indication

To improve wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.

pharmacology

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.

biotransformation

Hepatic

absorption

Rapid following oral administration.

half life

23-215 hours

route of elimination

The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites.

drug interactions

Carisoprodol: Strong CYP2C19 inhibitors such as modafinil may decrease the metabolism of CYP2C19 substrates such as carisoprodol. Consider an alternative for one of the interacting drugs in order to avoid toxicity of the substrate. Some combinations are specifically contraindicated by manufacturers. Suggested dosage adjustments are also offered by some manufacturers. Please review applicable package inserts. Monitor for increased effects of the CYP substrate if a CYP inhibitor is initiated/dose increased, and decreased effects if a CYP inhibitor is discontinued/dose decreased.

Clozapine: Modafinil increases the effect and toxicity of clozapine

Cyclosporine: Modafinil decreases the effect of cyclosporine

Ethinyl Estradiol: Modafinil may decrease the contraceptive effect of ethinyl estradiol. Hormonal contraception should not be solely relied on during concomitant therapy with modafinil.

Mestranol: Modafinil decreases the effect of the contraceptive

Telithromycin: Telithromycin may reduce clearance of Modafinil. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Modafinil if Telithromycin is initiated, discontinued or dose changed.

Triazolam: Modafinil decreases the effect of triazolam

Trimipramine: The strong CYP2C19 inhibitor, Modafinil, may decrease the metabolism and clearance of Trimipramine, a CYP2D6 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Modafinil is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of modafinil by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of modafinil if voriconazole is initiated, discontinued or dose changed.