Provigil (Modafinil) and Bupropion Interaction: Risks, Mechanism, and Monitoring

Is there a direct pharmacokinetic interaction?

The drug interactions section of the Provigil label describes two enzyme effects: induction of CYP3A4/5 (lower exposure of substrates such as steroidal contraceptives, cyclosporine, midazolam and triazolam) and inhibition of CYP2C19 (higher exposure of substrates such as phenytoin, diazepam, propranolol, omeprazole and clomipramine). It also mentions warfarin and MAO inhibitors [1]. Bupropion is not named there, and the label gives no modafinil dose adjustment for use with bupropion [1].

The Contrave label says bupropion is primarily metabolized to hydroxybupropion by CYP2B6, and its interaction section addresses CYP2B6 inhibitors and inducers [2]. Bupropion also inhibits CYP2D6, which the Contrave label says can raise concentrations of antidepressants, antipsychotics, beta-blockers and Type 1C antiarrhythmics [2].

What does bupropion's seizure warning say?

The Zyban (bupropion) label gives a seizure incidence of about 0.1% (1 in 1,000) with sustained-release bupropion up to 300 mg/day and about 0.4% (13 of 3,200) with immediate-release bupropion at 300 to 450 mg/day; for immediate-release, the estimated incidence rises almost tenfold between 450 and 600 mg/day [3].

The Contrave label says to use extreme caution when bupropion is combined with other drugs that lower the seizure threshold, naming antipsychotics, antidepressants, theophylline and systemic corticosteroids, with low initial doses and gradual increases [2].

Seizure is not among the Provigil label's warnings and precautions (rash, angioedema and anaphylaxis, multi-organ hypersensitivity, persistent sleepiness, psychiatric symptoms, driving, cardiovascular events) or its table of adverse reactions from placebo-controlled trials [1].

What should monitoring include?

The Contrave label says to monitor blood pressure and heart rate in all patients taking it [2]. The suicidality boxed warning applies to every bupropion product, including Zyban [2]. The Zyban label's warnings also describe postmarketing reports of mood changes, psychosis, hallucinations, aggression, agitation, anxiety and suicidal ideation [3].

Modafinil labeling says to reassess sleepiness frequently, use caution in people with a history of psychosis, depression or mania, and consider increased monitoring in known cardiovascular disease [1]. In Provigil trials, 2.4% of patients needed new or increased antihypertensive medicine versus 0.7% on placebo; in the OSA studies the figures were 3.4% versus 1.1% [1].

Both drugs carry psychiatric cautions. For modafinil, the label lists anxiety, nervousness, insomnia, confusion, agitation and depression in trials, plus postmarketing mania, delusions, hallucinations and aggression [1].

When is either medicine contraindicated?

Neither the Provigil label nor the bupropion labels cited here list the other medicine as a contraindication [1][2].

The Contrave label, which contains bupropion, lists these contraindications: seizure disorder; bulimia or anorexia nervosa; abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptic drugs; MAO inhibitors within 14 days; uncontrolled hypertension; chronic opioid use; and known allergy to its ingredients [2]. It also contraindicates use with other bupropion-containing products [2]. The Provigil label's only contraindication is known hypersensitivity to modafinil, armodafinil or their inactive ingredients [1]. For MAO inhibitors, the Provigil label advises caution rather than contraindication [1].

Dosing and legal status

The Provigil label lists 200 mg once daily in the morning for narcolepsy or OSA, and 200 mg about an hour before the work shift for shift work disorder; severe hepatic impairment calls for half the dose, and lower doses are to be considered in geriatric patients [1]. Modafinil is a Schedule IV controlled substance and is prescription-only [1]. Labeled daily maximums for bupropion are 300 mg for Zyban (smoking cessation) and 450 mg for immediate-release bupropion [3].