Coadministration has not been assessed in clinical studies. Modafinil is largely metabolized by hydrolysis (esterase-mediated) and to a lesser extent by CYP3A4-mediated oxidative metabolism. Modafinil is unlikely to impact cabotegravir as it is metabolized mainly by UGT1A1 and to a lesser extent by UGT1A9 and there is no evidence that modafinil induces UGT. However, modafinil is a moderate inducer of CYP3A and could decrease rilpivirine concentrations. A case report describes viral load increase in a virologically suppressed individual on long acting cabotegravir/rilpivirine after initiation of modafinil. Coadministration is contraindicated with CYP3A inducers due to the potential for loss of therapeutic effect and development of resistance. The drug interaction with rifabutin or other moderate inducers is predicted to be overcome by administering intramuscular cabotegravir/rilpivirine monthly together with a daily oral rilpivirine dose of 25 mg. After dose adjustment, rilpivirine and cabotegravir concentrations are predicted to remain below their safety threshold.