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Modafinil

Medically reviewed by Drugs.com. Last updated on Jul 13, 2020.

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. Modafinil has been shown to significantly increase dopamine in the brain by blocking dopamine transporters; however, has a lower affinity for dopamine receptors compared to amphetamines (Volkow 2009). EEG studies have shown modafinil increases high-frequency alpha waves while decreasing both delta and theta wave activity, effects consistent with generalized increases in mental alertness (James 2011). Studies also have demonstrated decreased GABA-mediated neurotransmission through increased turnover of serotonin and enhanced activity of 5-HT2 receptors and that an intact central alpha-adrenergic system is required for modafinil's activity (Kumar 2008; Schwartz 2008).

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-related excessive daytime sleepiness: To improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy.

Obstructive sleep apnea–related excessive daytime sleepiness: To improve wakefulness in adult patients with obstructive sleep apnea (OSA).

Shift work sleep disorder–related excessive daytime sleepiness: To improve wakefulness in adult patients with shift work sleep disorder (SWSD).

Off Label Uses

Cancer-related fatigue, severe (in patients receiving active treatment)

Data from a large, randomized phase 3 study support the use of modafinil for the management of severe cancer-related fatigue in adults receiving active cancer treatment [Jean-Pierre 2010].

Based on the American Society of Clinical Oncology guidelines for screening, assessment, and management of fatigue in adult survivors of cancer, modafinil may be used to manage fatigue in adult patients with advanced disease or in patients receiving active cancer treatment [Bower [ASCO 2014]].

Major depressive disorder (antidepressant augmentation)

Data from a meta-analysis (including 4 double-blind, randomized, placebo-controlled trials in patients with major depressive disorder) suggest that modafinil augmentation of antidepressants may be beneficial for the treatment of major depressive disorder characterized by excessive fatigue and sleepiness [Abolfazli 2011], [DeBattista 2003], [Dunlop 2007], [Fava 2005], [Goss 2013].

Based on the Canadian Network for Mood and Anxiety Treatments clinical guidelines for the treatment of major depressive disorder, modafinil is recommended as an alternative to preferred adjunctive treatments to antidepressant therapy in patients not responding or with incomplete response to antidepressants [CANMAT [Kennedy 2016]].

Multiple sclerosis–related fatigue

Data from a limited number of patients studied in open-label, single-blind, and randomized, double-blind studies suggest that lower doses (up to 200 mg) of modafinil may be beneficial for fatigue in patients with multiple sclerosis (MS), [Lange 2009], [Rammohan 2002], [Zifko 2002] while some randomized, double-blind, placebo-controlled studies demonstrated contradictory results or no benefit (including at higher doses [greater than 200 mg]) [Möller 2011], [Stankoff 2005].

Based on American Academy of Sleep Medicine practice parameters for the treatment of narcolepsy and other hypersomnias of central origin, modafinil may be effective for the treatment of daytime sleepiness due to MS.

Parkinson disease–related excessive daytime sleepiness

Data from a limited number of patients studied in 2 randomized, double-blind, placebo-controlled trials suggest that modafinil may be beneficial for improving subjective feelings of excessive daytime sleepiness in patients with Parkinson disease [Adler 2003], [Högl 2002].

Based on the National Institute for Health and Care Excellence guidelines for Parkinson disease in adults, modafinil is recommended for patients with Parkinson disease and excessive daytime sleepiness.

Contraindications

Known hypersensitivity to modafinil, armodafinil, or any component of the formulation.

Canadian labeling: Additional contraindications (not in the US labeling): Patients in agitated states or with severe anxiety; pregnancy; females who may become pregnant.

Dosing: Adult

Cancer-related fatigue, severe (in patients receiving active treatment) (off-label use): Oral: Initial: 100 mg once daily for 3 days, followed by 200 mg once daily during active treatment; refer to protocol for further details (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/day; further adjust dose based on response and tolerability up to 400 mg/day (Abolfazli 2011; DeBattista 2003; Dunlop 2007; Fava 2005).

Multiple sclerosis–related fatigue (off-label use): Oral: Initial: 100 mg/day; may increase daily dose based on response and tolerability in 100 mg increments at intervals ≥1 week up to 200 mg/day in 1 or 2 divided doses (morning and noon). Doses up to 400 mg/day have been evaluated; however, doses >200 mg/day have not demonstrated greater efficacy (Brown 2010; Lange 2009; Rammohan 2002; Zifko 2002).

Narcolepsy-related or obstructive sleep apnea–related excessive daytime sleepiness: 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.

Parkinson disease–related excessive daytime sleepiness (off-label use): Oral: Initial: 100 mg once daily; may increase dose after 1 week to 200 mg/day (Högl 2002).

Shift work sleep disorder–related excessive daytime sleepiness: Oral: Initial: 200 mg as a single dose ~1 hour prior to start of work shift.

Dosing: Geriatric

Consider initiating at lower doses.

Dosing: Pediatric

Attention deficit hyperactivity disorder (ADHD); refractory: Limited data available: Note: Due to reports of serious dermatologic adverse effects and psychiatric events in children, modafinil should only be used if first- and second-line treatments have failed and the benefits outweigh the risks.

Children ≥6 years and Adolescents ≤13 years:

Patient weight <30 kg: Oral: 200 to 340 mg once daily (Biederman 2006)

Patient weight >30 kg: Oral: 300 to 425 mg once daily (Biederman 2006)

Administration

Oral: In general, administer in dose in the morning.

Multiple sclerosis–related fatigue: With multiple sclerosis–related fatigue, may consider dividing doses between morning and noon in patients experiencing post-noon fatigue (Brown 2010).

Shift work sleep disorder: Administer dose ~1 hour prior to start of work shift.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

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

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

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

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

Alcohol (Ethyl): May diminish the therapeutic effect of Modafinil. Avoid combination

Alfentanil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and moderate CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Consider therapy modification

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

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

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

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

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

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

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

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

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

Benzhydrocodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Monitor therapy

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

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

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

Brigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Consider therapy modification

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

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

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

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

CloBAZam: CYP2C19 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Weak) may increase the serum concentration of CloBAZam. Monitor therapy

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

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

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

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

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

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

CYP3A4 Substrates (High risk with Inducers): CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Exceptions: Apixaban; Bromperidol; Rivaroxaban. Monitor therapy

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

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

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

Deflazacort: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Avoid combination

Doravirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Doravirine. 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

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Monitor therapy

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

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

Erdafitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erdafitinib. Management: Dose modifications of erdafitinib may be required. See full monograph for details. Consider therapy modification

Esketamine: May enhance the hypertensive effect of CNS Stimulants. Monitor therapy

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

Estrogen Derivatives (Contraceptive): Modafinil may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use alternative or concomitant methods of contraception in patients taking modafinil and for one month after modafinil discontinuation. Consider therapy modification

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

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

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

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

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

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

Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Monitor therapy

Fosphenytoin-Phenytoin: CYP2C19 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Glasdegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Consider therapy modification

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

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

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. 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. Monitor therapy

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 Radiopharmaceutical Products: CNS Stimulants may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Avoid combination

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

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

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

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

Lefamulin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

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

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

Letermovir: Modafinil may decrease the serum concentration of Letermovir. 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

Lorlatinib: CYP3A4 Inducers (Moderate) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, monitor AST, ALT, and bilirubin within 48 hours of starting the combination and at least three times within the first week of combined use. Consider therapy modification

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumacaftor and Ivacaftor. Monitor therapy

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

Lurasidone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days. Consider therapy modification

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

Macimorelin: Modafinil may diminish the diagnostic effect of Macimorelin. Monitor therapy

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

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

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

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

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

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

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

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

Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Management: Concomitant use of ozanimod with sympathomimetic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Consider therapy modification

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

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

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

Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers. Monitor perampanel response closely, particularly with changes to CYP3A4 inducer therapy. Consider therapy modification

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

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

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

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

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

Procarbazine: May enhance the adverse/toxic effect of Sympathomimetics. Management: Consider alternatives to this combination when possible. Procarbazine prescribing information states that this combination should be avoided. Consider therapy modification

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

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

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

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

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

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

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

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

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

Solriamfetol: CNS Stimulants may enhance the hypertensive effect of Solriamfetol. CNS Stimulants may enhance the tachycardic effect of Solriamfetol. Monitor therapy

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

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

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

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

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

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

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tezacaftor and Ivacaftor. Monitor therapy

Ubrogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Consider therapy modification

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

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

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

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

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

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

Voxelotor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Consider therapy modification

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

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

Adverse Reactions

>10%:

Central nervous system: Headache (adults: 34%; children: 20% [Biederman 2005])

Gastrointestinal: Decreased appetite (children: 16% [Biederman 2005]), abdominal pain (children: 12% [Greenhill 2006]), nausea (11%)

1% to 10%:

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

Central nervous system: Nervousness (7%), anxiety (5%), 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%)

Gastrointestinal: 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: Hepatic insufficiency (2%)

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

Ophthalmic: Visual disturbance (1%)

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

Frequency not defined:

Endocrine & metabolic: Increased gamma-glutamyl transferase

Hepatic: Increased serum alkaline phosphatase

<1%, postmarketing, and/or case reports: Aggressive behavior, agranulocytosis, anaphylaxis, angioedema, asystole, cerebrovascular accident, delusions, DRESS syndrome, erythema multiforme (pediatric patients), hallucination, hypersensitivity reaction, mania, multiorgan hypersensitivity, psychomotor agitation, psychosis, skin rash, 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.

• Seizure disorder: Limited information exists regarding the use of modafinil or other stimulants in patients with concomitant ADHD and seizure disorder. Whereas patients with ADHD are at an increased risk for seizure activity compared to the general population, a retrospective study using drug claims data showed that the use of stimulant medications was associated with a lower risk (Cortese 2013; Wiggs 2018). Manufacturers of some stimulants recommend discontinuing therapy if seizures occur.

• 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/tics: Use with caution in patients with Tourette syndrome or other tic disorders. Stimulants may exacerbate tics (motor and phonic) and Tourette syndrome; however, evidence demonstrating increased tics is limited. Evaluate for tics and Tourette syndrome prior to therapy initiation (AACAP [Murphy 2013]; Pliszka 2007).

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.

Monitoring Parameters

BP; heart rate; increased monitoring in patients with recent myocardial infarction or unstable angina; development of severe skin reactions; development or exacerbation of psychiatric symptoms (eg, agitation, anxiety, depression); pregnancy status within 1 week prior to treatment initiation (females of reproductive potential).

Reproductive Considerations

Evaluate pregnancy status within a week prior to modafinil initiation (Alertec Canadian product monograph).

Efficacy of steroidal contraceptives (including depot and implantable contraceptives) may be decreased; alternate means of effective contraception should be used during modafinil therapy and for ≥1 month after modafinil is discontinued.

Pregnancy Risk Factor

C

Pregnancy Considerations

Outcome information following modafinil use in pregnancy is limited (Calvo-Ferrandiz 2018; Cesta 2020; Damkier 2020; Haervig 2014). Preliminary data from the Nuvigil/Provigil pregnancy registry suggest an increased risk of major fetal congenital malformations, including congenital cardiac anomalies (Alertec Canadian product monograph). An increased risk of spontaneous abortion and intrauterine growth restriction has been reported with modafinil.

Data collection to monitor pregnancy and infant outcomes following exposure to modafinil is ongoing. Health care providers are encouraged to enroll patients exposed to modafinil during pregnancy in the registry (1-866-404-4106); pregnant patients may also enroll themselves.

Patient Education

What is this drug used for?

• It is used to treat a lot of sleepiness that may happen with sleep apnea, narcolepsy, or shift work problems.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Anxiety

• Diarrhea

• Trouble sleeping

• Back pain

• Nausea

• Runny nose

• Stuffy nose

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.

• Dark urine

• Yellow skin

• Change in amount of urine passed

• Unable to pass urine

• Chest pain

• Fast heartbeat

• Abnormal heartbeat

• Shortness of breath

• Joint pain

• Muscle pain

• Sensing things that seem real but are not

• Behavioral changes

• Confusion

• Severe headache

• Dizziness

• Passing out

• Vision changes

• Chills

• Sore throat

• Swelling of arms or legs

• Bruising

• Bleeding

• Swollen glands

• Severe loss of strength and energy

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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