Dosage & Administration
Administration Instructions
Recommended Dosage
Rheumatoid Arthritis
Psoriatic Arthritis (in combination with nonbiologic DMARDs)
Ankylosing Spondylitis
Ulcerative Colitis
Polyarticular Course Juvenile Idiopathic Arthritis
Dosage Adjustment
Xeljanz Prescribing Information
SERIOUS INFECTIONS
Patients treated with XELJANZ/XELJANZ XR/XELJANZ Oral Solution are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
If a serious infection develops, interrupt XELJANZ/XELJANZ XR/XELJANZ Oral Solution until the infection is controlled.
Reported infections include:
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- Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR/XELJANZ Oral Solution use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR/XELJANZ Oral Solution use.
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- Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
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- Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].
MORTALITY
In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day [see Warnings and Precautions (5.2)]. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].
MALIGNANCIES
Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers [see Warnings and Precautions (5.3)].
Lymphomas and lung cancers were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.
Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications [see Warnings and Precautions (5.3)].
MAJOR ADVERSE CARDIOVASCULAR EVENTS
RA patients 50 years of age and older with at least one cardiovascular risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions (5.4)].
THROMBOSIS
Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients at risk. Discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution and promptly evaluate patients with symptoms of thrombosis [see Warnings and Precautions (5.5)].
Rheumatoid Arthritis
XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more TNF blockers.
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- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Psoriatic Arthritis
XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers.
- •
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Ankylosing Spondylitis
XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more TNF blockers.
- •
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Ulcerative Colitis
XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have an inadequate response or intolerance to one or more TNF blockers.
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- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Polyarticular Course Juvenile Idiopathic Arthritis
XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.
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- Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Important Administration Instructions
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- XELJANZ XR (tofacitinib extended-release tablets) is not interchangeable or substitutable with XELJANZ Oral Solution.
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- Changes between XELJANZ and XELJANZ XR should be made by the healthcare provider [see Dosage and Administration (2.2)].
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- Do not initiate XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with an absolute lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3 or who have hemoglobin levels less than 9 g/dL.
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- Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions (5.8), Adverse Reactions (6.1)].
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- Interrupt use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions (5.1)].
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- Take XELJANZ/XELJANZ XR/XELJANZ Oral Solution with or without food [see Clinical Pharmacology (12.3)].
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- Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.
Recommended Dosage in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis
Table 1 displays the recommended adult daily dosage of XELJANZ and XELJANZ XR and dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis) or moderate hepatic impairment, with lymphopenia, neutropenia, or anemia.
| XELJANZ tablet | XELJANZ XR extended-release tablet | |
|---|---|---|
| ||
Adult patients | 5 mg twice daily | 11 mg once daily |
Patients receiving:
[see Drug Interactions (7)] | 5 mg once daily | Reduce to XELJANZ 5 mg once daily |
Patients with:
| 5 mg once daily | Reduce to XELJANZ 5 mg once daily |
For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended in patients after dialysis. | ||
Patients with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing | Discontinue dosing. | |
Patients with ANC 500 to 1000 cells/mm3 | Interrupt dosing. | Interrupt dosing. |
Patients with ANC less than 500 cells/mm3 | Discontinue dosing. | |
Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL | Interrupt dosing until hemoglobin values have normalized. | |
Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets
Patients treated with XELJANZ tablets 5 mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ 5 mg.
Recommended Dosage in Ulcerative Colitis
Table 2 displays the recommended adult daily dosage of XELJANZ/XELJANZ XR and dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis) or moderate hepatic impairment, with lymphopenia, neutropenia or anemia.
| XELJANZ tablet | XELJANZ XR extended-release tablet | |
|---|---|---|
| ||
Adult patients | Induction: 10 mg twice daily for at least 8 weeks [see Clinical Studies (14.4)]; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 10 mg twice daily for a maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved.
| Induction: 22 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 22 mg once daily for a maximum of 16 weeks. Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved.
|
Patients receiving:
[see Drug Interactions (7)] | If taking 10 mg twice daily, reduce to 5 mg twice daily.
| If taking 22 mg once daily, reduce to 11 mg once daily.
|
Patients with:
| If taking 10 mg twice daily, reduce to 5 mg twice daily.
| If taking 22 mg once daily, reduce to 11 mg once daily.
|
For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended in patients after dialysis. | ||
Patients with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing | Discontinue dosing. | |
Patients with ANC 500 to 1000 cells/mm3 | If taking 10 mg twice daily, reduce to 5 mg twice daily. When ANC is greater than 1000, increase to 10 mg twice daily based on clinical response.
| If taking 22 mg once daily, reduce to 11 mg once daily. When ANC is greater than 1000, increase to 22 mg once daily based on clinical response.
|
Patients with ANC less than 500 cells/mm3 | Discontinue dosing. | |
Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL | Interrupt dosing until hemoglobin values have normalized. | |
Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets
Patients treated with XELJANZ 5 mg tablets twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets 5 mg. Patients treated with XELJANZ 10 mg tablets twice daily may be switched to XELJANZ XR extended-release tablets 22 mg once daily the day following the last dose of XELJANZ 10 mg.
Recommended Dosage in Polyarticular Course Juvenile Idiopathic Arthritis
Table 3 displays the recommended body weight-based dosages for XELJANZ tablets/XELJANZ Oral Solution and dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7)], in patients with moderate or severe renal impairment, including but not limited to those undergoing hemodialysis [see Use in Specific Populations (8.7)], with moderate hepatic impairment [see Use in Specific Populations (8.8)], with lymphopenia, neutropenia, or anemia.
| XELJANZ tablets/XELJANZ Oral Solution | |
|---|---|
| |
pcJIA patients |
|
Patients receiving:
[see Drug Interactions (7)] | If taking 3.2 mg twice daily, reduce to 3.2 mg once daily.
|
Patients with:
| If taking 3.2 mg twice daily, reduce to 3.2 mg once daily.
|
Patients with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing | Discontinue dosing. |
Patients with ANC 500 to 1000 cells/mm3 | Interrupt dosing until ANC is greater than 1000 cells/mm3. |
Patients with ANC less than 500 cells/mm3 | Discontinue dosing. |
Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL | Interrupt dosing until hemoglobin values have normalized. |
Administer XELJANZ Oral Solution using the included press-in bottle adapter and oral dosing syringe [see Instructions for Use].
XELJANZ Tablets:
- o
- 5 mg tofacitinib: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side.
- o
- 10 mg tofacitinib: Blue, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 10" on the other side.
XELJANZ XR Tablets:
- o
- 11 mg tofacitinib: Pink, oval, extended-release film-coated tablets with a drilled hole at one end of the tablet band and "JKI 11" printed on one side of the tablet.
- o
- 22 mg tofacitinib: Beige, oval, extended-release film-coated tablets with a drilled hole at one end of the tablet band and "JKI 22" printed on one side of the tablet.
XELJANZ Oral Solution:
1 mg/mL tofacitinib: Clear, colorless oral solution.
All information provided in this section is applicable to XELJANZ/XELJANZ XR/XELJANZ Oral Solution as they contain the same active ingredient (tofacitinib).
Pregnancy
Risk Summary
The available data with XELJANZ/XELJANZ XR/XELJANZ Oral Solution from a pregnancy exposure registry that enrolled 11 exposed patients, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug‑associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy (see Clinical Considerations). In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).
The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
Data
Animal Data
In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). 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 recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).
In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) 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 recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).
In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). 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 recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).
Lactation
Risk Summary
Based on published data, tofacitinib is present in human milk. Data on the effects of tofacitinib on the breastfed infant is limited to a small number of cases with no reported adverse effects. There are no data on the effects on milk production. Given the serious adverse reactions seen in patients treated with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ/XELJANZ Oral Solution or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives).
Data
Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.
Females and Males of Reproductive Potential
Contraception
Females
In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 5 mg twice daily and 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings [see Use in Specific Populations (8.1)]. However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential.
Infertility
Females
Based on findings in rats, treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of XELJANZ/XELJANZ Oral Solution for the treatment of active pcJIA have been established in patients 2 years to 17 years of age. Use of XELJANZ/XELJANZ Oral Solution for the treatment of pediatric patients with active pcJIA in this age group is supported by evidence from adequate and well-controlled studies of XELJANZ in adult RA patients with additional data from a clinical trial of XELJANZ/XELJANZ Oral Solution in pediatric patients (2 years to 17 years of age) with active pcJIA consisting of an 18-week, open label, run-in period followed by a 26-week placebo-controlled, randomized withdrawal period [see Clinical Studies (14.5)]. The safety and effectiveness of XELJANZ/XELJANZ Oral Solution have not been established in pcJIA patients less than 2 years of age.
Adverse reactions observed in pediatric patients receiving XELJANZ/XELJANZ Oral Solution were consistent with those reported in RA patients [see Adverse Reactions (6.1)].
Safety and efficacy of XELJANZ/XELJANZ Oral Solution in pediatric patients for indications other than pcJIA have not been established.
The safety and effectiveness of XELJANZ XR in pediatric patients have not been established.
Geriatric Use
Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65.
Of the 1156 XELJANZ-treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients.
As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly [see Warnings and Precautions (5.1)].
Use in Diabetics
As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.
Renal Impairment
Moderate and Severe Impairment
XELJANZ-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function. Therefore, dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis) [see Dosage and Administration (2.2, 2.3, 2.4)].
Mild impairment
No dosage adjustment is required in patients with mild renal impairment.
Hepatic Impairment
Severe Impairment
XELJANZ/XELJANZ XR/XELJANZ Oral Solution has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with severe hepatic impairment is not recommended.
Moderate Impairment
XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Higher blood concentrations may increase the risk of some adverse reactions. Therefore, dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended in patients with moderate hepatic impairment [see Dosage and Administration (2.2, 2.3, 2.4)].
Mild Impairment
No dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is required in patients with mild hepatic impairment.
Hepatitis B or C Serology
The safety and efficacy of XELJANZ/XELJANZ XR/XELJANZ Oral Solution have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.
None.