Provigil (modafinil) is a prescription-only wakefulness-promoting agent indicated for the management of excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), and shift work sleep disorder (SWSD). It is classified as a Schedule IV controlled substance due to its potential for dependence. Unlike traditional stimulants, its precise mechanism of action is not fully understood but is believed to involve the selective activation of specific wake-promoting neuronal systems, including those utilizing dopamine, norepinephrine, histamine, and orexin. Its efficacy is well-documented in clinical trials, demonstrating significant improvement in the ability to maintain wakefulness.

Features

• Active Ingredient: Modafinil
• Available Strengths: 100 mg and 200 mg tablets
• Pharmacologic Class: Wakefulness-promoting agent; eugeroic
• Mechanism of Action: Exact mechanism unknown; believed to work through selective activation of hypothalamic wakefulness centers, with weak, atypical dopamine reuptake inhibition being a key component.
• Onset of Action: Typically within 1-2 hours of oral administration.
• Duration of Action: Up to 12-15 hours.
• Bioavailability: High, with peak plasma concentrations occurring at approximately 2-4 hours post-dose.
• Metabolism: Primarily hepatic, via CYP3A4/5-mediated pathways, with subsequent renal elimination of metabolites.

Benefits

• Promotes sustained wakefulness and alertness in patients with diagnosed sleep disorders, enabling full daytime function.
• Improves objective measures of attention, including performance on tests of memory and cognitive function in sleep-deprived states.
• Reduces the extreme, involuntary sleep episodes characteristic of narcolepsy.
• Helps normalize the sleep-wake cycle for individuals with non-standard work schedules (shift work sleep disorder).
• Offers a favorable side effect profile compared to traditional psychostimulants like amphetamines, with a lower incidence of euphoria and jitteriness.
• Provides a long duration of effect, often allowing for once-daily dosing to cover waking hours.

Common use

Provigil is FDA-approved for improving wakefulness in adult patients with excessive sleepiness associated with:

• Narcolepsy: A chronic neurological disorder characterized by the brain’s inability to regulate sleep-wake cycles normally, leading to overwhelming daytime drowsiness and sudden attacks of sleep.
• Obstructive Sleep Apnea (OSA): Used as adjunctive therapy to standard treatments like continuous positive airway pressure (CPAP) for residual daytime sleepiness. It is not a treatment for the underlying airway obstruction.
• Shift Work Sleep Disorder (SWSD): For patients who experience insomnia during scheduled sleep periods or excessive sleepiness during scheduled wake periods due to a work schedule that overlaps with the typical sleep period.

Its use for cognitive enhancement in healthy individuals (“off-label” use) is not approved by the FDA and is associated with significant risks, including cardiovascular events and potential for psychological dependence.

Dosage and direction

Dosage must be individualized based on clinical response and tolerability. It is typically administered as a single daily dose.

• Narcolepsy and OSA: The recommended dose is 200 mg taken orally once daily in the morning.
• Shift Work Sleep Disorder: The recommended dose is 200 mg taken orally approximately 1 hour prior to the start of the work shift.
• Dosage Adjustment: In elderly patients or those with severe hepatic impairment, a reduced initial dose of 100 mg daily is recommended. Dose titration may be considered based on efficacy and side effects.
• Administration: Tablets should be swallowed whole with a glass of water. It may be taken with or without food, although food may delay absorption slightly.

Precautions

• Cardiovascular Effects: May increase heart rate and blood pressure. Use with caution in patients with a history of left ventricular hypertrophy, mitral valve prolapse, coronary artery disease, or recent myocardial infarction. Blood pressure and heart rate should be monitored.
• Psychiatric Symptoms: May cause anxiety, nervousness, insomnia, agitation, aggression, or mania. Use with extreme caution in patients with a history of psychosis, depression, or mania. Patients should be monitored for the emergence or worsening of depression, suicidal ideation, or other psychiatric symptoms.
• Dependence Potential: As a Schedule IV controlled substance, Provigil has a known potential for dependence. A history of drug or alcohol addiction is a risk factor.
• Driving and Operating Machinery: Although Provigil promotes wakefulness, patients must be cautioned about operating automobiles or hazardous machinery until they are reasonably certain that Provigil does not adversely affect their performance.
• Pregnancy and Lactation: Provigil is Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Modafinil and its metabolites are excreted in breast milk; a decision should be made whether to discontinue nursing or discontinue the drug.

Contraindications

Provigil is contraindicated in patients with:

• Known hypersensitivity to modafinil, armodafinil, or any inactive ingredient of the formulation.
• A history of serious or life-threatening rash, including Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN), associated with modafinil or armodafinil use.

Possible side effect

The most common adverse reactions (≥5%) are headache, nausea, nervousness, anxiety, insomnia, dizziness, and diarrhea. Most are mild to moderate in severity.

• Very Common (≥10%): Headache.
• Common (1-10%): Nausea, decreased appetite, dry mouth, anxiety, nervousness, insomnia, dizziness, diarrhea, rhinitis, back pain.
• Uncommon (0.1-1%): Palpitations, tachycardia, hypertension, chest pain, dyspepsia, agitation, depression, confusion, paresthesia, blurred vision, eosinophilia.
• Rare (<0.1% but serious): Serious skin reactions (e.g., Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS]), angioedema, multi-organ hypersensitivity reactions, psychosis, mania, suicidal ideation.

Drug interaction

Provigil is primarily metabolized by the CYP3A4 enzyme system and can also induce CYP3A4, CYP2B6, and CYP2C19 isozymes. It is a weak inhibitor of CYP2C9 and CYP2C19. Key interactions include:

• CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort): May decrease plasma concentrations of modafinil, reducing its efficacy. Dose adjustment may be necessary.
• CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, erythromycin): May increase plasma concentrations of modafinil, increasing the risk of adverse effects.
• CYP2C19 Substrates (e.g., diazepam, phenytoin, propranolol, omeprazole): Provigil may increase the metabolism of these drugs, decreasing their plasma concentrations and efficacy.
• CYP2C9 Substrates (e.g., warfarin): Provigil may increase the metabolism of warfarin, decreasing its anticoagulant effect. Prothrombin time/INR should be monitored closely, especially during initiation and upon discontinuation of Provigil.
• Hormonal Contraceptives: Provigil can significantly reduce the plasma concentrations of ethinyl estradiol, the active component of many oral contraceptives, rendering them less effective. Alternative or concomitant methods of contraception are recommended during and for one month after discontinuation of Provigil therapy.
• Cyclosporine: Plasma concentrations of cyclosporine may be reduced. Monitoring of cyclosporine levels is recommended.

Missed dose

If a dose is missed, it should be taken as soon as possible on the same day. However, if it is late in the afternoon or evening, the missed dose should be skipped to avoid insomnia that night. Do not double the next dose.

Overdose

• Symptoms: Overdose may manifest as insomnia, central nervous system excitation (e.g., restlessness, agitation, confusion, anxiety, tremor), tachycardia, hypertension, nausea, and diarrhea. In very large overdoses, more severe effects are theoretically possible.
• Management: There is no specific antidote for modafinil overdose. Management consists of instituting supportive measures, including cardiovascular monitoring. Gastric lavage may be considered if performed soon after ingestion. The patient should be observed and treated symptomatically in a controlled environment.

Storage

• Store at room temperature, 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F).
• Keep the medication in its original container, tightly closed, and out of reach of children and pets.
• Protect from excessive moisture and light.
• Do not flush unused medication down the toilet or pour it into a drain. Dispose of medication through a medicine take-back program or according to FDA guidelines.

Disclaimer

This information is for educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or before starting any new treatment. Never disregard professional medical advice or delay in seeking it because of something you have read here. The information provided may not cover all possible uses, directions, precautions, drug interactions, or adverse effects.

Reviews

• Clinical Efficacy (Neurologist, 15 yrs exp.): “In my practice, Provigil has been a cornerstone for managing narcolepsy. Its ability to promote sustained wakefulness without the significant ‘crash’ associated with amphetamines is a marked benefit for patient quality of life. It is not a cure, but it is a highly effective tool for symptom management.”
• Patient Experience (SWSD Diagnosis): “As an emergency room nurse on rotating shifts, the sleepiness was debilitating. Since starting Provigil, taken an hour before my night shift, I am alert, focused, and able to provide safe patient care. The main side effect I experienced was a mild headache for the first week, which subsided.”
• Safety Profile (Clinical Pharmacist): “While generally well-tolerated, clinicians must be vigilant for two key areas: the potential for serious dermatologic reactions, which although rare require immediate discontinuation, and the significant drug interaction with hormonal contraceptives, which must be communicated clearly to all female patients of childbearing potential.”