What is the maximum recommended daily dose of Provigil (modafinil) for a patient with a history of hypertension, heart disease, or impaired liver or kidney function?

Maximum Recommended Daily Dose of Provigil (Modafinil)

The maximum recommended daily dose of Provigil (modafinil) is 400 mg/day for patients with normal hepatic and renal function, though this dose confers no consistent additional benefit beyond 200 mg/day. 1

Standard Dosing by Indication

• For narcolepsy and obstructive sleep apnea, the FDA-approved dosing is 200 mg once daily in the morning, with doses up to 400 mg/day given as a single dose being well tolerated 1
• For shift work disorder, the recommended dose is 200 mg taken approximately 1 hour prior to the start of the work shift 1
• Importantly, doses up to 400 mg/day have been well tolerated in clinical trials, but there is no consistent evidence that 400 mg/day provides additional benefit beyond the 200 mg/day dose 1

Dose Modifications for Special Populations

Patients with Hepatic Impairment

• In patients with severe hepatic impairment, reduce the dose to one-half of the recommended dose (i.e., 100 mg/day instead of 200 mg/day) 1
• This reduction is necessary because modafinil is extensively metabolized in the liver, and both maximum plasma concentration and elimination half-life are increased in patients with hepatic impairment 2, 3

Patients with Renal Impairment

• While the FDA label does not mandate specific dose reductions for renal impairment, caution is warranted because the elimination half-life of modafinil is increased in patients with renal impairment 2
• Less than 10% of modafinil is excreted unchanged in urine, with most elimination occurring via hepatic metabolism 3
• Substantial increases in levels of modafinil acid (an inactive metabolite) occur in severe renal insufficiency, necessitating caution 4

Geriatric Patients

• The FDA recommends consideration of lower doses and close monitoring in geriatric patients 1
• Elimination in the elderly may be reduced due to normal effects of aging on metabolic processes 3

Patients with Cardiovascular Disease

• For patients with a history of hypertension or heart disease, no specific dose reduction is mandated by the FDA label, but increased monitoring is recommended 1
• Modafinil is contraindicated in patients with moderate to severe hypertension 2
• Common adverse events include hypertension and elevated heart rate, which are particularly relevant in patients with pre-existing cardiovascular disease 4

Clinical Context and Limitations

• The 400 mg/day dose represents the upper limit of well-tolerated dosing in clinical trials, but efficacy data do not support routine use of this higher dose 1
• In long-term studies extending to 40 weeks, approximately 75% of patients received 400 mg daily, with disease severity rated as "much improved" or "very much improved" in 58% of patients 5
• The most common treatment-related adverse events at doses up to 400 mg/day include headache (13%), nervousness (8%), and nausea (5%), with most being mild to moderate in nature 5

Important Safety Considerations

• Serious rash, including Stevens-Johnson Syndrome, has been reported and requires immediate discontinuation of modafinil at the first sign of rash 1
• Modafinil may reduce the efficacy of low-dose oral contraceptives via enzymatic induction, necessitating alternative or concomitant contraceptive methods during treatment and for one month after discontinuation 2, 4
• The drug has potential for interactions with medications metabolized by CYP2C19, CYP3A4, and other cytochrome P450 enzymes 4, 3