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Armodafinil

Pronunciation

(ar moe DAF i nil)

Index Terms

  • R-modafinil

Dosage Forms

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

Tablet, Oral:

Nuvigil: 50 mg, 150 mg, 200 mg, 250 mg

Brand Names: U.S.

  • Nuvigil

Pharmacologic Category

  • Central Nervous System Stimulant

Pharmacology

The exact mechanism of action of armodafinil is unknown. It is the R-enantiomer of modafinil. Armodafinil binds to the dopamine transporter and inhibits dopamine reuptake, which may result in increased extracellular dopamine levels in the brain. However, it does not appear to be a dopamine receptor agonist and also does not appear to bind to or inhibit the most common receptors or enzymes that are relevant for sleep/wake regulation.

Absorption

Readily absorbed

Distribution

Vd: 42 L

Metabolism

Hepatic, multiple pathways, including amine hydrolysis and CYP3A4/5; metabolites include R-modafinil acid and modafinil sulfone

Excretion

Urine (based on modafinil: 80% predominantly as metabolites; <10% as unchanged drug)

Time to Peak

2 hours (fasted)

Half-Life Elimination

~15 hours

Protein Binding

~60% (based on modafinil; primarily albumin)

Special Populations: Renal Function Impairment

Severe chronic renal failure (CrCl ≤20 mL/minute) increased exposure to modafinil acid ninefold.

Special Populations: Hepatic Function Impairment

In patients with severe hepatic impairment, clearance of modafinil was decreased by ~60% and the steady-state concentration was doubled.

Special Populations: Elderly

Systemic exposure of armodafinil was ~15% higher and clearance was ~12% lower in patients greater than 65 years of age.

Use: Labeled Indications

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

Obstructive sleep apnea: To improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea (OSA).

Limitations of use: In OSA, armodafinil is indicated to treat excessive sleepiness and not as treatment 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 armodafinil for excessive sleepiness.

Shift-work disorder: To improve wakefulness in patients with excessive sleepiness associated with shift-work disorder.

Contraindications

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

Dosing: Adult

Narcolepsy: Oral: 150 to 250 mg once daily in the morning

Obstructive sleep apnea (OSA): Oral: 150 to 250 mg once daily in the morning; doses >150 mg have not been shown to have an increased benefit.

Shift-work disorder: Oral: 150 mg given once daily ~1 hour prior to work shift

Dosing: Geriatric

Refer to adult dosing. Consider lower initial dosage. Concentrations were almost doubled in clinical trials (based on modafinil).

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

Mild to moderate hepatic impairment: No dosage adjustment necessary.

Severe hepatic impairment: The manufacturer recommends a reduced dose; clearance of modafinil is decreased by ~60% and the steady-state concentration is doubled in this patient population.

Administration

May be administered without regard to food.

Dietary Considerations

Take with or without meals.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

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

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Contraceptives (Estrogens): Armodafinil 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 armodafinil. Consider therapy modification

CycloSPORINE (Systemic): Armodafinil 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 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Hydrocodone: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hydrocodone. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. 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: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. 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

Adverse Reactions

>10%: Central nervous system: Headache (14% to 23%; dose related)

1% to 10%:

Cardiovascular: Palpitations (2%), increased heart rate (1%)

Central nervous system: Insomnia (4% to 6%; dose related), dizziness (5%), anxiety (4%), depression (1% to 3%; dose related), fatigue (2%), agitation (1%), depressed mood (1%), lack of concentration (1%), migraine (1%), nervousness (1%), pain (1%), paresthesia (1%)

Dermatologic: Skin rash (1% to 4%; dose related), contact dermatitis (1%), diaphoresis (1%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (1%), increased thirst (1%)

Gastrointestinal: Nausea (6% to 9%; dose related), xerostomia (2% to 7%; dose related), diarrhea (4%), dyspepsia (2%), upper abdominal pain (2%), anorexia (1%), constipation (1%), decreased appetite (1%), loose stools (1%), vomiting (1%)

Hypersensitivity: Seasonal allergy (1%)

Neuromuscular & skeletal: Tremor (1%)

Renal: Polyuria (1%)

Respiratory: Dyspnea (1%), flu-like symptoms (1%)

Miscellaneous: Fever (1%)

<1% (Limited to important but life-threatening): Anaphylaxis, angioedema, DRESS syndrome, hypersensitivity, hypouricemia, increased liver enzymes, increased serum alkaline phosphatase, pancytopenia, Stevens-Johnson syndrome, suicidal ideation, systolic hypertension, 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, 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. In modafinil clinical trials, rashes were more likely to occur in children; serious, postmarketing reactions have occurred with modafinil in adults and children as well as with armodafinil in adults. Most cases have been reported within the first 5 weeks of initiating therapy; however, rare cases have occurred after prolonged therapy. No risk factors have been identified to predict occurrence or severity of these reactions. Patients should be advised to discontinue use at first sign of rash (unless the rash is clearly not drug-related).

• Hypersensitivity reactions: Rare cases of multiorgan hypersensitivity reactions with modafinil and cases of angioedema and anaphylactoid reactions (armodafinil) have been reported. Signs and symptoms of multiorgan hypersensitivity reactions are diverse. Patients typically present with fever and rash associated with other organ system involvement. Patients should be advised to discontinue therapy and promptly report any signs or symptoms related to these adverse effects.

Disease-related concerns:

• Cardiovascular disease: 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. Patients with these conditions may also experience chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG. Due to limited experience use caution in patients with history of myocardial infarction (MI) or angina. Increased blood pressure monitoring may be required in patients taking armodafinil. New or additional antihypertensive therapy may be needed.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction is recommended with severe dysfunction.

• Psychiatric disorders: Use caution in patients with a history of psychosis, depression, or mania. Modafinil has been shown to worsen the symptoms of these diseases (eg, mania, hallucinations, suicidal thoughts). Discontinue therapy if psychiatric symptoms develop.

• 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. Patients with excessive sleepiness should be advised to avoid driving or any other potentially dangerous activity. Use >12 weeks has not been studied; patient should be reevaluated to determine effectiveness if use exceeds 12 weeks.

• 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:

• Elderly: Use reduced doses in elderly patients; concentrations of armodafinil are significantly higher in patients >65 years of age.

Other warnings/precautions:

• Abuse potential: Use with caution in patients with a history of drug abuse; potential for drug dependency exists.

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

Monitoring Parameters

Signs of hypersensitivity, rash, psychiatric symptoms, levels of sleepiness, blood pressure, and drug abuse

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Efficacy of steroidal contraceptives may be decreased; alternate means of contraception should be considered during therapy and for 1 month after armodafinil is discontinued. A pregnancy registry has been established for patients exposed to armodafinil; healthcare providers are encouraged to register pregnant patients or pregnant women may register themselves by calling 1-866-404-4106.

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, agitation, diarrhea, insomnia, back pain, dizziness, nausea, or rhinitis. Have patient report immediately to prescriber 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), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), swollen glands, hallucinations, angina, tachycardia, confusion, severe headache, arrhythmia, chills, pharyngitis, shortness of breath, swelling of arms or legs, bruising, bleeding, severe loss of strength and energy, muscle pain, joint pain, 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.

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