What is Armodafinil (wakefulness-promoting agent)?

Armodafinil: A Wakefulness-Promoting Agent

Armodafinil is the R-enantiomer of modafinil, a wakefulness-promoting agent FDA-approved for treating excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, and shift work disorder (SWD). 1

Pharmacology and Mechanism of Action

Armodafinil works by:

• Enhancing activity in the hypothalamic wakefulness center
• Activating tuberomammillary nucleus neurons that release histamine
• Activating hypothalamic neurons that release orexin/hypocretin 2

Unlike modafinil (which is a 1:1 mixture of R and S enantiomers), armodafinil contains only the longer-lasting R-enantiomer. This pharmacokinetic difference results in:

• Similar terminal half-life (approximately 13-15 hours) to modafinil
• Higher plasma concentrations later in the day
• 33-40% higher area under the curve (AUC) on a milligram-to-milligram basis 3
• Monophasic decline in plasma concentration (versus biphasic with modafinil) 3

FDA-Approved Indications

Armodafinil is specifically indicated to improve wakefulness in adults with:

1. Obstructive Sleep Apnea (OSA)

   • Used only for treating excessive sleepiness, not the underlying obstruction
   • Patients should first have maximal CPAP treatment before starting armodafinil 1

2. Narcolepsy

   • Documentation typically requires Multiple Sleep Latency Test (MSLT) showing sleep-onset REM periods 2

3. Shift Work Disorder (SWD)

   • Taken before night shifts to improve wakefulness 1

Efficacy

Clinical trials have demonstrated that armodafinil:

• Significantly improves mean sleep latency compared to placebo as measured by MSLT or MWT 4
• Achieves higher response rates on Clinical Global Impressions of Change (CGI-C) scale 4
• Maintains efficacy for 12 months or longer in long-term studies 5, 6
• Improves Epworth Sleepiness Scale (ESS) scores in patients with OSA and narcolepsy 5

Dosing

• Standard dosing: 150-250 mg once daily for OSA and narcolepsy, taken in the morning
• For shift work disorder: 150 mg taken approximately 1 hour before the start of the work shift 1
• Dose-proportional pharmacokinetics observed over the 50-400 mg range 7
• Food delays peak concentration by 2-4 hours but does not affect overall bioavailability 7

Important Safety Considerations

Armodafinil:

• Is a Schedule IV controlled substance due to potential for abuse or dependence 1
• Should be stored securely to prevent misuse 1
• May cause serious side effects including:
  • Severe rash or allergic reactions (potentially life-threatening)
  • Stevens-Johnson syndrome (rare)
  • Effects on liver or blood cells 1

Common adverse events include:

• Headache (14-24% of patients)
• Nasopharyngitis (17%)
• Insomnia (14%)
• Dizziness
• Nausea 5, 6

Long-term use may be associated with modest increases in blood pressure (3.6/2.3 mmHg) and heart rate (6.7 beats per minute), with most changes occurring within the first 3 months 6

Special Populations and Drug Interactions

Armodafinil:

• May reduce the effectiveness of hormonal contraceptives; alternative birth control methods should be used during treatment and for one month after discontinuation 1
• May cause fetal harm based on animal data; human data insufficient to determine risk 1
• Is not approved for use in children under 18 years 1
• May interact with medications metabolized by CYP enzymes 1

Comparison to Modafinil

While structurally related to modafinil, armodafinil has:

• Higher plasma concentrations later in the day
• More monophasic elimination profile
• Similar terminal half-life (approximately 13-15 hours)
• Greater bioavailability on a milligram-to-milligram basis 3

The American Academy of Sleep Medicine suggests both modafinil and armodafinil for treating narcolepsy and hypersomnia secondary to traumatic brain injury, with conditional recommendations for both medications 8.