDA 20-717
`
`Provigil® (modafinil) — FDA Approved Draft Labeling 12/98
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`Labor and Delivery
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`The effect of modafinil on labor and delivery in humans has not been systematically
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`investigated. Seven normal births occurred in patients who had received modafinil during
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`pregnancy. One patient gave birth 3 weeks earlier than the expected range of delivery
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`dates (estimated using ultrasound) to a healthy male infant. One woman with a history of
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`spontaneous abortions suffered a spontaneous abortion while being treated with modafinil.
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`Nursing Mothers
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`It is not known whether modafinil or its metabolites are excreted in human milk. Because
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`many drugs are excreted in human milk, caution should be exercised when PROVlGlL
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`tablets are administered to a nursing woman.
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`PEDIATRIC USE
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`Safety and effectiveness in individuals below 16 years of age have not been established.
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`GERIATRIC USE
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`Safety and effectiveness in individuals above 65 years of age have not been established.
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`Experience in a limited number of patients (15) who were greater than 65 years of age in
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`US clinical trials showed an incidence of adverse experiences similar to other age groups.
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`ADVERSE REACTIONS
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`Modafinil has been evaluated for safety in over 2200 subjects, of whom more than 900
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`subjects with narcolepsy or narcolepsy/hypersomnia were given at least one dose of
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`modafinil. Modafinil has been found to be generally well-tolerated.
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`In controlled clinical
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`trials, most adverse experiences were mild to moderate.
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`The most commonly observed adverse events (25%) associated with the use of modafinil
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`more