What are the differences between modafinil (Provigil) and armodafinil (Nuvigil)?

Differences Between Modafinil and Armodafinil

Chemical Composition and Structure

Armodafinil is the isolated R-enantiomer of modafinil, while modafinil is a racemic 1:1 mixture of both R- and S-enantiomers. 1, 2

• Chemical distinction: Armodafinil contains only the longer-lasting R-isomer, whereas modafinil contains equal parts of both R- and S-isomers 3
• Molecular formula: Both share the same molecular formula (C15H15NO2S) and molecular weight (273.35), but differ in their stereochemistry 1

Pharmacokinetic Differences

Despite having similar terminal elimination half-lives of approximately 13 hours, armodafinil maintains significantly higher plasma concentrations later in the day compared to modafinil on a milligram-to-milligram basis. 3

• Plasma concentration profile: After reaching peak concentration (Cmax), armodafinil declines in a monophasic manner, while modafinil declines biphasically due to rapid initial elimination of its S-isomer 3
• Area under the curve (AUC): Armodafinil demonstrates 33% higher AUClast and 40% higher AUCinfinity values compared to modafinil on equal doses 3
• Duration above therapeutic threshold: Armodafinil 200 mg maintains plasma concentrations above the EC50 (4.6 µg/mL) for 9 hours, whereas modafinil 200 mg does not exceed the EC50 4
• Half-life range: Armodafinil has a reported half-life of 10-15 hours, while modafinil's half-life is approximately 15 hours 5, 2

Clinical Efficacy Differences

Armodafinil produces greater wakefulness-promoting effects late in the dosing interval compared to modafinil, particularly 8-10 hours after administration. 4

• Sustained wakefulness: Armodafinil 200 mg produces 0.5-1 minute greater increases in placebo-subtracted Multiple Sleep Latency Test (MSLT) times up to 10 hours after dosing compared to modafinil 200 mg 4
• Lower effective doses: Armodafinil achieves enhanced efficacy for wake promotion using lower doses than modafinil due to its longer duration of effect 2
• Late-day performance: The different pharmacokinetic profile results in improved wakefulness throughout the day, particularly in the latter portion of the dosing interval 3, 6

Dosing Differences

Armodafinil is typically dosed at 150-250 mg once daily, while modafinil's maximum dose is 400 mg per day. 5

• Standard dosing: Armodafinil is commonly prescribed at 150 mg or 250 mg once daily 7
• Modafinil dosing range: Modafinil doses range from 50-400 mg per day, with higher doses (200-400 mg/day) used for sleepiness 5
• Timing flexibility: Both are typically taken in the morning for narcolepsy/OSA, or approximately 1 hour before work shifts for shift work disorder 1

FDA Approval Status

Both medications share identical FDA-approved indications for excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work disorder. 2, 8

• Approval timeline: Armodafinil was approved in June 2007, after modafinil 2
• Controlled substance classification: Both are classified as Schedule IV controlled substances (C-IV) due to potential for abuse, though risk is lower than traditional stimulants 5, 1

Safety and Tolerability Profile

The safety profiles of armodafinil and modafinil are essentially identical, with both being generally well tolerated. 2, 6

• Common adverse effects: Both share the same adverse effects (≥5%) including headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia 5
• Serious risks: Both carry identical warnings for serious rash (including DRESS syndrome), multi-organ hypersensitivity reactions, angioedema, and psychiatric symptoms 1
• Cardiovascular effects: Both produce small increases in blood pressure (1.2-4.3 mmHg) and heart rate (0.9-3.5 BPM) 1
• Abuse potential: Both have low potential for abuse or tolerance compared to traditional stimulants 5, 6

Mechanism of Action

Both medications share the same incompletely understood mechanism involving enhancement of hypothalamic wakefulness centers, though armodafinil's effects are attributed solely to the R-enantiomer. 5, 2

• Hypothalamic activation: Both likely enhance activity in the hypothalamic wakefulness center and activate tuberomammillary nucleus neurons releasing histamine 5
• Orexin/hypocretin system: Both activate hypothalamic neurons that release orexin/hypocretin 5

Clinical Application in Cancer-Related Fatigue

Neither armodafinil nor modafinil demonstrated significant benefit over placebo for cancer-related fatigue in post-treatment survivors. 7

• Armodafinil evidence: A phase III trial (N=328) in glioma patients showed no significant difference between armodafinil 150 mg, 250 mg, or placebo in reducing fatigue 7
• Limited efficacy: Both agents failed to address the multifactorial nature of cancer-related fatigue in completed treatment settings 7