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MODAFINIL
FDA Approved Indications
1) Narcolepsy, Improve wakefulness in patients with excessive daytime sleepiness
2) Obstructive sleep apnea, Improve excessive sleepiness, as an adjunct to standard treatment(s) for the underlying obstruction; Adjunct
3) Shift work sleep disorder
2) Obstructive sleep apnea, Improve excessive sleepiness, as an adjunct to standard treatment(s) for the underlying obstruction; Adjunct
3) Shift work sleep disorder
Mechanism of Action / Pharmacology
A) MECHANISM OF ACTION
1) Modafinil is a central nervous system stimulant (Bastuji & Jouvet, 1988; Lyons & French, 1991). Structurally, modafinil is benzhydrylsulfinylacetamide compound and bears only a distant similarity to dextroamphetamine. The precise mechanism of action of modafinil in producing stimulatory effects is unclear. It appears to lack the peripheral sympathomimetic effects observed with amphetamines (Duteil et al, 1979).
2) The exact mechanism by which MODAFINIL produces wakefulness is unknown. At therapeutic concentrations, MODAFINIL does not bind to potentially relevant receptors, including receptors for norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, or benzodiazepines. The drug is not a direct- or indirect-acting dopamine receptor agonist. MODAFINIL does not appear to be a direct or indirect alpha-1 adrenergic agonist (Prod Info Provigil(R), 1998b).
3) In animal studies, modafinil has been demonstrated to induce hypermotility and reduce barbiturate-induced loss of the righting reflex; hypermotility has been antagonized by the alpha-1 adrenergic blocker prazosin (Saletu et al, 1989; Duteil et al, 1979; Saletu et al, 1990). Recent studies have also suggested a role of alpha-adrenoceptors in narcolepsy. A reduced density of alpha-1 adrenoceptors has been observed in the cerebral cortex of narcoleptic patients, and prazosin has produced exacerbation of cataplexy in these patients (Boivin et al, 1993; Aldrich & Rogers, 1986). Both the putative alpha-1 agonist modafinil and the alpha-2 agonist clonidine have been reported to improve narcoleptic symptoms (Boivin et al, 1993; Lyons & French, 1991; Salin-Pascual et al, 1985), and collectively these data suggest alpha-adrenoceptor agonism as a mechanism of action of these agents as well as involvement of this receptor in disorders of hypersomnia.
4) However, at relatively high doses in animals (monkeys), modafinil has induced behavioral stereotypy that can be reversed by pimozide, a dopamine antagonist, but not by prazosin (Lyons & French, 1991). An impairment of dopaminergic transmission has also been postulated in narcolepsy; further studies are needed to determine if central dopaminergic effects of modafinil contribute to alerting effects in humans. Dextroamphetamine and methylphenidate, both of which are effective in narcolepsy, enhance dopamine release in the central nervous system. These agents also increase norepinephrine release, and noradrenergic transmission has also been hypothesized to play a role in narcolepsy (Boivin et al, 1993).
B) EFFECTS ON PERFORMANCE2) The exact mechanism by which MODAFINIL produces wakefulness is unknown. At therapeutic concentrations, MODAFINIL does not bind to potentially relevant receptors, including receptors for norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, or benzodiazepines. The drug is not a direct- or indirect-acting dopamine receptor agonist. MODAFINIL does not appear to be a direct or indirect alpha-1 adrenergic agonist (Prod Info Provigil(R), 1998b).
3) In animal studies, modafinil has been demonstrated to induce hypermotility and reduce barbiturate-induced loss of the righting reflex; hypermotility has been antagonized by the alpha-1 adrenergic blocker prazosin (Saletu et al, 1989; Duteil et al, 1979; Saletu et al, 1990). Recent studies have also suggested a role of alpha-adrenoceptors in narcolepsy. A reduced density of alpha-1 adrenoceptors has been observed in the cerebral cortex of narcoleptic patients, and prazosin has produced exacerbation of cataplexy in these patients (Boivin et al, 1993; Aldrich & Rogers, 1986). Both the putative alpha-1 agonist modafinil and the alpha-2 agonist clonidine have been reported to improve narcoleptic symptoms (Boivin et al, 1993; Lyons & French, 1991; Salin-Pascual et al, 1985), and collectively these data suggest alpha-adrenoceptor agonism as a mechanism of action of these agents as well as involvement of this receptor in disorders of hypersomnia.
4) However, at relatively high doses in animals (monkeys), modafinil has induced behavioral stereotypy that can be reversed by pimozide, a dopamine antagonist, but not by prazosin (Lyons & French, 1991). An impairment of dopaminergic transmission has also been postulated in narcolepsy; further studies are needed to determine if central dopaminergic effects of modafinil contribute to alerting effects in humans. Dextroamphetamine and methylphenidate, both of which are effective in narcolepsy, enhance dopamine release in the central nervous system. These agents also increase norepinephrine release, and noradrenergic transmission has also been hypothesized to play a role in narcolepsy (Boivin et al, 1993).
1) Placebo-controlled performance studies in elderly subjects have indicated an improvement in vigilance with oral administration of modafinil 200- to 600-mg (morning) doses. Computer-assisted spectral analysis of the electroencephalogram (EEG) revealed an increase of alpha activity and a decrease of delta, theta, and very fast beta activity after modafinil; slow beta activity tended to be increased. The drug was associated with enhanced concentration, cognitive function, and mood, and a paradoxical decrease in psychomotor activity; critical flicker frequency threshold was increased (Saletu et al, 1989a; Lyons & French, 1991).
2) A further study in sleep-deprived subjects reported a reduced subjective feeling of sleepiness and improved performance on memory and search tasks following 200-mg oral doses of modafinil (nighttime) (Lyons & French, 1991).
3) In studies involving healthy young and elderly subjects, oral modafinil 100 to 200 mg at night was associated with less deterioration of normal sleep than with dextroamphetamine 10 to 20 mg. Specifically, dextroamphetamine produced greater impairment of sleep maintenance and sleep architecture, and deterioration of subjective sleep quality. The investigators suggest the importance of differentiating "vigilance-promoting" qualities of modafinil from "vigilance-increasing" properties of amphetamines (Saletu et al, 1989a; Saletu et al, 1989). However, differences between the 2 agents were not always significant in these studies. Total sleep time and sleep efficiency were also reduced significantly by modafinil compared to baseline, although less so than with dextroamphetamine.
C) REVIEW ARTICLES2) A further study in sleep-deprived subjects reported a reduced subjective feeling of sleepiness and improved performance on memory and search tasks following 200-mg oral doses of modafinil (nighttime) (Lyons & French, 1991).
3) In studies involving healthy young and elderly subjects, oral modafinil 100 to 200 mg at night was associated with less deterioration of normal sleep than with dextroamphetamine 10 to 20 mg. Specifically, dextroamphetamine produced greater impairment of sleep maintenance and sleep architecture, and deterioration of subjective sleep quality. The investigators suggest the importance of differentiating "vigilance-promoting" qualities of modafinil from "vigilance-increasing" properties of amphetamines (Saletu et al, 1989a; Saletu et al, 1989). However, differences between the 2 agents were not always significant in these studies. Total sleep time and sleep efficiency were also reduced significantly by modafinil compared to baseline, although less so than with dextroamphetamine.
1) Etiologies, diagnosis, and treatment of excessive daytime sleepiness are discussed in this review article (Roth & Roehrs, 1996).
2) The pharmacology and clinical efficacy of modafinil in the treatment of narcolepsy are reviewed (McClellan & Spencer, 1998).
2) The pharmacology and clinical efficacy of modafinil in the treatment of narcolepsy are reviewed (McClellan & Spencer, 1998).
Normal Dosage
1.3.1.A Oral route
Narcolepsy, Improve wakefulness in patients with excessive daytime sleepiness
Obstructive sleep apnea, Improve excessive sleepiness, as an adjunct to standard treatment(s) for the underlying obstruction; Adjunct
Shift work sleep disorder
1.3.1.A.1 Narcolepsy, Improve wakefulness in patients with excessive daytime sleepiness
a) In the treatment of NARCOLEPSY, the indicated dose is 200 milligrams per day, given as a single oral dose in the morning. Single 400-milligram daily doses (oral) have been well tolerated, but the manufacturer found no consistent evidence that the higher dose provided benefits beyond those associated with 200-milligram daily doses (Prod Info Provigil(R), 1998c).
b) The addition of a tricyclic antidepressant (eg, clomipramine 10 to 20 milligrams daily) may be required to reduce cataplexy in narcoleptic patients (Bastuji & Jouvet, 1988b).
b) The addition of a tricyclic antidepressant (eg, clomipramine 10 to 20 milligrams daily) may be required to reduce cataplexy in narcoleptic patients (Bastuji & Jouvet, 1988b).
1.3.1.A.2 Obstructive sleep apnea, Improve excessive sleepiness, as an adjunct to standard treatment(s) for the underlying obstruction; Adjunct
a) For the treatment of OBSTRUCTIVE SLEEP APNEA/HYPOPNEA SYNDROME, modafinil is indicated as an adjunct to standard treatment(s) for the underlying obstruction. The recommended dose is 200 milligrams per day, given as a single daily oral dose in the morning. Single doses up to 400 milligrams per day have been well tolerated, but there is no consistent evidence of additional benefit at doses greater than 200 milligrams per day (Prod Info Provigil(R) modafinil, 2004).
1.3.1.A.3 Shift work sleep disorder
a) For the treatment of SHIFT WORK SLEEP DISORDER, the recommended dose is 200 milligrams per day, given as a single daily oral dose approximately 1 hour prior to the start of the patients' work shift. Single doses up to 400 milligrams per day have been well tolerated, but there is no consistent evidence of additional benefit at doses greater than 200 milligrams per day (Prod Info Provigil(R) modafinil, 2004).
1.3.2 Dosage in Renal Failure
A) Severe chronic renal failure (creatine clearance equal or less than 20 mL/min) did not significantly affect the pharmacokinetics of MODAFINIL in a study using single 200-mg doses (Prod Info Provigil(R), 1998c).
B) Because modafinil half-life increases in patients with decreased renal function, treatment should begin at a reduced dosage of 100 to 200 milligrams daily. The dose may be gradually increased based on safety and tolerability (Moachon et al, 1996a).
B) Because modafinil half-life increases in patients with decreased renal function, treatment should begin at a reduced dosage of 100 to 200 milligrams daily. The dose may be gradually increased based on safety and tolerability (Moachon et al, 1996a).
1.3.3 Dosage in Hepatic Insufficiency
A) A reduced dose (50%) is recommended in severe hepatic insufficiency (Prod Info Provigil(R), 1998c). Modafinil 100 milligrams once daily is indicated in patients with severe hepatic impairment.
1.3.4 Dosage in Geriatric Patients
A) Existing evidence suggests that the clearance of MODAFINIL may be reduced in the elderly, especially in those with diminished renal and/or hepatic function; use of reduced doses should be considered in this patient population (Prod Info Provigil(R), 1998c).
Pregnancy Category: C
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