ition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) [see Dosage and Administration (2.1) and Figure 3].
7.3 Potent CYP3A4 Inducers
Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin) [see Dosage and Administration (2.1) and Figure 3].
7.4 Immunosuppressive Drugs
There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic effects:
Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).
In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
Nonteratogenic effects:
In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
8.3 Nursing Mothers
Tofacitinib was secreted in milk of lactati |
