What are the indications for Modafinil (Provigil)?

Indications for Modafinil (Provigil)

Modafinil is FDA-approved for three specific conditions: excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome (as adjunctive therapy), and shift work sleep disorder. 1

FDA-Approved Indications

Primary Approved Uses

• Narcolepsy: Modafinil 200 mg once daily in the morning is the recommended dose to improve wakefulness in adults with excessive sleepiness from narcolepsy 1. The American Academy of Sleep Medicine strongly recommends modafinil as first-line treatment, based on 9 RCTs and 4 observational studies demonstrating clinically significant improvements in excessive daytime sleepiness, disease severity, and quality of life 2.

• Obstructive Sleep Apnea/Hypopnea Syndrome (OSA): Modafinil 200 mg once daily in the morning is indicated specifically for residual excessive sleepiness in patients already receiving optimal continuous positive airway pressure (CPAP) therapy 1. Critical caveat: Modafinil is NOT a treatment for the underlying airway obstruction itself—it only addresses residual sleepiness despite adequate CPAP compliance 1.

• Shift Work Sleep Disorder (SWSD): Modafinil 200 mg taken approximately one hour prior to the start of the work shift improves night-time wakefulness without disrupting subsequent daytime sleep 1, 3.

Dosing Considerations by Indication

Standard Dosing

• Maximum daily dose: 400 mg per day, typically as a single morning dose or divided into two doses 4
• Higher doses (200-400 mg/day): More effective for treating sleepiness 2
• Lower doses (50-200 mg/day): More appropriate for concentration problems and fatigue 2

Special Populations Requiring Dose Adjustment

• Severe hepatic impairment: Reduce dose to half the recommended dose 1
• Elderly patients: Start with 100 mg once upon awakening, increase at weekly intervals as necessary 4
• Geriatric patients: Consider lower doses due to altered pharmacokinetics 1

Off-Label Uses (Not FDA-Approved)

While modafinil has been studied for various off-label indications, these lack FDA approval:

Cancer-Related Fatigue

• The National Comprehensive Cancer Network discusses modafinil as a treatment option for cancer-related fatigue, with open-label studies showing 75% of patients improved at 4 weeks 2
• However, this remains an off-label use without definitive evidence from large randomized controlled trials

Other Conditions Studied

• Augmentation of antidepressants in major depressive disorder 2
• Adjunct treatment of bipolar depression 2
• Persistent fatigue and sleepiness despite antidepressant treatment 2
• Multiple sclerosis-related fatigue 2

Important Safety Warnings and Contraindications

Absolute Contraindications

• Known hypersensitivity to modafinil or armodafinil 1

Black Box Warnings and Serious Risks

• Serious rash including Stevens-Johnson syndrome: Discontinue immediately at first sign of rash unless clearly not drug-related 1, 4
• Angioedema and anaphylaxis reactions: Discontinue if suspected 1
• Multi-organ hypersensitivity reactions: Discontinue if suspected 1

Pregnancy and Reproductive Considerations

• May cause fetal harm based on animal data; a 2018 pregnancy registry showed higher rates of major congenital anomalies in children exposed in utero 2
• Reduces effectiveness of oral contraception: Use alternative or concomitant contraceptive methods during treatment and for one month after discontinuation 1, 2

Common Adverse Events (≥5%)

• Headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia 1, 2

Key Clinical Advantages

Compared to Traditional Stimulants

• Lower abuse potential: Modafinil is a Schedule IV controlled substance with less abuse potential than amphetamines or methylphenidate 2, 4
• No rebound phenomena: Unlike amphetamines, modafinil does not cause withdrawal symptoms or rebound sleepiness after discontinuation 5
• Does not disrupt nocturnal sleep architecture: Unlike traditional stimulants, modafinil does not affect nighttime sleep quality 5

Pharmacokinetic Profile

• Half-life: Approximately 15 hours 2
• Steady state: Reached after 2-4 days of dosing 2

Clinical Pitfalls to Avoid

1. Do not use modafinil as monotherapy for OSA: It must be adjunctive to CPAP or other treatments addressing the underlying obstruction 1

2. Monitor for persistent sleepiness: Assess patients frequently and advise against driving or dangerous activities if sleepiness persists 1

3. Psychiatric monitoring: Use caution in patients with history of psychosis, depression, or mania; consider discontinuation if psychiatric symptoms develop 1

4. Drug interactions: Modafinil affects CYP450 pathways, reducing cyclosporine levels and increasing exposure to CYP2C19 substrates (omeprazole, phenytoin, diazepam) 1

5. Not approved for pediatric use: Modafinil is not FDA-approved for patients under 17 years due to Stevens-Johnson syndrome risk 4