Provigil - Drug Monograph

Introduction

Provigil (modafinil) is a wakefulness-promoting agent approved by the FDA in 1998. It is classified as a Schedule IV controlled substance due to its potential for abuse and dependence. Modafinil represents a distinct pharmacological approach to treating excessive sleepiness compared to traditional stimulants like amphetamines.

Mechanism of Action

Modafinil's exact mechanism of action remains incompletely understood. Unlike traditional stimulants, it does not appear to act primarily through dopamine or norepinephrine systems. Current evidence suggests modafinil:

• Binds to the dopamine transporter and inhibits dopamine reuptake
• Increases neuronal activity in wake-promoting centers of the brain (hypothalamus)
• May interact with orexin/hypocretin systems involved in sleep-wake regulation
• Exhibits weak to negligible affinity for other neurotransmitter systems (norepinephrine, serotonin, GABA, adenosine)

Indications

FDA-approved indications:

• Narcolepsy
• Obstructive sleep apnea/hypopnea syndrome (as adjunct therapy to continuous positive airway pressure)
• Shift work sleep disorder

Off-label uses (not FDA-approved but supported by some evidence):

• Attention deficit hyperactivity disorder (ADHD)
• Fatigue associated with medical conditions (multiple sclerosis, Parkinson's disease, depression)
• Jet lag

Dosage and Administration

• Initial dose: 200 mg orally once daily
• Maximum dose: 400 mg/day (as single or divided dose)

• Hepatic impairment (severe): Reduce dose by 50%
• Renal impairment (severe): Use with caution
• Elderly: Consider lower initial dose due to potential decreased clearance
• Pediatric: Safety and efficacy not established

• Administer in the morning for narcolepsy and OSA
• Administer 1 hour before shift start for shift work disorder
• May be taken with or without food

Pharmacokinetics

Contraindications

• Hypersensitivity to modafinil or armodafinil
• History of left ventricular hypertrophy or mitral valve prolapse syndrome with modafinil use
• Concomitant use with monoamine oxidase inhibitors (risk of hypertensive crisis)

Warnings and Precautions

• Serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Angioedema and anaphylactoid reactions
• Multi-organ hypersensitivity reactions
• Psychiatric symptoms (anxiety, mania, hallucinations, suicidal ideation)
• Cardiovascular events in patients with underlying cardiac disease

• Use with caution in patients with history of psychosis, mania, or depression
• Monitor blood pressure in hypertensive patients
• Consider pregnancy testing in women of childbearing potential
• May reduce efficacy of hormonal contraceptives

Drug Interactions

• Carbamazepine, phenytoin, rifampin: May decrease modafinil levels

• Ketoconazole, itraconazole: May increase modafinil levels

• Diazepam, phenytoin, propranolol: Modafinil may decrease their levels

• Modafinil may reduce efficacy of ethinyl estradiol-containing contraceptives

• Modafinil may decrease warfarin efficacy via CYP2C19 induction

Adverse Effects

• Headache (30%)
• Nausea (11%)
• Nervousness (7%)
• Anxiety (5%)
• Insomnia (5%)
• Dizziness (5%)

• Stevens-Johnson syndrome
• Angioedema
• Psychiatric symptoms (mania, hallucinations, suicidal ideation)
• Cardiovascular events (chest pain, palpitations, hypertension)
• Multiorgan hypersensitivity reactions

Monitoring Parameters

• Comprehensive medical history (focus on cardiovascular, psychiatric, skin disorders)
• Pregnancy test in women of childbearing potential
• Blood pressure and heart rate

• Blood pressure (periodically, especially in hypertensive patients)
• Psychiatric status
• Signs of abuse or misuse
• Skin reactions
• Efficacy assessment (Epworth Sleepiness Scale, functional improvement)

• Hepatic function in patients with liver impairment
• International normalized ratio (INR) in patients on warfarin

Patient Education

• Take as prescribed; do not increase dose without medical supervision
• Use effective non-hormonal contraception if taking hormonal birth control
• Report any skin rash immediately
• Monitor for psychiatric symptoms (anxiety, depression, unusual thoughts)
• Avoid alcohol during treatment
• Do not operate machinery until effects are known
• Store securely to prevent misuse by others
• Do not share medication with anyone
• Report chest pain, palpitations, or breathing difficulties

• Maintain good sleep hygiene practices
• Continue CPAP therapy if prescribed for sleep apnea
• Avoid driving or dangerous activities if experiencing drowsiness

References

1. FDA Prescribing Information: Provigil (modafinil) tablets. 2020 2. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803-1839 3. Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry. 2006;67(4):554-566 4. Morgenthaler TI, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705-1711 5. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43(1):88-97 6. Wong YN, et al. Clinical pharmacokinetics of modafinil. Clin Pharmacokinet. 1999;37(1):75-91 7. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. 2014