Introduction
Nuvigil (armodafinil) is a wakefulness-promoting agent approved for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), and shift work sleep disorder (SWSD). It is the R-enantiomer of modafinil, offering a longer half-life and potentially improved pharmacokinetic profile compared to the racemic mixture.
Mechanism of Action
Armodafinil's exact mechanism of action remains incompletely understood. Unlike traditional stimulants, it does not appear to act primarily through dopaminergic or adrenergic systems. Current evidence suggests:
- Weak, atypical dopamine reuptake inhibition
- Activation of orexin/hypocretin neurons in the hypothalamus
- Enhancement of histaminergic and noradrenergic transmission
- Minimal effect on other neurotransmitter systems (GABA, glutamate, serotonin)
The wake-promoting effects are believed to result from increased activation of cortical regions rather than generalized CNS stimulation.
Indications
FDA-approved indications:
- Narcolepsy: Treatment of excessive daytime sleepiness
- Obstructive Sleep Apnea (OSA): Adjunctive treatment of residual excessive sleepiness in adequately treated patients
- Shift Work Sleep Disorder: Treatment of excessive sleepiness in those with work schedules overlapping usual sleep periods
Off-label uses (not FDA-approved):
- Fatigue associated with multiple sclerosis
- Fatigue in Parkinson's disease
- Adjuvant treatment in depression
- Cognitive enhancement (controversial)
Dosage and Administration
Standard dosing:- Narcolepsy and OSA: 150 mg or 250 mg once daily in the morning
- SWSD: 150 mg taken approximately 1 hour prior to work shift
- Oral administration with or without food
- Tablets should be swallowed whole
- Morning administration recommended to avoid insomnia
- Renal impairment: Use with caution in severe impairment
- Hepatic impairment: Reduced dose recommended in severe impairment
- Geriatric patients: Consider lower starting doses
- Pediatric patients: Safety and efficacy not established
Pharmacokinetics
Absorption: Well absorbed orally, Tmax approximately 2 hours Distribution: Volume of distribution ~0.8 L/kg, 60% protein bound Metabolism: Extensive hepatic metabolism via:- CYP3A4 (primary)
- CYP1A2, CYP2B6, CYP2C9/19 (secondary)
- Hydrolysis and S-oxidation
Contraindications
- Hypersensitivity to modafinil, armodafinil, or any product components
- History of left ventricular hypertrophy or mitral valve prolapse secondary to stimulant use
- Concomitant use with monoamine oxidase inhibitors (MAOIs)
Warnings and Precautions
Boxed Warning: Potential for abuse and dependence (Schedule IV controlled substance) Serious warnings:- Serious skin reactions (Stevens-Johnson Syndrome, toxic epidermal necrolysis)
- Angioedema and anaphylactoid reactions
- Multiorgan hypersensitivity reactions
- Persistent sleepiness despite treatment
- Psychiatric symptoms: anxiety, depression, psychosis, mania
- Cardiovascular effects: increased blood pressure, tachycardia
- Use caution in patients with history of psychosis, mania, or cardiovascular disease
- Monitor for signs of misuse or abuse
- Consider cardiac evaluation in patients with risk factors
- May reduce efficacy of hormonal contraceptives
Drug Interactions
Clinically significant interactions:- CYP3A4 inducers (carbamazepine, phenobarbital, rifampin): May decrease armodafinil levels
- CYP3A4 inhibitors (ketoconazole, erythromycin): May increase armodafinil levels
- Armodafinil may induce CYP3A4: Reduces levels of:
- Ethinyl estradiol (oral contraceptives) - Cyclosporine - Midazolam - Triazolam
- Armodafinil may inhibit CYP2C19: Increases levels of:
- Diazepam - Phenytoin - Propranolol
- May interact with warfarin (monitor INR)
Adverse Effects
Common (≥5%):- Headache (15-23%)
- Nausea (5-11%)
- Anxiety (5-8%)
- Insomnia (5-7%)
- Dizziness (5-6%)
- Dry mouth
- Diarrhea
- Constipation
- Palpitations
- Increased blood pressure
- Severe cutaneous adverse reactions
- Angioedema
- Psychiatric symptoms (psychosis, mania)
- Cardiovascular events
- Multiorgan hypersensitivity
Monitoring Parameters
Baseline:- Comprehensive medical history
- Cardiovascular assessment (BP, HR)
- Psychiatric history evaluation
- Pregnancy test if appropriate
- Blood pressure and heart rate regularly
- Assessment of sleep patterns and daytime sleepiness
- Monitoring for signs of misuse or abuse
- Psychiatric status evaluation
- Efficacy assessment using appropriate scales (Epworth Sleepiness Scale)
- Liver function tests (if clinically indicated)
- Review of concomitant medications
- Assessment of continued need for therapy
Patient Education
Key points to discuss:- Take medication exactly as prescribed
- Do not crush or chew tablets
- Report any skin rash immediately
- Use effective contraception (may reduce oral contraceptive efficacy)
- Avoid alcohol during treatment
- Do not operate machinery until effects are known
- Report chest pain, palpitations, or psychiatric symptoms
- Maintain good sleep hygiene practices
- Do not share medication with others
- Store securely to prevent misuse
- Maintain regular sleep schedule
- Practice good sleep hygiene
- Avoid caffeine and other stimulants
- Report persistent sleepiness to provider
References
1. FDA Prescribing Information: Nuvigil (armodafinil) tablets. Revised 2023. 2. Darwish M, Kirby M, Hellriegel ET, et al. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin Drug Investig. 2009;29(9):613-623. 3. Roth T, White D, Schmidt-Nowara W, et al. Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults. Clin Ther. 2006;28(5):689-706. 4. Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin. 2006;22(4):761-774. 5. Czeisler CA, Walsh JK, Wesnes KA, et al. Armodafinil for treatment of excessive sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin Proc. 2009;84(11):958-972. 6. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition. 7. Lexicomp Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2023.