Pronunciation: moe-DAF-i-nil
Class: Analeptic

Trade Names

Provigil
- Tablets, oral 100 mg
- Tablets, oral 200 mg

Alertec (Canada)

Pharmacology

Wakefulness-promoting agent; however, the precise mechanism(s) is unknown.

Slideshow: What is Asthma? Causes, Symptoms, and Treatment

Pharmacokinetics

Absorption

Absorption is rapid. T _max is 2 to 4 h. Steady state is reached after 2 to 4 days of dosing. Food delays T _max approximately 1 h.

Distribution

Apparent Vd is 0.9 L/kg and protein binding is approximately 60%, mainly to albumin.

Metabolism

Primary site is hepatic via hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Major inactive metabolites are modafinil acid and modafinil sulfone. Modafinil induces its own metabolism via CYP3A4 after long-term administration.

Elimination

Approximately 80% (urine) and 1% (feces) excreted in 11 days. The elimination half-life is approximately 15 h.

Special Populations

Renal Function Impairment

Severe, chronic renal failure (CrCl 20 mL/min or less) did not influence the pharmacokinetics, but exposure to modafinil was increased 9-fold.

Hepatic Function Impairment

In patients with severe hepatic impairment, Cl is decreased approximately 60% and steady-state concentrations are doubled.

Elderly

There is a decrease of approximately 20% in oral Cl in patients with a mean age of 63 y; this is not likely to be clinically important.

Gender

The pharmacokinetics of modafinil are not affected by gender.

Race

The influence of race on the pharmacokinetics of modafinil has not been studied.

Indications and Usage

To improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work sleep disorder.

Unlabeled Uses

Treatment of fatigue associated with multiple sclerosis; attention deficit hyperactivity disorder; multiple sclerosis related nocturnal enuresis; Parkinson-related fatigue; sedation (drug induced); management of underarousal in patients with brain injury.

Contraindications

Hypersensitivity to armodafinil, modafinil, or any component of the product.

Dosage and Administration

Narcolepsy/Obstructive Sleep Apnea
Adults and Children 16 y and older

PO 200 mg as a single dose in the morning.

Shift Work Sleep Disorder
Adults and Children 16 y and older

PO 200 mg approximately 1 h prior to the start of work shift.

Elderly

PO Consider using lower doses.

Hepatic function impairment

PO 100 mg as a single dose in patients with severe hepatic impairment.

General Advice

• Consider dosage adjustment for concomitant medications that are substrates for CYP3A4, such as triazolam and cyclosporine.
• Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9), or S-mephenytoin, may have prolonged elimination when coadministered with modafinil and may require dosage reduction and monitoring for toxicity.

Storage/Stability

Store between 68° and 77°F.

Drug Interactions

Alcohol

Avoid coadministration.

Cabazitaxel

Plasma concentrations and pharmacologic effects of cabazitaxel may be decreased. Avoid coadministration.

Certain tricyclic antidepressants (eg, desipramine)

Plasma levels of certain tricyclic antidepressants may be increased. Monitor for toxicity. Dosage reduction may be necessary.

Clozapine

Clozapine serum concentrations may be elevated, increasing the pharmacologic and toxic effects. Closely observe the clinical response of the patient when starting or stopping modafinil.

Contraceptives, hormonal

Efficacy may be decreased by modafinil, increasing the risk of unintended pregnancy. Alternative or concomitant methods of contraception are recommended while patients are being treated with modafinil and for 1 mo after discontinuation of modafinil.

Cyclosporine, ethinyl estradiol

Blood levels may be decreased by modafinil. Dosage adjustment may be needed.

CYP3A4 inducers (eg, axitinib, carbamazepine, estradiol valerate, phenobarbital, rifampin, ulipristal) or inhibitors (eg, itraconazole, ketoconazole)

Coadministration could alter the plasma levels of modafinil. Monitor the clinical response and adjust treatment as needed.

Dextroamphetamine, methylphenidate

May delay the absorption of modafinil. However, there were no significant effects on the pharmacokinetics of modafinil.

Drugs eliminated by CYP2C19 metabolism (eg, diazepam, phenytoin, propranolol, SSRIs)

May have prolonged elimination, and may require dosage reduction, as well as monitoring for toxicity.

MAOIs (eg, isocarboxazid)

Use with caution.

Prazosin

Pharmacologic effects of modafinil may be decreased. Clinical effect is not known. If coadministration cannot be avoided, larger doses of modafinil may be needed.

Triazolam

Triazolam concentration may be decreased, reducing the clinical effect. Dosage adjustments may be required.

Warfarin

Modafinil does not appear to alter the pharmacokinetics of warfarin. However, more frequent monitoring of PT and INR is recommended when modafinil is coadministered.

Adverse Reactions

Cardiovascular

Hypertension (3%); palpitation, tachycardia, vasodilatation (2%).

CNS

Headache (34%); nervousness (7%); anxiety, dizziness, insomnia (5%); depression, paresthesia, somnolence (2%); agitation, confusion, dyskinesia, emotional lability, hyperkinesia, hypertonia, tremor, vertigo (1%); aggression, delusions, hallucinations, mania, suicidal ideation (postmarketing).

Dermatologic

Herpes simplex, sweating (1%); serious or life-threatening rash, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and TEN (postmarketing).

EENT

Rhinitis (7%); abnormal vision, amblyopia, epistaxis, eye pain (1%).

GI

Nausea (11%); diarrhea (6%); dyspepsia (5%); anorexia, dry mouth (4%); constipation (2%); flatulence, mouth ulceration, taste perversion, thirst (1%).

Genitourinary

Hematuria, pyuria, urine abnormality (1%).

Hematologic-Lymphatic

Eosinophilia (1%); agranulocytosis (postmarketing).

Hypersensitivity

Angioedema, hypersensitivity (with rash, dysphagia, and bronchospasm), multiorgan hypersensitivity with death (postmarketing).

Lab Tests

Increased GGT and alkaline phosphatase.

Musculoskeletal

Back pain (6%); neck rigidity (1%).

Respiratory

Pharyngitis (4%); lung disorder (2%); asthma (1%).

Miscellaneous

Flu syndrome (4%); chest pain (3%); abnormal liver function (2%); chills, edema (1%).

Precautions

Monitor Monitor for rash and for emergence or exacerbation of psychiatric symptoms. Frequently reassess patients with excessive sleepiness for their degrees of sleepiness. Increased monitoring of BP may be appropriate. Observe patients for signs of misuse or abuse (eg, incrementation of doses, drug-seeking behavior). Periodically reevaluate the long-term usefulness for the individual patient during long-term therapy.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 16 y has not been established. Serious rashes, including erythema multiforme major and Stevens-Johnson syndrome, have been associated with modafinil use in pediatric patients.

Elderly

Because elimination of modafinil and its metabolites may be reduced, consider using a lower dose.

Hypersensitivity

Rarely, serious angioedema and hypersensitivity, with rash, dysphagia, and bronchospasm, have been reported. Multiorgan hypersensitivity (including 1 fatality) has been reported in postmarketing experience.

Hepatic Function

Dosage reduction is recommended in patients with severe hepatic impairment.

Hazardous Tasks

May alter judgment, motor skills, or thinking.

CV effects

Not recommended for use in patients with a history of left ventricular hypertrophy or mitral valve prolapse who have experienced the mitral valve prolapse syndrome when receiving CNS stimulants. Use with caution in patients with a recent history of MI or unstable angina.

Dermatologic effects

Serious rash, which may be life-threatening or require hospitalization (eg, Stevens-Johnson syndrome, drug rash with eosinophilia, TEN), has been reported.

Drug dependence

Because of psychoactive and euphoric effects, modafinil has potential for abuse.

Psychiatric effects

Psychiatric adverse reactions, including aggression, delusions, hallucinations, mania, and suicidal ideation, some resulting in hospitalization, have been reported. Exercise caution when modafinil is given to patients with a history of psychosis, depression, or mania.

Wakefulness

May not return to normal in patients taking modafinil.

Overdosage

Symptoms

Aggressiveness, agitation, anxiety, confusion, decreased PT, diarrhea, excitation, insomnia, irritability, nausea, nervousness, palpitations, sleep disturbances, slight to moderate elevations in hemodynamic parameters, tremor.

Patient Information

• Advise patients to read to Medication Guide before starting therapy and with each refill.
• Advise patients that modafinil is not a replacement for sleep.
• Advise patients to continue to take previously prescribed treatments (eg, continuous positive airway pressure for patients with OSA) as instructed by their health care provider.
• Caution patients not to alter previous behavior with regard to potentially dangerous activities (eg, driving, operating machinery) or other activities requiring appropriate levels of wakefulness until, and unless, treatment with modafinil has been shown to produce levels of wakefulness that permit such activities.
• Inform patients that it is prudent to avoid alcohol while taking modafinil.
• Advise patients to notify their health care provider if they experience anxiety, chest pain, depression, or signs of psychosis or mania.
• Advise patients to stop taking modafinil and immediately notify their health care provider if blisters, mouth sores, peeling skin, trouble breathing or swallowing, rash, hives, or other symptoms of anaphylaxis, angioedema, or other allergic reactions occur.
• Advise patients to notify their health care provider if they become pregnant, intend to become pregnant during therapy, or are breast-feeding an infant. Advise women using hormonal contraception (oral, depot, or implantable) to use alternative or concomitant methods of contraception with and for 1 mo following discontinuation of therapy.
• Advise patients to inform their health care providers if they are taking, or planning to take, any prescription or nonprescription drugs because of the potential for interactions between modafinil and other drugs.

Copyright © 2009 Wolters Kluwer Health.