Armodafinil

Approved Indications

• Narcolepsy: To improve wakefulness in adults with excessive daytime sleepiness.
• Obstructive Sleep Apnea (OSA): As an adjunct to standard treatment (e.g., CPAP) to treat residual excessive sleepiness.
• Shift Work Sleep Disorder (SWSD): For individuals with excessive sleepiness due to altered sleep schedules.

Clinically Accepted Off-label Uses

• Attention-Deficit/Hyperactivity Disorder (ADHD): Particularly in adults when conventional treatments fail or are not tolerated.
• Major Depressive Disorder (MDD): As an adjunct to antidepressants in treatment-resistant depression.
• Fatigue in Multiple Sclerosis (MS) and other chronic disorders (e.g., cancer-related fatigue, Parkinson’s disease).
• Cognitive enhancement in select off-label therapeutic settings under medical supervision.

Adults

• Narcolepsy/OSA: 150 mg once daily in the morning.
• SWSD: 150 mg taken approximately 1 hour before starting the work shift.

Pediatric Use

• Not approved for use in children under 17 years due to limited safety data.

Elderly

• Start at the lower end of the dosage range. Monitor closely due to possible reduced hepatic, renal, or cardiac function.

Hepatic Impairment

• Reduce dose to 75 mg once daily in moderate to severe hepatic impairment due to decreased clearance.

Renal Impairment

• Use with caution in severe renal dysfunction; dose adjustment may be necessary.

Administration

• Oral; may be taken with or without food. Onset may be delayed if taken with food.
• Avoid taking late in the day to minimize insomnia risk.

Armodafinil is the R-enantiomer of modafinil and acts as a central nervous system stimulant with wakefulness-promoting properties. It exerts its effects primarily through inhibition of dopamine reuptake by binding to the dopamine transporter (DAT), leading to increased extracellular dopamine levels. While its precise mechanism is not fully understood, armodafinil also influences other neurotransmitter systems, including orexin, histamine, norepinephrine, and serotonin pathways. These combined effects enhance alertness and reduce excessive sleepiness in patients with sleep-wake disorders.

• Absorption: Well absorbed orally; peak plasma concentration occurs ~2 hours after administration.
• Bioavailability: Approximately 90% (not affected significantly by food).
• Distribution: Volume of distribution ~42–50 L; ~60% plasma protein binding.
• Metabolism: Primarily hepatic via amide hydrolysis and CYP3A4 oxidation; minor pathways involve CYP1A2, CYP2C19.
• Half-life: 12–15 hours (longer than racemic modafinil).
• Excretion: Mostly renal (inactive metabolites); <10% excreted unchanged in urine.

• Pregnancy: Category C. Animal studies have shown adverse effects on the fetus; use only if potential benefit justifies the risk. Consider alternative therapies during pregnancy.
• Lactation: Unknown whether armodafinil is excreted in human milk. Due to potential for serious adverse effects in nursing infants, discontinue breastfeeding or the drug, weighing risks and benefits.
• Caution is advised in both pregnant and breastfeeding women.

• Primary Class: CNS Stimulant / Wakefulness-promoting agent
• Subclass: Atypical psychostimulant; Dopamine reuptake inhibitor (selective)
• Generation: Second-generation enantiomer of modafinil

• Known hypersensitivity to armodafinil, modafinil, or any formulation component
• History of rash or serious dermatologic reaction to modafinil/armodafinil
• Uncontrolled hypertension or significant cardiac arrhythmias (relative contraindication)

• Serious Skin Reactions: Rare but life-threatening rashes (e.g., Stevens-Johnson Syndrome); discontinue at first sign of rash.
• Psychiatric Symptoms: May exacerbate anxiety, mania, or psychosis; caution in individuals with psychiatric disorders.
• Cardiovascular Risk: Monitor heart rate and blood pressure regularly, especially in patients with cardiac conditions.
• Substance Abuse: Although low, there is potential for misuse; use caution in patients with history of drug abuse.
• Severe Allergic Reactions: Angioedema, multi-organ hypersensitivity have been reported.

Common Side Effects

• Central Nervous System: Headache, dizziness, insomnia, anxiety, agitation
• Gastrointestinal: Nausea, dry mouth, dyspepsia
• General: Fatigue, back pain

Serious Side Effects

• Stevens-Johnson syndrome, Toxic epidermal necrolysis
• Hallucinations, mania, suicidal ideation
• Palpitations, hypertension, tachycardia
• Liver function abnormalities

Rare Side Effects

• Psychomotor hyperactivity
• Visual disturbances
• Blood dyscrasias

Onset is typically within the first few days to weeks of therapy; dose-related in some cases.

• CYP3A4 Substrates: May reduce efficacy of oral contraceptives, cyclosporine, and other drugs metabolized by CYP3A4.
• CYP2C19 Substrates: May increase levels of diazepam, phenytoin, omeprazole, leading to toxicity.
• CNS Stimulants or Depressants: Caution with concurrent use due to additive CNS effects.
• MAO Inhibitors: Concomitant use not recommended due to risk of hypertensive crisis.
• Alcohol: May potentiate CNS effects and is best avoided.

• FDA and EMA continue to emphasize armodafinil’s use strictly for approved indications.
• New updates recommend caution with off-label cognitive enhancement use, highlighting ethical and dependency concerns.
• Revised prescribing information includes stronger warnings for dermatologic and psychiatric adverse effects.

• Temperature: Store below 30°C (room temperature).
• Humidity: Protect from excessive moisture.
• Light: Store in original container; protect from direct light.
• Handling: No special reconstitution needed; keep out of reach of children.
• Disposal: Follow national/local guidelines for safe disposal.