Potential for other medicinal products to affect the pharmacokinetics of upadacitinib: Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can be affected by medicinal products that strongly inhibit or induce CYP3A4.
Coadministration with CYP3A4 inhibitors: Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, and clarithromycin). In a clinical study, coadministration of upadacitinib with ketoconazole resulted in 70% and 75% increases in upadacitinib Cmax and AUC, respectively. Upadacitinib should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Consider alternatives to strong CYP3A4 inhibitor medications when used in the long-term.
Coadministration with CYP3A4 inducers: Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such as rifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinical study, coadministration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer) resulted in approximately 50% and 60% decreases in upadacitinib Cmax and AUC, respectively. Patients should be monitored for changes in disease activity if upadacitinib is co-administered with strong CYP3A4 inducers.
Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have no effect on upadacitinib plasma exposures.
Potential for upadacitinib to affect the pharmacokinetics of other medicinal products: Administration of multiple 30 mg once daily doses of upadacitinib (a dose that is twice the recommended upadacitinib dose) to healthy subjects had a limited effect on midazolam (sensitive drug substrate for CYP3A) plasma exposures (26% decrease in midazolam AUC and Cmax), indicating that upadacitinib 30 mg once daily may have a weak induction effect on CYP3A. In a clinical study, rosuvastatin and atorvastatin AUC were decreased by 33% and 23%, respectively, and rosuvastatin Cmax was decreased by 23% following the administration of multiple 30 mg once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevant effect on atorvastatin Cmax or on plasma exposures of ortho-hydroxyatorvastatin (major active metabolite for atorvastatin). No dose adjustment is recommended for CYP3A substrates or for rosuvastatin or atorvastatin when coadministered with upadacitinib.
Upadacitinib has no relevant effects on plasma exposures of ethinylestradiol, levonorgestrel, methotrexate, or medicinal products that are substrates for metabolism by CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.