What are the indications, dosing, contraindications, and monitoring recommendations for modafinil?

Modafinil: Indications, Dosing, Contraindications, and Monitoring

Modafinil is FDA-approved for excessive daytime sleepiness in narcolepsy, obstructive sleep apnea (as adjunct to CPAP), and shift work disorder, with a standard dose of 200 mg once daily in the morning and a maximum of 400 mg/day. 1

FDA-Approved Indications

Modafinil is indicated to improve wakefulness in three specific conditions: 1

• Narcolepsy: Treats excessive daytime sleepiness but does NOT suppress cataplexy 1, 2
• Obstructive Sleep Apnea (OSA): Only as adjunct therapy for residual sleepiness despite optimal CPAP use—not a treatment for the underlying airway obstruction 1
• Shift Work Disorder (SWD): Reduces sleepiness during night shifts and decreases accident risk during commute home 1

Dosing Recommendations

Standard Dosing by Indication

• Narcolepsy or OSA: 200 mg once daily in the morning 1
• Shift Work Disorder: 200 mg once daily, taken approximately 1 hour before the start of the work shift 1
• Maximum daily dose: 400 mg/day, given as single morning dose or split into morning and midday doses (last dose no later than 2:00 PM to avoid insomnia) 3, 2

Dose Titration Strategy

For cancer-related fatigue, the National Comprehensive Cancer Network recommends: 4

• Weeks 1-2: 100 mg daily
• Weeks 3-4: Escalate to 200 mg daily
• Higher doses (200-400 mg/day): More effective for sleepiness 3, 4
• Lower doses (50-200 mg/day): More appropriate for concentration problems and fatigue 3, 4

Special Populations

• 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 3
• Severe renal insufficiency: Use caution due to substantial increases in modafinil acid levels 5

Pharmacokinetic Considerations

• Half-life: Approximately 15 hours 3, 4
• Steady state: Reached after 2-4 days of dosing 3, 4
• Peak plasma concentration: 2-3 hours after oral administration 6

Contraindications

Absolute contraindication: Known hypersensitivity to modafinil or armodafinil 1

Warnings and Precautions

Serious Dermatologic Reactions

• Stevens-Johnson Syndrome: Discontinue modafinil immediately at the first sign of rash unless clearly not drug-related 1
• Pediatric risk: The American Academy of Sleep Medicine reports higher risk in children; modafinil is NOT FDA-approved for patients under 17 years 3

Cardiovascular Monitoring

• Baseline assessment: Establish blood pressure and heart rate before starting treatment 3
• Regular monitoring: Especially in patients with pre-existing cardiovascular disease to detect hypertension or other adverse effects 3
• Known cardiovascular disease: Consider increased monitoring frequency 1

Psychiatric Symptoms

• Use caution in patients with history of psychosis, depression, or mania 1
• Monitor closely for mood destabilization (irritability, reduced need for sleep, racing thoughts, increased energy, psychotic symptoms), especially during first 2-4 weeks 3
• Consider discontinuing if psychiatric symptoms develop 1

Pregnancy and Reproductive Safety

• Teratogenicity: A 2018 pregnancy registry showed higher rates of major congenital anomalies in infants exposed to modafinil in utero 2, 3
• Contraceptive interaction: Modafinil induces hepatic enzymes that reduce effectiveness of hormonal contraceptives 2, 1
• Contraceptive recommendations: Women of childbearing potential must use alternative or additional contraception during treatment and for one month after discontinuation 3, 1

Other Precautions

• Angioedema and anaphylaxis: If suspected, discontinue immediately 1
• Multi-organ hypersensitivity reactions: If suspected, discontinue immediately 1
• Persistent sleepiness: Assess patients frequently and advise to avoid driving or dangerous activities if sleepiness persists 1

Adverse Effects

Common Adverse Events (≥5%)

The most frequently reported adverse effects include: 1, 3

• Headache (34% vs 23% placebo) 7
• Nausea (11% vs 3% placebo) 7
• Nervousness 1, 3
• Insomnia 2, 3
• Diarrhea 2, 1
• Back pain 3, 1
• Anxiety 1
• Dizziness 1
• Dyspepsia 3, 1
• Rhinitis 1
• Dry mouth 2

Cardiovascular Effects

• Clinically significant increases in diastolic or systolic blood pressure are infrequent (<1% of patients) 7
• Clinically significant increases in heart rate are rare 7
• Does not adversely affect cardiovascular parameters when used appropriately 7

Drug Interactions

Significant Interactions Requiring Action

• Hormonal contraceptives (e.g., ethinyl estradiol): Use alternative or concomitant contraception during treatment and for one month after discontinuation 1
• Cyclosporine: Blood concentrations may be reduced; monitor levels 1
• CYP2C19 substrates (omeprazole, phenytoin, diazepam): Exposure may be increased; monitor for toxicity 1

Monitoring Recommendations

Pre-Treatment Assessment

• Baseline blood pressure and heart rate 3
• Cardiovascular history and examination 3
• Psychiatric history (psychosis, depression, mania) 1
• Pregnancy status in women of childbearing potential 3

Ongoing Monitoring

• Cardiovascular: Regular blood pressure and heart rate monitoring, especially in patients with pre-existing cardiovascular disease 3
• Psychiatric: Monitor for mood destabilization, irritability, reduced sleep need, racing thoughts, increased energy, or psychotic symptoms during first 2-4 weeks 3
• Dermatologic: Monitor for rash, especially in first weeks of treatment 1
• Efficacy: Assess degree of sleepiness frequently; if inadequate response after 4 weeks at maximum dose (400 mg), reassess with standardized fatigue-measurement tools 3

Diagnostic Testing Considerations

• Before MSLT: Minimum washout of 7 days after stopping modafinil to prevent drug-induced prolongation of sleep latency 8
• Actigraphy: Continuous monitoring for 7-14 days before polysomnography/MSLT, beginning at start of modafinil washout 8

Controlled Substance Status and Abuse Potential

• DEA Schedule: C-IV federally controlled substance 2, 1
• Abuse potential: Significantly lower than traditional stimulants (amphetamines, methylphenidate) 2, 3, 4
• Physical dependence: Limited risk; no rebound phenomena or withdrawal symptoms after treatment cessation 6

Clinical Pearls and Common Pitfalls

Timing of Administration

• Last dose should be no later than 2:00 PM to avoid insomnia 2, 3
• For shift work disorder, take 1 hour before shift start 1

Does Not Affect Sleep Architecture

• Unlike traditional stimulants, modafinil does not disturb nighttime sleep patterns or polysomnography parameters 4, 7
• Patients can still nap when necessary 6

Escalation Strategy for Refractory Fatigue

If fatigue persists after 4 weeks at maximum 400 mg modafinil dose: 3

• Consider adding or switching to dextroamphetamine 10 mg twice daily (morning and early afternoon)
• Methylphenidate is an alternative with stronger evidence than mixed amphetamine salts
• Reassess for sleep-disordered breathing, restless leg syndrome, depression, thyroid dysfunction, anemia, or medication-induced fatigue

Off-Label Use in Bipolar Disorder

• Only as adjunct to mood stabilizer (lithium or valproate)—never as monotherapy 3
• Not a first-line option; use remains off-label 3
• Close monitoring required for mood destabilization 3