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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Induces CYP3A4 and inhibits CYP2C19 affecting many drugs Can cause serious skin reactions and psychiatric symptoms.
| Breastfeeding | Modafinil is excreted into human breast milk. The milk-to-plasma ratio (M/P ratio) is approximately 0.8. A nursing infant would receive approximately 0.3-0.5% of the maternal weight-adjusted dose. Given the potential for serious adverse reactions in the infant (including insomnia, agitation, and feeding difficulties), breastfeeding is not recommended during modafinil therapy. Consider alternative treatments or discontinue breastfeeding. |
| 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. |
■ FDA Black Box Warning
None
| Common Effects | sleep apnea |
| Serious Effects |
["Known hypersensitivity to modafinil or any excipient","Use in patients with a history of left ventricular hypertrophy or mitral valve prolapse and associated symptoms (e.g., chest pain, palpitations, dyspnea) with prior CNS stimulant use"]
| 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"] |
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| 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. |