Skip to Content
Find MS events and support groups near you! Get started >>

Modafinil

Pronunciation

Pronunciation

(moe DAF i nil)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Provigil: 100 mg

Provigil: 200 mg [scored]

Generic: 100 mg, 200 mg

Brand Names: U.S.

  • Provigil

Pharmacologic Category

  • Central Nervous System Stimulant

Pharmacology

The exact mechanism of action is unclear, it does not appear to alter the release of dopamine or norepinephrine, it may exert its stimulant effects by decreasing GABA-mediated neurotransmission, although this theory has not yet been fully evaluated; several studies also suggest that an intact central alpha-adrenergic system is required for modafinil's activity; the drug increases high-frequency alpha waves while decreasing both delta and theta wave activity, and these effects are consistent with generalized increases in mental alertness

Distribution

Vd: 0.9 L/kg

Metabolism

Hepatic; multiple pathways including CYP3A4

Excretion

Urine (80% as metabolites, <10% as unchanged drug); feces (1%)

Time to Peak

Serum: 2 to 4 hours; may be delayed ~1 hour with food.

Half-Life Elimination

Effective half-life: 15 hours

Protein Binding

~60%, primarily to albumin

Special Populations: Renal Function Impairment

In severe, chronic renal failure (CrCl ≤20 mL/minute), exposure to modafinil acid (inactive metabolite) was increased 9-fold.

Special Populations: Hepatic Function Impairment

In patients with cirrhosis of the liver, clearance is decreased ~60% and steady-state concentrations are doubled.

Special Populations: Elderly

Oral clearance decreased approximately 20% in patients with a mean age of 63 years of age.

Use: Labeled Indications

Narcolepsy: To improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy.

Obstructive sleep apnea: To improve wakefulness in adult patients with obstructive sleep apnea (OSA)

Shift work sleep disorder: To improve wakefulness in adult patients with shift work sleep disorder (SWSD)

Use: Unlabeled

Attention-deficit/hyperactivity disorder (ADHD); treatment of fatigue in MS and other disorders

Contraindications

Hypersensitivity to modafinil, armodafinil, or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Patients in agitated states or with severe anxiety

Dosing: Adult

US labeling:

Narcolepsy, obstructive sleep apnea (OSA): Oral: Initial: 200 mg as a single daily dose in the morning. Note: Doses up to 400 mg once daily have been well tolerated, but there is no consistent evidence that this dose confers additional benefit.

Shift work sleep disorder (SWSD): Oral: Initial: 200 mg as a single dose ~1 hour prior to start of work shift

Canadian labeling:

Narcolepsy: Oral: Initial: 200 mg daily in 2 divided doses (first dose in the morning and second dose at noon [or no later than early afternoon]); may titrate dose upward in 100 mg increments as needed and tolerated (maximum single dose: < 300 mg; maximum daily dose: 400 mg). Single doses ≥300 mg and daily doses >400 mg are associated with increased side effects and are not recommended.

Obstructive sleep apnea: Oral: 200 mg once daily in the morning.

Shift work sleep disorder (SWSD): Oral: 200 mg as a single dose taken ~1 hour prior to start of work shift

Off-label uses:

Attention-deficit/hyperactivity disorder (ADHD) (off-label use): Oral: 100 to 400 mg daily (Taylor 2000)

Fatigue, cancer-related, severe (in patients receiving active treatment) (off-label use): Oral: 100 mg once daily for 3 days (beginning on day 5 of second chemotherapy cycle), followed by 200 mg once daily during active treatment (Jean-Pierre 2010).

Major depressive disorder (antidepressant augmentation) (off-label use): Oral: Initial: 100 mg/day for 3 to 7 days, then increase to 200 mg daily; further adjust dose based on response and tolerability up to 400 mg/day (Abolfazli 2011; DeBattista 2003; Dunlop 2007; Fava 2005). Additional data may be necessary to further define the role of modafinil in this condition.

Multiple sclerosis-related fatigue (off-label use): Oral: 100 mg once daily initially, increased as tolerated to 200 mg once daily or if patient experiences post-noon fatigue, 100 mg twice daily (ie, morning and noon). Higher daily doses (greater than 200 mg) do not appear to be effective (Brown, 2010; Moller 2011; Rammohan, 2002; Stankoff 2005; Zifko 2002).

Dosing: Geriatric

Consider initiating at lower doses.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

Mild to moderate hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe hepatic impairment: Dose should be reduced to one-half of that recommended for patients with normal liver function.

Administration

US labeling: For the treatment of narcolepsy and obstructive sleep apnea/hypopnea syndrome, administer dose in the morning. For the treatment of shift work sleep disorder, administer dose ~1 hour prior to start of work shift.

Canadian labeling: For the treatment of narcolepsy, administer in 2 divided doses with first dose given in the morning and the second dose given at noon (or no later than early afternoon) to avoid potential for insomnia. For treatment of obstructive sleep apnea, administer as a single dose in the morning. For the treatment of shift work sleep disorder, administer dose ~1 hour prior to start of work shift.

Storage

Provigil: Store at 20°C to 25°C (68°F to 77°F).

Alertec (Canadian availability; not available in US): Store at 15°C to 30°C (59°F to 86°F).

Drug Interactions

Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Avoid combination

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clarithromycin: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Contraceptives (Estrogens): Modafinil may decrease the serum concentration of Contraceptives (Estrogens). Management: The manufacturer recommends that patients use nonhormonal contraceptives, in addition to or in place of hormonal contraceptives, during and for one month following treatment with modafinil. Consider therapy modification

CycloSPORINE (Systemic): Modafinil may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning. Consider therapy modification

HYDROcodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Management: Although moderate CYP3A inducers are not specifically contraindicated with ibrutinib, prescribing information indicates that they may decrease AUC up to 3-fold. If possible, alternatives with less CYP3A induction should be considered. Consider therapy modification

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Management: Monitor for reduced rolapitant response. Recommended dexamethasone regimens should be used with rolapitant. Higher dexamethasone doses or more prolonged use may increase the potential for a significant interaction. Monitor therapy

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Sofosbuvir: Modafinil may decrease the serum concentration of Sofosbuvir. Avoid combination

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Zolpidem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem. Monitor therapy

Adverse Reactions

Frequency not always defined.

Cardiovascular: Chest pain (3%), hypertension (3%), palpitations (2%), tachycardia (2%), vasodilatation (2%), edema (1%)

Central nervous system: Headache (adults 34%; children 20% [Biederman 2005]; dose related), nervousness (7%), anxiety (5%; dose related), dizziness (5%), insomnia (5%), depression (2%), drowsiness (2%), paresthesia (2%), agitation (1%), chills (1%), confusion (1%), emotional lability (1%), hypertonia (1%), vertigo (1%)

Dermatologic: Diaphoresis (1%)

Endocrine & metabolic: Weight loss (children 5% [Greenhill 2006]), increased thirst (1%), increased gamma-glutamyl transferase

Gastrointestinal: Decreased appetite (children 16% [Biederman 2005]), abdominal pain (children 12% [Greenhill 2006]), nausea (11%), diarrhea (6%), dyspepsia (5%), xerostomia (4%), anorexia (4%), constipation (2%), dysgeusia (1%), flatulence (1%), oral mucosa ulcer (1%)

Genitourinary: Urine abnormality (1%)

Hematologic & oncologic: Eosinophilia (1%)

Hepatic: Abnormal hepatic function tests (2%), increased serum alkaline phosphatase

Neuromuscular & skeletal: Back pain (6%), dyskinesia (1%), hyperkinesia (1%), tremor (1%)

Ocular: Abnormal vision (1%)

Respiratory: Rhinitis (7%), pharyngitis (4%), asthma (1%), epistaxis (1%)

<1% (Limited to important or life-threatening): Agranulocytosis, DRESS syndrome, erythema multiforme (pediatric patients), hallucination, hypersensitivity, mania, multiorgan hypersensitivity, psychomotor agitation, psychosis, Stevens-Johnson syndrome, suicidal ideation, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: May impair the ability to engage in potentially hazardous activities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic effects (severe): Serious and life-threatening rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported. Although initially reported in children during clinical trials, postmarketing cases have occurred in both children and adults. Most cases have occurred within the first 5 weeks of therapy; however, rare cases have occurred after long-term use (eg, 3 months). No risk factors have been identified to predict occurrence or severity. Patients should be advised to discontinue at first sign of rash (unless the rash is clearly not drug-related). As a result of these serious dermatologic adverse events, approval for the use of modafinil in children for ADHD was denied by the FDA.

• Hypersensitivity reactions: Rare cases of multiorgan hypersensitivity reactions (with fatality) in association with modafinil use; lone cases of angioedema and anaphylactoid reactions with armodafinil have been reported (angioedema has been noted in postmarketing reports with modafinil). Signs and symptoms are diverse, reflecting the involvement of specific organs; patients typically present with fever and rash associated with organ-system dysfunction. No risk factors have been identified to predict occurrence or severity of multiorgan hypersensitivity reactions. Patients should be advised to report any signs and symptoms related to these effects; discontinuation of therapy is recommended.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; increased blood pressure and heart rate monitoring may be required. Use is not recommended in patients with a history of left ventricular hypertrophy or patients with mitral valve prolapse who have developed mitral valve prolapse syndrome with previous CNS stimulant use. Increased monitoring should be considered in patients with a recent history of myocardial infarction or unstable angina.

• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage reduction is recommended in patients with severe hepatic impairment.

• Psychiatric disorders: Use with caution in patients with a history of psychosis, depression, or mania. Use may result in emergence of or exacerbation of psychiatric symptoms. Observe for symptoms of aggression, hallucinations, mania, delusions, or suicidal ideation. Consider discontinuing therapy if psychiatric symptoms develop.

• Renal impairment: Use with caution in patients with renal impairment.

• Sleep disorders: Appropriate use: The degree of sleepiness should be reassessed frequently; some patients may not return to a normal level of wakefulness. In obstructive sleep apnea, modafinil is indicated as treatment for excessive sleepiness and not for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating and during treatment with modafinil for excessive sleepiness.

• Tourette syndrome: Use with caution in patients with Tourette syndrome; limited evidence suggests stimulants may exacerbate tics and Tourette syndrome (AACAP [Murphy 2013]; Pringsheim 2012; Rossner 2011).

Special populations:

• Pediatric: Modafinil is not FDA-approved for use in pediatrics for any indication. Serious skin reactions and psychiatric events have been observed in pediatric patients treated with modafinil. The serious nature of these adverse effects resulted in the FDA’s Pediatric Advisory Committee unanimously recommending that a specific warning against the use of modafinil in children be added to the manufacturer’s labeling.

Other warnings/precautions:

• Ethanol use: Instruct patients to avoid concomitant ethanol consumption.

Monitoring Parameters

Levels of sleepiness; blood pressure; heart rate; increased monitoring in patients with recent MI or unstable angina; development of severe skin reactions; development or exacerbation of psychiatric symptoms (eg, agitation, anxiety, depression)

When used for the treatment of ADHD, thoroughly evaluate for cardiovascular risk. Monitor heart rate, blood pressure, and consider obtaining ECG prior to initiation (Vetter 2008).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. An increased risk of spontaneous abortion and intrauterine growth restriction has been reported with modafinil. Efficacy of steroidal contraceptives (including depot and implantable contraceptives) may be decreased; alternate means of contraception should be considered during therapy and for 1 month after modafinil is discontinued.

Health care providers are encouraged to register pregnant patients exposed to modafinil, or pregnant women may enroll themselves, by calling (866-404-4106).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience anxiety, diarrhea, insomnia, back pain, dizziness, nausea, rhinorrhea, or rhinitis. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), angina, tachycardia, arrhythmia, shortness of breath, joint pain, muscle pain, hallucinations, confusion, severe headache, chills, pharyngitis, swelling of arms or legs, bruising, bleeding, enlarged lymph nodes, severe loss of strength and energy, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide