modafinil (Rx)

>10%

Headache (45-50%)

Rhinitis (11-15%)

Decreased appetite (16%)

Nausea (11%)

Abdominal pain (12%)

1-10%

Nervousness (6-10%)

Syncope (1-5%)

Frequency Not Defined

Arrhythmia

Hypotension

Hypertension

T-wave changes

Amnesia

Anxiety

Cataplexy

Chills

Depression

Dizziness

Epistaxis

Fever

Insomnia

Paresthesia

Reversible psychosis (rare)

Tremor

Drug hypersensitivity syndrome

Stevens-Johnson syndrome

Toxic epidermal necrolysis due to drug

Anorexia

Diarrhea

Dry mouth

Mouth ulcer

Vomiting

Abnormal LFT

Chest pain

Neck pain

Dyspnea

Pharyngitis

Postmarketing Reports

Aggression

Psychomotor hyperactivity

Contraindications

Hypersensitivity

Cautions

Risk of skin reactions (eg SJS, toxic necrolysis, and drug rash with eosinophilia and systemic symptoms); discontinue if rash or other hypersensitivity reactions occur

May impair ability to operate heavy machinery and perform hazardous tasks

Not recommended in patients with angina, cardiac ischemia, recent history of myocardial infarction, left ventricular hypertrophy, or mitral valve prolapse

Use with caution in severe hepatic impairment, elderly, history of: depression, psychosis (may exacerbate psychiatric symptoms), or mania

Use with caution in patients with Tourette syndrome; stimulants may unmask ticks

May reduce effectiveness of steroidal contraceptives 1 month after discontinuation of drug therapy

Reassess degree of sleepiness frequently; if used adjunctively with continuous positive airway pressure (CPAP): Periodic assessment of CPAP compliance is necessary

Discontinue at first sign of serious rash

Discontinue therapy if symptoms suggest angioedema or anaphylaxis

Discontinue if multiorgan hypersensitivity reaction is suspected

Drug interaction overview

• CYP3A4/5 substrates

  • Modafinil moderately induces CYP3A4/5, which may result in lower systemic exposure of CYP3A4/5 substrates (eg, hormonal contraceptives, cyclosporine, midazolam, triazolam)
  • Dose adjustment of substrate may be required

• CYP2C19 substrates

  • Modafinil weakly inhibits CYP2C19, which may result in higher systemic exposure of CYP2C19 substrates (eg, phenytoin, diazepam, propranolol, omeprazole, clomipramine)
  • Individuals deficient in CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19 (eg, TCAs, SSRIs), may be increased by coadministration
  • Dose adjustments of these drugs and other drugs that are substrates for CYP2C19 may be necessary if modafinil is coadministered

• Warfarin

  • Modafinil appeared to produce a concentration-related suppression of CYP2C9 activity, therefore suggesting potential for CYP2C9 inhibition; caution if drugs that have a narrow therapeutic index
  • Consider more frequent monitoring of prothrombin times/INR

• MAO inhibitors

  • Other CNS stimulants may induce severe cardiovascular reactions; avoid coadministration

Pregnancy

Well controlled studies in pregnant women have not been performed

Intrauterine growth restriction and spontaneous abortion have been reported with modafinil and armodafinil

In studies conducted in rats (modafinil, armodafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures

Pregnancy registry to collect information on pregnancy outcomes of women exposed to modafinil: 866-404-4106

Lactation

Unknown is excreted in human milk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Unknown; not sympathomimetic; may increase dopamine levels in the brain by binding to the dopamine transporter and inhibiting dopamine reuptake

Absorption

Peak plasma time: 2-4 hr

Distribution

Protein bound: 60%

Vd: 0.9 L/kg

Metabolism

Hepatic

Enzymes induced: CYP1A2, CYP2B6, CYP3A4; induces its own metabolism (chronic)

Enzymes inhibited: CYP2C19

Elimination

Half-life: 15 hr

Excretion: Urine (80%)