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Click on icon to see table/diagram/imageInteractions 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 coadministered 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).
Tofacitinib exposure is decreased when coadministered 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. Coadministration of ketoconazole, a strong CYP3A4 inhibitor, with a single dose of tofacitinib increased the AUC and Cmax by 103% and 16%, respectively. Coadministration 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. Coadministration of tacrolimus (Tac), a mild inhibitor of CYP3A4, increased the AUC of tofacitinib by 21% and decreased the Cmax of tofacitinib by 9%. Coadministration 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, psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, or polyarticular course juvenile idiopathic arthritis. Coadministration of rifampin, a strong CYP3A4 inducer, decreased the AUC and Cmax of tofacitinib by 84% and 74%, respectively.
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 and 10 mg twice daily doses in rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, and polyarticular course juvenile idiopathic 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 coadministered 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 and 10 mg twice daily doses in rheumatoid arthritis, psoriatic arthritis, psoriasis patients, ulcerative colitis patients and polyarticular course juvenile idiopathic arthritis.
In rheumatoid arthritis patients, psoriasis patients, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis patients the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in these patients. Therefore, coadministration with tofacitinib is not expected to result in clinically relevant increases in the metabolism of CYP substrates in RA patients, psoriasis patients, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis patients.
