Modafinil - Drug Monograph

Introduction

Modafinil is a wakefulness-promoting agent classified as a eugeroic (arousal-producing) medication. First approved by the FDA in 1998, it represents a distinct pharmacological class with a unique mechanism of action compared to traditional stimulants. Modafinil has gained significant clinical importance for managing excessive sleepiness associated with various sleep disorders and has been studied for numerous off-label cognitive enhancement applications.

Mechanism of Action

Modafinil's exact mechanism of action remains incompletely understood but differs from traditional CNS stimulants. The drug appears to work through multiple neurotransmitter systems:

• Dopamine reuptake inhibition: Primary mechanism involving blockade of dopamine transporters, increasing extracellular dopamine in the nucleus accumbens and other brain regions
• Norepinephrine system modulation: Increases extracellular norepinephrine in hypothalamic regions
• Histaminergic activation: Indirect stimulation of hypothalamic histaminergic neurons
• Orexin system involvement: May interact with the orexin/hypocretin system, though this remains controversial

Unlike amphetamines, modafinil does not appear to cause widespread neurotransmitter release or significant peripheral sympathomimetic effects.

Indications

• Narcolepsy (with or without cataplexy)
• Obstructive sleep apnea/hypopnea syndrome (as adjunct therapy to continuous positive airway pressure)
• Shift work sleep disorder

• Attention-deficit/hyperactivity disorder (ADHD)
• Fatigue associated with multiple sclerosis
• Cancer-related fatigue
• Depression-associated fatigue (particularly in bipolar depression)

Dosage and Administration

• Initial dose: 200 mg once daily
• Maximum dose: 400 mg daily (divided or single dose)
• Administration: Oral, with or without food

• Elderly: Consider reduced starting dose (100 mg daily) due to potential decreased clearance
• Hepatic impairment: Reduce dose by 50% in severe hepatic impairment
• Renal impairment: Use with caution; no specific dosing recommendations
• Pediatric: Safety and efficacy not established under age 17

Pharmacokinetics

• Absorption: Rapid but food may delay Tmax by approximately 1 hour
• Distribution: Volume of distribution ~0.9 L/kg; 60% plasma protein bound
• Metabolism: Extensive hepatic metabolism via CYP3A4-mediated hydrolysis, with some contribution from CYP2C19 and other enzymes
• Elimination: Half-life 12-15 hours; primarily renal excretion (80%) as metabolites
• Steady-state: Reached after 2-4 days of repeated dosing

Contraindications

• Hypersensitivity to modafinil or armodafinil
• History of modafinil-associated rash or other serious hypersensitivity reactions
• Use with caution in patients with known cardiovascular disease

Warnings and Precautions

• Serious dermatologic reactions including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS)

• Psychiatric effects: May cause anxiety, nervousness, insomnia, or psychosis
• Cardiovascular effects: May increase blood pressure and heart rate
• Dependence potential: Schedule IV controlled substance with abuse potential
• Pregnancy: Category C; use only if potential benefit justifies risk
• Driving caution: Patients should be cautioned about operating vehicles or machinery until they know how modafinil affects them

Drug Interactions

• CYP3A4 inducers (carbamazepine, phenobarbital, rifampin): May decrease modafinil concentrations
• CYP3A4 inhibitors (ketoconazole, erythromycin): May increase modafinil concentrations
• Hormonal contraceptives: Modafinil decreases efficacy by inducing CYP3A4; alternative contraception required
• Warfarin: Modafinil may decrease warfarin efficacy via CYP2C9 induction
• Cyclosporine, tacrolimus: Modafinil may decrease concentrations via CYP3A4 induction
• SSRIs, TCAs: Potential pharmacokinetic interactions

Adverse Effects

• Headache (34%)
• Nausea (11%)
• Nervousness (7%)
• Anxiety (5%)
• Insomnia (5%)
• Dizziness (5%)

• Stevens-Johnson Syndrome/toxic epidermal necrolysis
• DRESS syndrome
• Psychiatric symptoms (mania, psychosis, hallucinations)
• Cardiovascular events (hypertension, tachycardia, chest pain)
• Multiorgan hypersensitivity reactions

Monitoring Parameters

• Efficacy: Epworth Sleepiness Scale, maintenance of wakefulness tests
• Safety: Blood pressure, heart rate at baseline and periodically
• Dermatologic: Skin examination for rash, especially during first few months
• Psychiatric: Mood changes, anxiety, psychotic symptoms
• Hepatic: Liver function tests in patients with hepatic impairment

Patient Education

• Take medication as prescribed; do not crush or chew tablets
• Report any skin rash or hypersensitivity symptoms immediately
• Use effective non-hormonal contraception if applicable
• Avoid alcohol consumption during treatment
• Be aware of potential for nervousness, anxiety, or insomnia
• Do not operate machinery until effects are known
• Do not discontinue abruptly if used long-term
• Inform all healthcare providers about modafinil use

References

1. US Food and Drug Administration. (2007). Provigil (modafinil) prescribing information. 2. Ballon JS, Feifel D. (2006). A systematic review of modafinil: Potential clinical uses and mechanisms of action. Journal of Clinical Psychiatry, 67(4), 554-566. 3. Kumar R. (2008). Approved and investigational uses of modafinil: an evidence-based review. Drugs, 68(13), 1803-1839. 4. Robertson P Jr, Hellriegel ET. (2003). Clinical pharmacokinetic profile of modafinil. Clinical Pharmacokinetics, 42(2), 123-137. 5. American Academy of Sleep Medicine. (2014). International Classification of Sleep Disorders, 3rd edition. 6. Mignot EJ, et al. (2015). Safety and efficacy of modafinil for the treatment of hypersomnia associated with narcolepsy. Sleep Medicine, 16(6), 755-762.