Modafinil and Vyvanse (Lisdexamfetamine) Interactions
Modafinil and Vyvanse can be used together without clinically significant pharmacokinetic interactions, though caution is warranted due to potential additive cardiovascular effects and the theoretical risk of modafinil reducing efficacy of certain medications through enzyme induction.
Pharmacokinetic Interaction Profile
No direct pharmacokinetic interaction exists between modafinil and lisdexamfetamine. The evidence demonstrates:
Modafinil does not significantly alter amphetamine pharmacokinetics. A controlled study in healthy volunteers showed that concomitant administration of modafinil (200 mg) and dextroamphetamine (10 mg) produced no clinically significant effects on the pharmacokinetic profile of either agent 1.
Lisdexamfetamine is a prodrug of dextroamphetamine, converted via hydrolysis rather than cytochrome P450 metabolism, making it unlikely to be affected by modafinil's enzyme-inducing properties 2.
Modafinil's metabolism occurs primarily through amide hydrolysis with minor contributions from CYP-mediated pathways, and it is not significantly metabolized by the same pathways that would interact with amphetamines 2.
Enzyme Induction Considerations
While not directly affecting amphetamines, modafinil does have enzyme-inducing properties that warrant awareness:
Modafinil induces CYP3A4, CYP1A2, and CYP2B6 in human hepatocytes, primarily affecting drugs metabolized through these pathways 2.
This induction is most relevant for oral contraceptives and certain benzodiazepines (like triazolam), not for amphetamine-based medications 2.
The hepatitis C treatment guidelines consistently list modafinil as a moderate P-glycoprotein inducer that can reduce drug levels of certain hepatitis medications, but this mechanism does not apply to lisdexamfetamine 3.
Cardiovascular Monitoring Requirements
Both medications increase blood pressure and heart rate, requiring baseline and ongoing cardiovascular monitoring:
Check blood pressure and pulse at baseline and regularly during treatment when using either stimulant medication 4.
The combination was well tolerated in clinical studies, with only a slightly greater incidence of adverse events when modafinil and dextroamphetamine were administered together, but no serious cardiovascular events were reported 1.
Monitor for additive sympathomimetic effects including tachycardia, hypertension, and potential cardiac arrhythmias, though these were not observed at therapeutic doses in controlled studies 1.
Abuse Liability and Behavioral Effects
The combination does not appear to enhance abuse potential:
Animal studies showed that modafinil (64 mg/kg) combined with low-dose amphetamine (0.3 mg/kg) did not establish conditioned place preference or significantly alter the rewarding effects of amphetamine 5.
Modafinil did not significantly increase the hyperlocomotor effects of amphetamine in controlled settings, suggesting minimal additive stimulant effects at therapeutic doses 5.
Clinical Implementation
When prescribing these medications together:
No dose adjustment is required for either medication based on pharmacokinetic data 1.
No washout period is necessary when adding one medication to the other, as they work through complementary rather than competing mechanisms 4.
Cardiovascular monitoring should follow standard stimulant protocols: baseline ECG if indicated by history, regular blood pressure and pulse checks 4.
Be aware that modafinil may reduce efficacy of oral contraceptives through CYP3A4 induction, requiring alternative or additional contraceptive methods 3, 2.
Common Pitfalls to Avoid
Do not assume enzyme induction affects amphetamine metabolism - the interaction data specifically shows no significant pharmacokinetic changes 1.
Do not confuse modafinil's interactions with hepatitis medications (where it acts as a P-gp inducer) with its lack of interaction with amphetamines 3.
Do not overlook the delayed absorption effect - modafinil may slightly delay time to maximum concentration of co-administered drugs, though this is not clinically significant for amphetamines 6.