Some of the drugs that frequently interact with modafinil include aripiprazole (an antipsychotic), amphetamine (including its enantiomers and salts; stimulants), aspirin, diphenhydramine (an antihistamine), and others.
Modafinil is a weak to moderate inducer of CYP3A4 and a weak inhibitor of CYP2C19, enzymes of the cytochrome P450 group of enzymes. Modafinil also induces or inhibits other cytochrome P450 enzymes. One in vitro study predicts that modafinil may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19. However, other in-vitro studies find no significant inhibition of CYP2C9. Modafinil may induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin.
It was clinically found that modafinil affects pharmacodynamics of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family, so that interactions of modafinil with these drugs were observed in real people, rather than being predicted in a lab setting. For instance, it was observed that induction of CYP3A4 by modafinil affects metabolism of the following medications and endogenous substances:
* opioids, such as methadone, hydrocodone, oxycodone, or fentanyl – modafinil may result in a drop in opioid plasma concentrations because of faster clearance of opioids by CYP3A4. If the patient is not monitored closely, reduced efficacy or withdrawal symptoms can occur.
* steroid hormones, such as estradiol, progesterone or cortisol. Modafinil may have an adverse effect on hormonal contraceptives (such as birth control pills, patches, etc.) for up to a month after discontinuation. Both modafinil and armodafinil in the United States and the United Kingdom come with package inserts that highlight the interaction between these medications and hormonal birth control. Modafinil may induce cytochrome P450 enzymes that are involved in the clearance of steroid hormones taken as hormonal contraceptives, reducing their effectiveness, which may lead to pregnancy despite taking the birth control medication. Besides steroid hormones, modafinil may affect pituitary gland hormones. In a 2006 study, a single dose of modafinil  caused a decrease in blood prolactin levels, although it did not affect human growth hormone or thyroid-stimulating hormone. Since modafinil induces the activity of the CYP3A4 enzyme involved in cortisol clearance, modafinil may reduce the bioavailability of hydrocortisone. Therefore, it may be necessary to adjust the steroid substitution dose in people receiving modafinil, which is a CYP3A4-metabolism-inducing drug.