Section 10 · Monograph

Modafinil

Reviewed Nov 2026FDA label

ProvigilWake-promoting agent

Indications

Improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy.FDA-labeled
Improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA); modafinil is indicated as an adjunct to standard OSA treatment (e.g., CPAP) for the sleepiness component and does not treat the underlying airway obstruction.FDA-labeled
Improve wakefulness in adult patients with excessive sleepiness associated with shift work disorder (SWD).FDA-labeled

Adjunctive treatment for fatigue/excessive sleepiness in depression (including bipolar depression) — off-label, evidence mixed.Off-label
Fatigue associated with multiple sclerosis.Off-label
Attention-deficit/hyperactivity disorder (ADHD) in adults — off-label, not FDA approved.Off-label
Cognitive enhancement / fatigue in cancer-related fatigue and post-chemotherapy fatigue — investigational/off-label.Off-label
Idiopathic hypersomnia — used off-label; not an FDA-approved indication for modafinil.Off-label

Precise mechanism of wake-promoting action is unknown.
Produces psychostimulant-like wake-promoting effects similar to sympathomimetic agents, including amphetamine and methylphenidate, although it lacks significant direct binding affinity for most receptors involved in sleep/wake regulation.
Binds to the dopamine transporter (DAT) and inhibits dopamine reuptake, increasing extracellular dopamine; wake-promoting effect is blocked by dopamine receptor antagonists.
Also modestly increases hypothalamic histamine and orexin/hypocretin signaling in some studies.
Has low abuse-liability relative to classic stimulants but is still classified as a Schedule IV controlled substance.

Narcolepsy and OSA: 200 mg orally once daily in the morning; doses up to 400 mg/day have been used but are not consistently associated with additional benefit over 200 mg.
Shift work disorder: 200 mg orally once daily, taken approximately 1 hour prior to the start of the work shift.
Elderly patients: consider lower dose/slower titration given reduced clearance.

No dedicated renal dosing adjustment established, but caution advised in severe renal impairment.

Severe hepatic impairment: reduce dose by half (to 100 mg/day for narcolepsy/OSA).

Pediatric use: not approved for any pediatric indication after FDA declined an ADHD indication due to serious skin reaction signal in a pediatric trial.

Known hypersensitivity to modafinil or armodafinil, or to any inactive ingredient in the formulation (reactions have included angioedema, anaphylaxis, and serious skin reactions).

Hormonal contraceptives: modafinil induces CYP3A4 and reduces efficacy; alternative or additional contraception recommended during treatment and for one month after discontinuation.
CYP3A4/5 substrates with narrow therapeutic index (cyclosporine, certain steroidal contraceptives): may have reduced plasma concentrations.
CYP2C19 substrates (phenytoin, diazepam, propranolol, omeprazole): modafinil inhibits CYP2C19, potentially increasing exposure.
Warfarin: monitor INR more frequently during initiation/dose changes.
TCAs and SSRIs that are CYP2D6 substrates: modafinil may inhibit CYP2D6-mediated metabolism in poor metabolizers.
MAO inhibitors: no formal interaction studies; caution advised.
CNS-active drugs/alcohol: modafinil does not reverse the effects of alcohol or other sedating agents on complex tasks such as driving.
Clomipramine: case reports of increased seizure threshold effects/exacerbation when combined.

Most common (≥5%): headache, nausea, nervousness/anxiety, rhinitis, back pain, diarrhea, insomnia, dizziness, dyspepsia.
Serious skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS — rare but potentially life-threatening; most occur within 1-5 weeks of initiation. Discontinue at first sign of rash unless clearly unrelated to the drug.
Multi-organ hypersensitivity reactions (fever and rash with involvement of other organ systems), including at least one postmarketing fatality; median time to detection ~13 days.
Angioedema and anaphylaxis.
Psychiatric symptoms: anxiety, insomnia, and postmarketing reports of mania, delusions, hallucinations, suicidal ideation, and aggression.
Cardiovascular: chest pain, palpitations, dyspnea, transient ischemic T-wave changes; avoid in patients with left ventricular hypertrophy or mitral valve prolapse with prior CNS stimulant-associated cardiac symptoms.
Persistent sleepiness: modafinil does not eliminate the need for adequate sleep.
Postmarketing: agranulocytosis (rare).

Baseline and periodic blood pressure and heart rate, particularly with cardiovascular disease.
Skin — educate patients to report any new rash immediately; discontinue promptly if a serious skin reaction is suspected.
Mental status/mood — monitor for new or worsening anxiety, psychosis, mania, or suicidal ideation.
Assess ongoing degree of excessive sleepiness and functional impairment/driving safety.
Hepatic function in patients with pre-existing hepatic impairment.
Signs/symptoms of hypersensitivity especially in first 2 months of therapy.
Contraceptive efficacy counseling.

Pregnancy: Human data from a pregnancy exposure registry suggest an increased risk of major congenital malformations, particularly cardiac malformations; animal studies also showed developmental toxicity. Modafinil should generally be avoided during pregnancy; encourage enrollment in the modafinil pregnancy registry (1-866-404-4106).
Lactation: No data on presence in human milk, effects on the breastfed infant, or on milk production.