MODAFINIL
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
The precise mechanism of action is unknown. Modafinil is a wakefulness-promoting agent that may have direct or indirect effects on dopamine, norepinephrine, serotonin, GABA, glutamate, and orexin systems. It binds to the dopamine transporter and inhibits dopamine reuptake.
| Metabolism | Metabolized primarily in the liver via amide hydrolysis, with minor contributions from CYP3A4. Major metabolites are inactive. Excreted renally. |
| Excretion | Primarily renal (as metabolites and unchanged drug); approximately 80% of the dose is recovered in urine, with less than 10% as unchanged modafinil. Fecal excretion accounts for less than 1%. |
| Half-life | Terminal elimination half-life is approximately 15 hours (range 10–30 hours). This supports once-daily dosing for sustained wakefulness. |
| Protein binding | Approximately 60% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 0.9 L/kg, indicating distribution into total body water and some tissue binding. |
| Bioavailability | Oral bioavailability is approximately 80% (range 60–95%) based on absolute bioavailability studies. |
| Onset of Action | Oral: Onset of clinical effect (improved wakefulness) occurs within 1–2 hours after a single oral dose. |
| Duration of Action | Duration of effect is approximately 8–12 hours after a single oral dose. Clinical improvement in wakefulness persists for the dosing interval (24 hours) with daily dosing. |
| Molecular Weight | 273.35 |
200 mg orally once daily in the morning.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Severe impairment (GFR < 30 mL/min): reduce dose to 100 mg once daily. |
| Liver impairment | Child-Pugh Class A or B: no adjustment. Child-Pugh Class C: reduce dose to 100 mg once daily. |
| Pediatric use | Not recommended for use in children < 17 years due to increased risk of serious adverse reactions. |
| Geriatric use | Start at 100 mg once daily; may increase to 200 mg based on tolerability and response. |
| 1st trimester | Limited human data; animal studies show increased fetal resorptions and visceral/skeletal anomalies at high doses. Avoid unless clearly needed. |
| 2nd trimester | Limited human data; may be associated with intrauterine growth restriction. Use only if benefit outweighs risk. |
| 3rd trimester | Limited human data; neonatal withdrawal symptoms (jitteriness, irritability) reported. Avoid near term. |
Clinical note
Induces CYP3A4 and inhibits CYP2C19 affecting many drugs Can cause serious skin reactions and psychiatric symptoms.
| Placental transfer | Modafinil crosses the placenta in humans. In a study, cord blood concentrations were approximately 50% of maternal plasma levels at delivery. |
| Breastfeeding | Modafinil and its metabolites are excreted into human milk. A case report indicates milk concentrations approximately 30% of maternal plasma. Potential for infant toxicity and adverse effects on sleep/wake cycle. Avoid breastfeeding or consider alternative therapy. |
■ FDA Black Box Warning
None
| Common Effects | sleep apnea |
| Serious Effects |
Known hypersensitivity to modafinil or any excipientHistory of left ventricular hypertrophy or clinically significant mitral valve prolapse (risk of adverse cardiac effects)
| Precautions | Serious rash requiring hospitalization and discontinuation (including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome), Angioedema and anaphylactoid reactions, Multi-organ hypersensitivity reactions, Persistent sleepiness despite treatment, Psychiatric adverse reactions (mania, delusions, hallucinations, suicidal ideation), Cardiovascular events in patients with left ventricular hypertrophy or mitral valve prolapse, or in those receiving CNS stimulants, Hepatic impairment, Use caution in renal impairment, Decreased efficacy of hormonal contraceptives, Somnolence and fatigue with sleep deprivation |
| Food/Dietary |
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| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Modafinil is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animal studies, modafinil caused developmental toxicity (increased fetal resorptions, reduced fetal body weight, and increased incidence of skeletal variations) at doses approximately equal to the maximum recommended human dose (MRHD) on a mg/m² basis. The risk during the first trimester is unknown; however, due to potential harm, use during pregnancy only if the potential benefit justifies the risk to the fetus. Limited data suggest a possible increased risk of major congenital malformations, particularly cardiac defects, but causation is not established. |
| Fetal Monitoring | For pregnant women on modafinil, baseline and serial fetal ultrasound assessments are recommended to monitor fetal growth and anatomy. Consider fetal echocardiography given potential cardiac risks. Monitor maternal vital signs, weight gain, and sleep patterns. Assess for signs of abuse or dependence. Postnatal follow-up of the infant for adverse effects is advised. |
| Fertility Effects | Modafinil may reduce the efficacy of hormonal contraceptives (including oral, injectable, implantable, or intrauterine devices) for up to one month after discontinuation, potentially impacting fertility. Non-hormonal contraceptive methods should be used during treatment and for at least one month after stopping. In animal studies, no significant effects on fertility were observed at clinically relevant doses. |
| No significant food interactions. Grapefruit juice does not alter modafinil pharmacokinetics. Food may delay absorption but does not affect overall exposure. Avoid excessive caffeine intake as it may potentiate side effects like jitteriness and insomnia. |
| Clinical Pearls | Modafinil is a wakefulness-promoting agent approved for narcolepsy, shift work sleep disorder, and obstructive sleep apnea (adjunctive). It has low abuse potential compared to traditional stimulants. Monitor for Stevens-Johnson syndrome and psychiatric adverse effects. CYP3A4 inducer; reduces efficacy of oral contraceptives, cyclosporine, and warfarin. Dose adjustment: 200 mg daily for narcolepsy/OSA; 200 mg 1 hour before shift for SWSD. Avoid use in patients with left ventricular hypertrophy or mitral valve prolapse. |
| Patient Advice | Take exactly as prescribed; do not increase dose without consulting your doctor. · May cause dizziness or blurred vision; avoid driving until you know how it affects you. · Use effective non-hormonal contraception if taking oral contraceptives; this drug can reduce their effectiveness. · Report any skin rash, blistering, or mouth sores immediately; this could be a sign of a serious reaction. · Avoid alcohol and other CNS depressants; they may interact with this medication. · Do not stop abruptly; consult your doctor if you need to discontinue. · This medication does not replace sleep; maintain good sleep hygiene. · Store at room temperature away from moisture and heat. |