Modafinil is a non-amphetamine central nervous system (CNS) stimulant with wakefulness-promoting properties. It is used in the treatment of conditions which cause excessive daytime sleepiness. In the United States, modafinil is FDA-approved for the treatment of the following in adults:
Additionally, modafinil has reported efficacy for the following “off-label” indications:
Modafinil is known to be a weak inhibitor of dopamine reuptake, which may be its primary clinically important property. It has little to no in vivo affinity for the serotonin (5HT) or norepinephrine (NE) transporters, although elevated concentrations of NE and 5HT in the prefrontal cortex and hypothalamus have been observed following modafinil administration, possibly as an indirect effect of increased extracellular dopamine. Additionally, modafinil has been postulated to increase signaling in the hypothalamic orexin and histamine neurotransmitter pathways, and animal studies have also suggested a glutamatergic effect. A potential advantage of modafinil is its very low observed propensity for causing euphoric effects associated with traditional psychostimulants (e.g., cocaine, amphetamine). This has been attributed to differences in its interaction with the dopamine transporter at the molecular level. In several laboratory studies of healthy subjects, modafinil has also been shown to reduce the euphoric effects of cocaine.
Modafinil exists as a racemic mixture of S- and R-enantiomers. Of note, the R-enantiomer is thought to be the source of modafinil’s psychotropic properties and is marketed independently as armodafinil.
Modafinil is available exclusively in the form of oral tablets; the usual dose is 200mg once daily. It is insoluble in aqueous solution and therefore cannot be administered intravenously. The elimination half-life of a single dose in healthy subjects is approximately 15 hours. Maximum plasma concentration is reached 2-4 hours after administration. Modafinil undergoes hepatic metabolism via multiple pathways, including CYP3A4. 80% of the dose is recovered in the urine in the form of metabolites. Severe renal and/or hepatic impairment are known to cause significantly increased steady-state drug concentrations. Dose reduction is recommended in patients with severe hepatic impairment.
Modafinil is generally well-tolerated stimulant. The most commonly reported adverse effects of modafinil (less than 10% of users) are a headache, nausea, and decreased appetite. Other commonly reported adverse effects (5% to 10% of users) include anxiety, insomnia, dizziness, diarrhea, and rhinitis.
Regarding serious adverse effects, cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in postmarketing surveillance. These life-threatening rashes associated with modafinil appear to be extremely rare, although the precise incidence rates are not known. Most of the reported cases have occurred within six weeks of drug initiation. Therefore, any patient who develops a rash during this time frame is advised to notify the prescribing physician immediately.
There are few, if any, absolute contraindications to the use of modafinil. The following is a list of relative contraindications, cautions, and special considerations:
There is no requirement for specific monitoring of patients receiving modafinil. However, a variety of drug-drug interactions are possible. Modafinil is a substrate of hepatic CYP3A4, a moderate inducer of CYP3A4, and a weak inhibitor of CYP2C19.
Modafinil may decrease serum concentrations of other drugs to a clinically significant extent, including the following:
Serum concentrations of modafinil may be decreased to a clinically significant extent in the presence of drugs that induce CYP3A4. These include rifampin, phenytoin, St. John’s Wort, and efavirenz.
Serum concentrations of modafinil may be increased to a clinically significant extent in the presence of drugs that inhibit CYP3A4. These include ketoconazole, itraconazole, ritonavir, and clarithromycin.
Case reports of modafinil overdose/toxicity are rare. Clinical manifestations of modafinil overdose are relatively mild but may include hypertension, tachycardia, agitation, and/or psychosis. Symptoms typically respond to supportive therapy, although augmentation with benzodiazepines is occasionally required.
Modafinil is a stimulant medication that is generally safe, well-tolerated, and carries very low potential for abuse and dependence. It is used to treat excessive daytime sleepiness associated with narcolepsy, sleep work shift disorder, and obstructive sleep apnea. For these conditions, it is often used in conjunction with other medical and lifestyle treatments. Most patients can safely receive modafinil, although it should be used cautiously in patients with structural cardiac disease, severe hepatic impairment, or a history of psychosis/mania. Although no specific monitoring is recommended for patients on modafinil, nurses, pharmacists and physicians should be aware of the variety of possible drug-drug interactions, notably including oral contraceptive pills.
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