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Interactions Affecting the Use of XELJANZ: Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when co-administered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole) or when administration of one or more concomitant medications results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) (see Dosage & Administration).
Tofacitinib exposure is decreased when co-administered with potent CYP inducers (e.g., rifampin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib.
Concomitant administration with methotrexate (15-25 mg MTX once weekly) had no effect on the PK of tofacitinib. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, with a single dose of tofacitinib increased the AUC and Cmax by 103% and 16%, respectively. Co-administration of fluconazole, a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C19, increased the AUC and Cmax of tofacitinib by 79% and 27%, respectively. Co-administration of tacrolimus (Tac), a mild inhibitor of CYP3A4, increased the AUC of tofacitinib by 21% and decreased the Cmax of tofacitinib by 9%. Co-administration of cyclosporine (CsA), a moderate inhibitor of CYP3A4, increased the AUC of tofacitinib by 73% and decreased Cmax of tofacitinib by 17%. The combined use of multiple-dose tofacitinib with these potent immunosuppressives has not been studied in patients with rheumatoid arthritis or psoriatic arthritis. Co-administration of rifampin, a strong CYP3A4 inducer, decreased the AUC and Cmax of tofacitinib by 84% and 74%, respectively (see Dosage & Administration).
Potential for XELJANZ to Influence the PK of Other Drugs: In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 80 times the steady-state total Cmax at 5 mg twice daily doses in rheumatoid arthritis patients and psoriatic arthritis patients. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when co-administered with tofacitinib.
In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs), [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady-state total Cmax at 5 mg twice daily dose in rheumatoid arthritis patients and psoriatic arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters, such as P-glycoprotein, organic anion transporting polypeptide, organic anionic or cationic transporters at therapeutic concentrations is also low.
Co-administration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestrel and ethinyl estradiol, in healthy female volunteers.
Co-administration of tofacitinib with methotrexate 15-25 mg once weekly decreased the AUC and Cmax of methotrexate by 10% and 13% respectively. The extent of decrease in methotrexate exposure does not warrant modifications to the individualized dosing of methotrexate.
Co-administration of tofacitinib did not have an effect on the PK of metformin, indicating that tofacitinib does not interfere with the organic cationic transporter (OCT2) in healthy volunteers.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in RA patients. Therefore, co-administration with tofacitinib is not expected to result in clinically relevant increases in the metabolism of CYP substrates in RA patients.
Pediatric Population: Studies have only been performed in adults.
