armodafinil (Rx)

>10%

Headache (14-23%)

1-10%

Nausea (6-9%)

Dry mouth (2-7%)

Dizziness (5%)

Anxiety (4%)

Diarrhea (4%)

Insomnia (4%)

Rash (1-4%)

Depression (1-3%)

Dyspepsia (2%)

Fatigue (2%)

Palpitations (2%)

Agitation (1%)

Anorexia (1%)

Attention disturbances (1%)

Contact dermatitis (1%)

Dyspnea (1%)

Hyperhidrosis (1%)

Nervousness (1%)

Paresthesia (1%)

Pyrexia (1%)

<1%

Angioedema

Dysphagia

Bronchospasm

Reversible psychosis

Postmarketing Reports

Aggression

Mouth Sores

Persistent sleepiness

Contraindications

Hypersensitivity to modafinil, armodafinil, or other ingredients

Cautions

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

Use caution in patients with history of left ventricular hypertrophy/mitral valve prolapse who have had mitral valve prolapse syndrome when previously receiving CNS stimulants; consider increased monitoring

Use caution in severe hepatic impairment and the elderly

History of depression, psychosis, mania; consider discontinuing armodafinil if psychiatric symptoms develop

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

If used adjunctively with continuous positive airway pressure (CPAP), periodic assessment of CPAP compliance is necessary

Serious rash requiring hospitalization and discontinuation of treatment has been reported; discontinue at first sign of serious rash

Discontinue therapy if symptoms suggest angioedema or anaphylaxis

Skin and mouth sores, blistering, and ulceration reported

Persistent sleepiness

• Patients with abnormal levels of sleepiness who receive therapy should be advised that their level of wakefulness may not return to normal
• Patients with excessive sleepiness, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity
• Prescribers should be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities

Dermatologic reactions

• Rare cases of serious or life-threatening rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), reported in adults and children in worldwide post-marketing experience
• There are no factors, including duration of therapy, known to predict risk of occurrence or severity of rash associated with therapy; discontinue therapy at first sign of rash, skin or mouth sores, or blistering or ulceration, unless rash is clearly not drug-related
• Discontinuation of treatment may not prevent rash from becoming life-threatening or permanently disabling or disfiguring

Multiorgan hypersensitivity

• DRESS, also known as multi-organ hypersensitivity, has been reported; important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident
• If multi-organ hypersensitivity reaction suspected, discontinue therapy; although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility

Cardiovascular events

• Cardiovascular adverse reactions, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG reported in association with mitral valve prolapse or left ventricular hypertrophy
• Recommended that medication not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants
• Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia; if new onset of any of these findings occurs, consider cardiac evaluation
• Increased monitoring of heart rate and blood pressure may be appropriate in patients on therapy; exercise caution when prescribing therapy to patients with known cardiovascular disease

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

Limited available data in pregnant women are insufficient to inform about drug associated risk of adverse pregnancy outcomes; intrauterine growth restriction and spontaneous abortion reported in association with armodafinil and modafinil; although the pharmacology of armodafinil not identical to that of sympathomimetic amines, armodafinil shares some pharmacologic properties with this class; sympathomimetics have been associated with intrauterine growth restriction and spontaneous abortions

Effectiveness of hormonal contraceptives may be reduced up to for one month after discontinuation of therapy; advise women who using a hormonal method of contraception to use additional barrier method or alternative non-hormonal method of contraception during treatment and for one month after discontinuation of treatment

Lactation

There are no data on presence of armodafinil or metabolite in human milk, effects on breastfed infant, or effect of this drug on milk production; modafinil was present in rat milk when animals were dosed during the lactation period; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for armodafinil and any potential adverse effects on breastfed child from armodafinil or from underlying maternal condition

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 (R-enantiomer of modafinil); may increase dopamine levels in the brain by binding to the dopamine transporter and inhibiting dopamine reuptake

Absorption

Peak plasma time: 2 hr

Distribution

Protein bound: 60%

Vd: 42 L

Metabolism

Hepatic; primarily amide hydrolysis; also sulfone formation by CYP3A4/5

Enzymes induced: CYP1A2, possibly CYP3A4 in a concentration-related manner

Enzymes inhibited: CYP2C19

Pharmacokinetics

Half-life: 15 hr

Excretion: Urine (80%)