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Pronunciation
(moe DAF i nil)
Generic Available (U.S.)
No
Controlled Substance
C-IV
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM231722.pdf, must be dispensed with this medication.
REMS Components
Provigil®: Released from REMS requirement 1/13/2012
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy and shift work sleep disorder (SWSD); adjunctive therapy for obstructive sleep apnea/hypopnea syndrome (OSAHS)
Use: Unlabeled
Attention-deficit/hyperactivity disorder (ADHD); treatment of fatigue in MS and other disorders
Pregnancy Risk Factor
C
Pregnancy Considerations
Embryotoxic effects have been observed in some, but not all animal studies. There are no adequate and well-controlled studies in pregnant women; use only when the potential risk of drug therapy is outweighed by the drug's benefits.Healthcare providers are encouraged to register pregnant patients exposed to modafinil by calling 1-866-404-4106.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.
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to modafinil, armodafinil, or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: May impair the ability to engage in potentially hazardous activities. The degree of sleepiness should be reassessed frequently; some patients may not return to a normal level of wakefulness.
• Dermatologic effects (severe): Serious and life-threatening rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with modafinil. 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. No risk factors have been identified to predict occurrence or severity. Patients should be advised to discontinue at first sign of rash. 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 in association with modafinil use and lone cases of angioedema and anaphylactoid reactions with armodafinil have been reported. Signs and symptoms are diverse, reflecting the involvement of specific organs. Patients typically present with fever and rash associated with organ-system dysfunction. 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 is not recommended in patients with a history of angina, cardiac ischemia, recent history of myocardial infarction, left ventricular hypertrophy, or patients with mitral valve prolapse who have developed mitral valve prolapse syndrome with previous CNS stimulant use. Increase monitoring in patients with hypertension; additional therapy may be necessary.
• 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 pre-existing psychosis or bipolar disorder (may induce mixed/manic episode). May exacerbate symptoms of behavior and thought disorder in psychotic patients; new onset psychosis or mania may occur with stimulant use; observe for symptoms of aggression, hostility, or suicidal ideation.
• Renal impairment: Use with caution in patients with renal impairment.
• Sleep disorders: Appropriate use: For use following complete evaluation of sleepiness and in conjunction with other standard treatments (eg, CPAP). The degree of sleepiness should be reassessed frequently; some patients may not return to a normal level of wakefulness.
• Tourette's syndrome: Use with caution in patients with Tourette's syndrome; stimulants may unmask tics.
Special populations:
• Pediatrics: 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.
Adverse Reactions
>10%:
Central nervous system: Headache (adults 34%; children 20%; dose related)
Gastrointestinal: Appetite decreased (children 16%), abdominal pain (children 12%), nausea (11%)
1% to 10%:
Cardiovascular: Chest pain (3%), hypertension (3%), palpitation (2%), tachycardia (2%), vasodilation (2%), edema (1%)
Central nervous system: Nervousness (7%), dizziness (5%), anxiety (5%; dose related), insomnia (5%), depression (2%), somnolence (2%), chills (1%), agitation (1%), confusion (1%), emotional lability (1%), vertigo (1%)
Dermatologic: Rash (1%; includes some severe cases requiring hospitalization)
Gastrointestinal: Diarrhea (6%), dyspepsia (5%), weight loss (children 5%), xerostomia (4%), anorexia (4%), constipation (2%), flatulence (1%), mouth ulceration (1%), taste perversion (1%)
Genitourinary: Abnormal urine (1%), hematuria (1%), pyuria (1%)
Hematologic: Eosinophilia (1%)
Hepatic: LFTs abnormal (2%)
Neuromuscular & skeletal: Back pain (6%), paresthesia (2%), dyskinesia (1%), hyperkinesia (1%), hypertonia (1%), neck rigidity (1%), tremor (1%)
Ocular: Amblyopia (1%), eye pain (1%), vision abnormal (1%)
Respiratory: Rhinitis (7%), pharyngitis (4%), lung disorder (2%), asthma (1%), epistaxis (1%)
Miscellaneous: Flu-like syndrome (4%), thirst (1%), diaphoresis (1%), herpes simplex infection (1%)
Postmarketing and/or case reports: Agranulocytosis, anaphylactic reaction, angioedema, DRESS syndrome, erythema multiforme, hypersensitivity syndrome (multiorgan), mania, psychosis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2A6 (weak), CYP2C19 (strong), CYP2C9 (weak), CYP2E1 (weak), CYP3A4 (weak); Induces CYP1A2 (weak/moderate), CYP2B6 (weak/moderate), CYP3A4 (weak/moderate)
Drug Interactions
ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a weak CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Axitinib: CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum concentration of Axitinib. Risk X: Avoid combination
Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Citalopram: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a strong CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Risk D: Consider therapy modification
Clopidogrel: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: 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. Risk D: Consider therapy modification
CycloSPORINE: Modafinil may decrease the serum concentration of CycloSPORINE. Risk C: Monitor therapy
CycloSPORINE (Systemic): Modafinil may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol.
Food: Delays absorption, but does not affect bioavailability.
Storage
Store at 20°C to 25°C (68°F to 77°F).
Mechanism of Action
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
Pharmacodynamics/Kinetics
Modafinil is a racemic compound (10% d-isomer and 90% l-isomer at steady state) whose enantiomers have different pharmacokinetics
Distribution: Vd: 0.9 L/kg
Protein binding: ~60%, primarily to albumin
Metabolism: Hepatic; multiple pathways including CYP3A4
Half-life elimination: Effective half-life: 15 hours
Time to peak, serum: 2-4 hours
Excretion: Urine (as metabolites, <10% as unchanged drug)
Dosage
Oral:
Adults:
ADHD (unlabeled use): 100-400 mg/day (Taylor, 2000)
Narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS): Initial: 200 mg as a single daily dose in the morning
Shift work sleep disorder (SWSD): Initial: 200 mg as a single dose taken ~1 hour prior to start of work shift
Note: Doses of 400 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit.
Elderly: Elimination of modafinil and its metabolites may be reduced as a consequence of aging and as a result, consider initiating at lower doses in this patient population.
Dosing adjustment in renal impairment: Safety and efficacy have not been established in severe renal impairment.
Dosing adjustment in hepatic impairment: Severe hepatic impairment: Dose should be reduced to one-half of that recommended for patients with normal liver function.
Administration: Oral
For the treatment of narcolepsy and obstructive sleep apnea/hypopnea syndrome (OSAHS), administer dose in the morning. For the treatment of shift work sleep disorder (SWSD), administer dose ~1 hour prior to start of work shift.
Monitoring Parameters
Levels of sleepiness; blood pressure in patients with hypertension; body mass index and weight loss; 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).
Patient Education
Avoid alcohol or caffeine. You may experience headache, nervousness, dizziness, diarrhea, dry mouth, or loss of appetite. If you have diabetes, monitor glucose levels closely. Report chest pain or palpitations, respiratory difficulty, insomnia, agitation, depression, rash, or weight loss.
Geriatric Considerations
Clearance of modafinil may be reduced in the elderly. Safety and effectiveness in persons >65 years of age have not been established. In the limited number of elderly patients studied, the incidence of adverse events was similar to younger patients.
Cardiovascular Considerations
In an effort to reduce the rate of sudden cardiac death especially in pediatric patients receiving stimulant medications for the treatment of attention-deficit/hyperactivity disorder (ADHD), the American Heart Association (AHA) issued a statement in April 2008 (Vetter, 2008) recommending that all children diagnosed with ADHD who may be candidates for stimulant medications have a thorough cardiovascular assessment (including a combination of a thorough medical history, family history, and physical examination with the intent to identify risk factors for sudden death) prior to initiation of drug therapy. Although not mandatory, physicians should consider obtaining an ECG. These recommendations are based on the Food and Drug Administration (FDA) reports of serious cardiovascular adverse events (including sudden death) in patients (both children and adults) taking usual doses of stimulant medications. Most of these patients were found to have underlying structural heart disease (eg, hypertrophic obstructive cardiomyopathy). Stimulant medications theoretically increase cardiovascular risk due to potential effects on blood pressure elevation and increased heart rate. These effects have generally been considered clinically insignificant in most children, however, may be detrimental in certain patients with underlying cardiovascular disease. None of the medications have been shown to cause heart conditions or proven to have caused sudden cardiac death.
Modafinil is not FDA-approved for pediatric use for any indication.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), oral ulceration, gingivitis, and taste perversion.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Use vasoconstrictor with caution. Patients may experience heart palpitations and increased heart rate when taking modafinil.
Mental Health: Child/Adolescent Considerations
Across three large randomized, double-blind, placebo-controlled trials, a total of 638 children and adolescents (range: 6-17 years of age) with ADHD were treated with modafinil (170-425 mg once daily) or placebo for 7-9 weeks (Biederman, 2005; Greenhill, 2006; Swanson, 2006). Modafinil treatment was associated with significant decreases in the ADHD-RS-IV scores compared relative to baseline and significantly compared to placebo (p<0.0001) for all three studies. Despite the demonstrated efficacy, these studies revealed a high rate of serious dermatological reactions (including Stevens-Johnson syndrome) in these patients.
Biederman J, Swanson JM, Wigal SB, et al, “Efficacy and Safety of Modafinil Film-Coated Tablets in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Study,” Pediatrics, 2005, 116(6):e777-84.
Greenhill LL, Biederman J, Boellner SW, et al, “A Randomized, Double-Blind, Placebo-Controlled Study of Modafinil Film-Coated Tablets in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder,” J Am Acad Child Adolesc Psychiatry, 2006, 45(5):503-11.
Swanson JM, Greenhill LL, Lopez FA, et al, “Modafinil Film-Coated Tablets in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose Study Followed by Abrupt Discontinuation,” J Clin Psychiatry, 2006, 67(1):137-47.
Nursing: Physical Assessment/Monitoring
Perform careful cardiovascular assessment prior to initiating therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Provigil®: 100 mg
Provigil®: 200 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Provigil)
100 mg (30): $608.38
200 mg (30): $787.99
References
Biederman J and Pliszka SR, “Modafinil Improves Symptoms of Attention-Deficit/Hyperactivity Disorder Across Subtypes in Children and Adolescents,” J Pediatr, 2008, 152(3):394-9.
Broughton, RJ, “Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Modafinil in the Treatment of Excessive Daytime Sleepiness in Narcolepsy,” Neurology, 1997, 49(2):444-451.
Grozinger M, “Interaction of Modafinil and Clomipramine as Comedication in a Narcoleptic Patient,” Clin Neuropharmacol, 1998, 21(2):127-129.
Kumar R, “Approved and Investigational Uses of Modafinil: An Evidence-Based Review,” Drugs, 2008, 68(13):1803-39.
National Institute for Health and Clinical Excellence (NICE), National Collaborating Centre for Mental Health , “Attention Deficit Hyperactivity Disorder, The NICE Guideline on Diagnosis and Management of ADHD in Children, Young People and Adults,” National Clinical Practice Guideline Number 72, 2008:1-664. Available at www.nice.org.uk/cg072.
Schwartz JR, “Modafinil in the Treatment of Excessive Sleepiness,” Drug Des Devel Ther, 2009, 2:71-85.
Taylor FB and Russo J, “Efficacy of Modafinil Compared to Dextroamphetamine for the Treatment of Attention Deficit Hyperactivity Disorder in Adults,” J Child Adolesc Psychopharmacol, 2000, 10(4):311-20.
U.S. Modafinil in Narcolepsy Multicenter Study Group, “Randomized Trial of Modafinil for the Treatment of Pathological Somnolence in Narcolepsy,” Ann Neurol, 1998, 43(1):88-97.
Vetter VL, Elia J, Erickson CH, et al, “Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Stimulant Drugs. A Scientific Statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing,” Circulation, 2008, 117:2407-23.
Wong, YN, “Single-Dose Pharmacokinetics of Modafinil and Methylphenidate Given Alone or in Combination in Healthy Male Volunteers,” J Clin Pharmacol, 1998, 38(3):276-282.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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