Coadministration has not been studied. Fentanyl undergoes extensive CYP3A4 metabolism. Coadministration is expected to increase fentanyl concentrations due to inhibition of CYP3A4, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Coadministration would require dosage adjustment and careful monitoring of therapeutic and adverse effects including potentially fatal respiratory depression. If it is decided to stop fentanyl and treat with another analgesic during nirmatrelvir/ritonavir treatment, fentanyl treatment should be resumed 3 days after the last dose of nirmatrelvir/ritonavir due to the mechanism-based inhibition of ritonavir. Note, the use of fentanyl in a non-therapeutic setting (i.e., as a recreational drug) should be avoided with nirmatrelvir/ritonavir as fentanyl exposure is expected to significantly increase and serious, life-threatening, or fatal respiratory depression may occur. Patients should be aware that recreational use could be potentially fatal.