Brands, Medical Use, Clinical Data
- Neuroprotective Agents
- Central Nervous System Agents
- Anorexigenic Agents
Brands / Synonyms
Dea No. 1680; Modafinil [Usan:Inn]; Modafinilo [Spanish]; Modafinilum [Latin]; Moderateafinil; Modiodal; Provigil; Provigil
To improve wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.
Modafinil is a stimulant drug marketed as a 'wakefulness promoting agent' and is one of the stimulants used in the treatment of narcolepsy. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins, whose neurons are activated by modafinil. The prexin neuron activation is associated with psychoactivation and euphoria. Modafinil is not indicated for complaints of lack of energy or fatigue; but it appears to be very helpful for some patients. Also, it has been used in the treatment of hypersomnia, a disorder in which patients lack the capacity for meaningful sleep and may require ten or more hours per day. Recent studies have have found that modafinil may help recovering cocaine addicts fight their addiction.
Mechanism of Action
The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors.
Rapid following oral administration.
Biotrnasformation / Drug Metabolism
PROVIGIL is contraindicated in patients with known hypersensitivity to modafinil.
CNS Active Drugs
Methylphenidate - In a single-dose study in healthy volunteers, coadministration of modafinil (200 mg) with
methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However,
the absorption of PROVIGIL may be delayed by approximately one hour when coadministered with methylphenidate.
Dextroamphetamine - In a single dose study in healthy volunteers, simultaneous administration of
modafinil (200 mg) with dextroamphetamine (10 mg) did not cause any significant alterations in the pharmacokinetics
of either drug. However, the absorption of PROVIGIL may be delayed by approximately one hour when coadministered with
Clomipramine - The coadministration of a single dose of clomipramine (50 mg) on the first of three days of
treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the pharmacokinetics of either
drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has
been reported in a patient with narcolepsy during treatment with modafinil.
Triazolam - In the drug interaction study between PROVIGIL and ethinyl estradiol (EE2), on the
same days as those for the plasma sampling for EE2 pharmacokinetics, a single dose of triazolam (0.125 mg)
was also administered. Mean Cmax and AUC0-∞ of triazolam were decreased by 42% and 59%,
respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.
Monoamine Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidase inhibitors have not been
performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil.
Warfarin - There were no significant changes in the pharmacokinetic profiles of R- and S-
warfarin in healthy subjects given a single dose of racemic warfarin (5 mg) following chronic administration of
modafinil (200 mg/day for 7 days) followed by 400 mg/day for 27 days) relative to the profiles in subjects given
placebo. However, more frequent monitoring of prothrombin times/INR is advisable whenever PROVIGIL is coadministered
Ethinyl Estradiol - Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed
by 400 mg/day for 21 days resulted in a mean 11% decrease in Cmax and 18% decrease in AUC0-24
of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change
in the elimination rate of ethinyl estradiol.
Cyclosporine - One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been
reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200
mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the
increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had
changed. Dosage adjustment for cyclosporine may be needed.
Potential Interactions with Drugs That Inhibit , Induce, or are Metabolized by Cytochrome P-450
Isoenzymes and Other Hepatic Enzymes
In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce
CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro
experiments are not necessarily predictive of response in vivo, caution needs to be exercised when PROVIGIL is
coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of
such drugs could result.
The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of
expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and
the substrates of this enzyme (e.g., S-warfarin and phenytoin). In a subsequent clinical study in healthy volunteers,
chronic modafinil treatment did not show a significant effect on the single-dose pharmacokinetics of warfarin when
compared to placebo.
In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at
pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency,
by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are
much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial
inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol,
phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with PROVIGIL and
may require dosage reduction and monitoring for toxicity.
Tricyclic antidepressants - CYP2C19 also provides an ancillary pathway for the metabolism of
certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In
tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the
Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be
substantially increased. PROVIGIL may cause elevation of the levels of the tricyclics in this subset of patients.
Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients.
In addition, due to the partial involvement of CYP3A4 in the metabolic elimination of modafinil, coadministration
of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e.g.,
ketoconazole, itraconazole) could alter the plasma levels of modafinil.