CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Rheumatoid Arthritis The XELJANZ clinical development program included six confirmatory trials. Although other doses have been studied, the recommended dose of XELJANZ is mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)]. Confirmatory TrialsStudy RA-I (NCT00814307) was 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to DMARD (nonbiologic or biologic) received XELJANZ or 10 mg twice daily or placebo. At the Month visit, all patients randomized to placebo treatment were advanced in blinded fashion to second predetermined treatment of XELJANZ or 10 mg twice daily. The primary endpoints at Month were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.Study RA-II (NCT00856544) was 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to nonbiologic DMARD received XELJANZ or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month visit, nonresponding patients were advanced in blinded fashion to second predetermined treatment of XELJANZ or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.Study RA-III (NCT00853385) was 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.Study RA-IV (NCT00847613) was 2-year trial with planned analysis at year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.Study RA-V (NCT00960440) was 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF blocking biologic agent received XELJANZ or 10 mg twice daily or placebo added to background MTX. At the Month visit, all patients randomized to placebo treatment were advanced in blinded fashion to second predetermined treatment of XELJANZ or 10 mg twice daily. The primary endpoints at Month were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.Study RA-VI (NCT01039688) was 2-year monotherapy trial with planned analysis at year in which 952 MTX-naive patients with moderate to severe active rheumatoid arthritis received XELJANZ or 10 mg twice daily or MTX dose-titrated over weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month and the proportion of patients who achieved an ACR70 response at Month 6.. Clinical ResponseThe percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and are shown in Table 9. Similar results were observed with Studies RA-II and III. In trials RA-I through V, patients treated with mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month and Month 6. Higher ACR20 response rates were observed within weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at and 12 months.Table 9: Proportion of Patients with an ACR ResponsePercent of PatientsMonotherapy in Nonbiologic or Biologic DMARD Inadequate RespondersInadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity. MTX Inadequate RespondersInadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria. TNF Blocker Inadequate RespondersInadequate response to least one TNF blocker due to lack of efficacy and/or intolerance. Study IStudy IVStudy VNN is number of randomized and treated patients. PBOXELJANZ5 mg Twice DailyPBO MTXXELJANZ mg Twice Daily MTXPBO MTXXELJANZ mg Twice Daily MTX122243160321132133ACR20Month 326%59%27%55%24%41%Month 6NANA Not applicable, as data for placebo treatment is not available beyond months in Studies and due to placebo advancement. 69%25%50%NA51%ACR50Month 312%31%8%29%8%26%Month 6NA42%9%32%NA37%ACR70Month 36%15%3%11%2%14%Month 6NA22%1%14%NA16%In Study RA-IV, greater proportion of patients treated with XELJANZ mg twice daily plus MTX achieved low level of disease activity as measured by DAS28-4(ESR) less than 2.6 at months compared to those treated with MTX alone (Table 10).Table 10: Proportion of Patients with DAS28-4(ESR) Less Than 2.6 with Number of Residual Active JointsStudy IVDAS28-4(ESR) Less Than 2.6Placebo MTXXELJANZ mg Twice Daily MTX160321Proportion of responders at Month (n)1% (2)6% (19)Of responders, proportion with active joints (n)50% (1)42% (8)Of responders, proportion with active joint (n)05% (1)Of responders, proportion with active joints (n)032% (6)Of responders, proportion with or more active joints (n)50% (1)21% (4)The results of the components of the ACR response criteria for Study RA-IV are shown in Table 11. Similar results were observed for XELJANZ in Studies RA-I, II, III, V, and VI.Table 11: Components of ACR Response at Month 3Study IVXELJANZ mg Twice Daily MTXPlacebo MTXN=321N=160Component (mean) Data shown is mean (Standard Deviation) at Month 3. BaselineMonth BaselineMonth Number of tender joints(0-68)24(14)13(14)23(13)18(14)Number of swollen joints(0-66)14(8)6(8)14(9)10(9)PainVisual analog scale: = best, 100 worst. 58(23)34(23)55(24)47(24)Patient global assessment 58(24)35(23)54(23)47(24)Disability index(HAQ-DI)Health Assessment Questionnaire Disability Index: = best, = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. 1.41(0.68)0.99(0.65)1.32(0.67)1.19(0.68)Physician global assessment 59(16)30(19)56(18)43(22)CRP (mg/L)15.3(19.0)7.1(19.1)13.7(14.9)14.6(18.7)The percent of ACR20 responders by visit for Study RA-IV is shown in Figure 4. Similar responses were observed for XELJANZ in Studies RA-I, II, III, V, and VI.Figure 4: Percentage of ACR20 Responders by Visit for Study RA-IV Figure 4. Radiographic ResponseTwo studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study RA-IV and Study RA-VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.In Study RA-IV, XELJANZ mg twice daily reduced the mean progression of structural damage (not statistically significant) as shown in Table 12. Analyses of erosion and joint space narrowing scores were consistent with the overall results.In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month compared to 84% of patients treated with XELJANZ plus MTX mg twice daily.In Study RA-VI, XELJANZ monotherapy inhibited the progression of structural damage compared to MTX at Months and 12 as shown in Table 12. Analyses of erosion and joint space narrowing scores were consistent with the overall results.In the MTX group, 55% of patients experienced no radiographic progression at Month compared to 73% of patients treated with XELJANZ mg twice daily.Table 12: Radiographic Changes at Months and 12Study IVPlaceboN=139Mean (SD)SD Standard Deviation XELJANZ mg Twice DailyN=277Mean (SD) XELJANZ mg Twice DailyMean Difference from PlaceboDifference between least squares means XELJANZ minus placebo or MTX (95% CI 95% confidence interval) (CI)mTSSMonth and Month 12 data are mean change from baseline. Baseline33 (42)31 (48)-Month 60.5 (2.0)0.1 (1.7)-0.3 (-0.7, 0.0)Study VIMTXN=166Mean (SD) XELJANZ mg Twice DailyN=346Mean (SD) XELJANZ mg Twice DailyMean Difference from MTX (CI)mTSS Baseline17 (29)20 (40)-Month 60.8 (2.7)0.2 (2.3)-0.7 (-1.0, -0.3)Month 121.3 (3.7)0.4 (3.0)-0.9 (-1.4, -0.4). Physical Function Response Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month in Study RA-III was -0.22 (-0.35, -0.10) in patients receiving mg XELJANZ twice daily. Similar results were obtained in Studies RA-I, II, IV and V. In the 12-month trials, HAQ-DI results in XELJANZ-treated patients were consistent at and 12 months.. Other Health-Related OutcomesGeneral health status was assessed by the Short Form health survey (SF-36). In Studies RA-I, IV, and V, patients receiving XELJANZ mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all domains of the SF-36 at Month 3.. 14.2 Psoriatic Arthritis. The XELJANZ clinical development program to assess efficacy and safety included multicenter, randomized, double-blind, placebo-controlled confirmatory trials in 816 patients 18 years of age and older (PsA-I and PsA-II). Although other doses have been studied, the recommended dose of XELJANZ is mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of psoriatic arthritis [see Dosage and Administration (2.2)]. All patients had active psoriatic arthritis for at least months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least tender/painful joints and at least swollen joints, and active plaque psoriasis. Patients randomized and treated across the clinical trials represented different psoriatic arthritis subtypes at screening, including <5 joints or asymmetric involvement (21%), >=5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had diagnosis of psoriatic arthritis for mean (SD) of 7.7 (7.2) years. At baseline, 80% and 53% of patients had enthesitis and dactylitis, respectively. At baseline, all patients were required to receive treatment with stable dose of nonbiologic DMARD (79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other nonbiologic DMARDs). In both clinical trials, the primary endpoints were the ACR20 response and the change from baseline in HAQ-DI at Month 3.Study PsA-I was 12-month clinical trial in 422 patients who had an inadequate response to nonbiologic DMARD (67% and 33% were inadequate responders to nonbiologic DMARD and >=2 nonbiologic DMARDs, respectively) and who were naive to treatment with TNF blocker. Patients were randomized in 2:2:2:1:1 ratio to receive XELJANZ mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every weeks, placebo to XELJANZ mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month visit, all patients randomized to placebo treatment were advanced in blinded fashion to predetermined XELJANZ dose of mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.Study PsA-II was 6-month clinical trial in 394 patients who had an inadequate response to at least approved TNF blocker (66%, 19%, and 15% were inadequate responders to TNF blocker, TNF blockers and >=3 TNF blockers, respectively). Patients were randomized in 2:2:1:1 ratio to receive XELJANZ mg twice daily, XELJANZ 10 mg twice daily, placebo to XELJANZ mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month visit, placebo patients were advanced in blinded fashion to predetermined XELJANZ dose of mg or 10 mg twice daily as in Study PsA-I.. Clinical ResponseAt Month 3, patients treated with XELJANZ mg twice daily had higher (p<=0.05) response rates versus placebo for ACR20, ACR50, and ACR70 in Study PsA-I and for ACR20 and ACR50 in Study PsA-II; ACR70 response rates were also higher for XELJANZ mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Tables 13 and 14).Table 13: Proportion of Patients with an ACR Response in Study PsA-ISubjects received one concomitant nonbiologic DMARD. [Nonbiologic DMARD Inadequate Responders (TNF Blocker-Naive)]Treatment GroupPlaceboXELJANZ5 mgTwice DailyNN is number of randomized and treated patients. 105107Response RateResponse RateDifference (%)95% CI from PlaceboSubjects with missing data were treated as non-responders.Month ACR2033%50%17.1 (4.1, 30.2) ACR5010%28%18.5 (8.3, 28.7) ACR705%17%12.1 (3.9, 20.2)Table 14: Proportion of Patients with an ACR Response in Study PsA-IISubjects received one concomitant nonbiologic DMARD. (TNF Blocker Inadequate Responders)Treatment GroupPlaceboXELJANZ5 mgTwice DailyNN is number of randomized and treated patients. 131131Response RateResponse RateDifference (%)95% CI from PlaceboSubjects with missing data were treated as non-responders.Month ACR2024%50%26.0 (14.7, 37.2) ACR5015%30%15.3 (5.4, 25.2) ACR7010%17%6.9 (-1.3, 15.1)Improvements from baseline in the ACR response criteria components for both studies are shown in Table 15.Table 15: Components of ACR Response at Baseline and Month in Studies PsA-I and PsA-IINonbiologic DMARD Inadequate Responders (TNF Blocker-Naive)TNF Blocker Inadequate RespondersStudy PsA-ISubjects received one concomitant nonbiologic DMARD. Study PsA-II Treatment GroupPlaceboXELJANZ5 mgTwice DailyPlaceboXELJANZ5 mgTwice DailyN at Baseline105107131131ACR ComponentData shown are mean value at baseline and at Month 3. Number of tender/painful joints (0-68) Baseline20.620.519.820.5 Month 314.612.215.111.5Number of swollen joints (0-66) Baseline11.512.910.512.1 Month 37.16.37.74.8Patient assessment of arthritis painVisual analog scale (VAS): = best, 100 worst. Baseline53.255.754.956.4 Month 344.734.748.036.1Patient global assessment of arthritis Baseline53.954.755.857.4 Month 344.435.549.236.9HAQ-DIHAQ-DI Health Assessment Questionnaire Disability Index: = best, = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. Baseline1.111.161.251.26 Month 30.950.811.090.88Physicians Global Assessment of Arthritis Baseline53.854.653.753.5 Month 335.429.536.427.0CRP (mg/L) Baseline10.410.512.113.8 Month 38.64.011.47.7The percentage of ACR20 responders by visit for Study PsA-I is shown in Figure 5. Similar responses were observed in Study PsA-II. In both studies, improvement in ACR20 response on XELJANZ was observed at the first visit after baseline (Week 2).BID=twice daily; SE=standard error.Subjects with missing data were treated as non-responders.Figure 5: Percentage of ACR20 Responders by Visit Through Month in Study PsA-ISubjects received one concomitant nonbiologic DMARD. In patients with active psoriatic arthritis evidence of benefit in enthesitis and dactylitis was observed with XELJANZ treatment.. Figure 5. Physical FunctionImprovement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ mg twice daily demonstrated significantly greater improvement (p <=0.05) from baseline in physical functioning compared to placebo at Month (Table 16).Table 16: Change from Baseline in HAQ-DI in Studies PsA-I and PsA-IILeast Squares Mean Change from Baseline In HAQ-DI at Month 3Nonbiologic DMARD Inadequate RespondersInadequate response to at least one nonbiologic DMARD due to lack of efficacy and/or intolerability. (TNF Blocker-Naive)TNF Blocker Inadequate RespondersInadequate response to at least one TNF blocker due to lack of efficacy and/or intolerability. Study PsA-ISubjects received one concomitant nonbiologic DMARD. Study PsA-II Treatment GroupPlaceboXELJANZ mgTwice DailyPlaceboXELJANZ mgTwice DailyNN is the total number of subjects in the statistical analysis. 104107131129LSM Change from Baseline-0.18-0.35-0.14-0.39Difference from Placebo (95% CI)--0.17(-0.29, -0.05)--0.25(-0.38, -0.13)In Study PsA-I, the HAQ-DI responder rate (response defined as having improvement from baseline of >=0.35) at Month was 53% in patients receiving XELJANZ mg twice daily and 31% in patients receiving placebo. Similar responses were observed in Study PsA-II.. Other Health-Related OutcomesGeneral health status was assessed by the Short Form health survey (SF-36). In Studies PsA-I and PsA-II, patients receiving XELJANZ mg twice daily had greater improvement from baseline compared to placebo in Physical Component Summary (PCS) score, but not in Mental Component Summary (MCS) score at Month 3. Patients receiving XELJANZ mg twice daily reported consistently greater improvement relative to placebo in the domains of Physical Functioning, Bodily Pain, Vitality, and Social Functioning, but not in Role-Physical, General Health, Role-Emotional, or Mental Health.. Radiographic Response Treatment effect on inhibition of radiographic progression in psoriatic arthritis could not be established from the results of Study PsA-I.. 14.3 Ankylosing Spondylitis. The XELJANZ clinical development program to assess the efficacy and safety included one placebo-controlled confirmatory trial (Study AS-I). Patients had active disease as defined by both Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and back pain score (BASDAI question 2) of greater or equal to despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy.. Confirmatory Trial (Study AS-I)Study AS-I was randomized, double-blind, placebo-controlled, 48-week clinical trial in 269 adult patients who had an inadequate response (inadequate clinical response or intolerance) to at least NSAIDs. Patients were randomized and treated with XELJANZ mg twice daily or placebo for 16 weeks of blinded treatment and then all received treatment of XELJANZ mg twice daily for additional 32 weeks. The primary endpoint was to evaluate the proportion of patients who achieved an ASAS20 response at Week 16.Approximately 7% and 21% of patients used concomitant methotrexate or sulfasalazine, respectively from baseline to Week 16. Twenty-two percent of patients had an inadequate response to or TNF blockers.. Clinical ResponsePatients treated with XELJANZ mg twice daily achieved greater improvements in ASAS20 and ASAS40 responses compared to placebo at Week 16 (Table 17). Consistent results were observed in the subgroup of patients who had an inadequate response to TNF blockers for both the ASAS20 (primary endpoint) and ASAS40 (secondary endpoint) at Week 16 (Table 17).Table 17:ASAS20 and ASAS40 Responses at Week 16, Study AS-IPlaceboXELJANZ mg Twice DailyDifference from Placebo (95% CI)Abbreviations: CI confidence interval; TNFi-IR tumor necrosis factor inhibitor inadequate response.All patients (N)N=136N=133ASAS20 responsetype error-controlled., %295627 (16, 38)p-value <0.0001. ASAS40 response, %134128 (18, 38) TNFi-IR patients (N)N=30N=29ASAS20 response, %174125 (2, 47)ASAS40 response, %72821 (2, 39)The improvements in the components of the ASAS response and other measures of disease activity were higher in XELJANZ mg twice daily compared to placebo as shown in Table 18.Table 18:ASAS Components and Other Measures of Disease Activity at Week 16, Study AS-IPlacebo (N=136)XELJANZ mg Twice Daily (N=133)Baseline (mean)Week 16 (LSM change from Baseline)Estimates are generated based on mixed model for repeated measures using both on-treatment and off-treatment data. Baseline (mean)Week 16 (LSM change from Baseline) Difference from Placebo (95% CI) LSM least squares mean.ASAS Components-Patient Global Assessment of Disease Activity (0-10)Measured on numerical rating scale with = not active or no pain, 10 very active or most severe pain. type error-controlled. 7.0-1.06.9-2.5-1.5 (-2.00, -0.97)p 0.0001. -Total spinal pain (0-10) 6.9-1.16.9-2.6-1.5 (-2.00, -1.03) -BASFI (0-10)Bath Ankylosing Spondylitis Functional Index measured on numerical rating scale with = easy and 10 impossible. 5.9-0.85.8-2.0-1.2 (-1.64, -0.79) -Inflammation (0-10)Inflammation is the mean of two patient-reported stiffness self-assessments in BASDAI. 6.8-1.16.6-2.8-1.7 (-2.13, -1.18) BASDAI ScoreBath Ankylosing Spondylitis Disease Activity Index total score. 6.5-1.26.4-2.6-1.4 (-1.86, -0.98) BASMIBath Ankylosing Spondylitis Metrology Index. 4.4-0.14.5-0.6-0.5 (-0.66, -0.36) hsCRPHigh sensitivity C-reactive protein. (mg/dL)1.8-0.11.6-1.1-0.9 (-1.17, -0.69) The percentage of patients achieving ASAS20 response by visit is shown in Figure 6.Figure 6: ASAS20 Response Over Time Up to Week 16, Study AS-ISE=standard error. Patients with missing data were treated as non-responders.. -Patient Global Assessment of Disease Activity (0-10)Measured on numerical rating scale with = not active or no pain, 10 very active or most severe pain. type error-controlled. -Total spinal pain (0-10) . -BASFI (0-10)Bath Ankylosing Spondylitis Functional Index measured on numerical rating scale with = easy and 10 impossible. . -Inflammation (0-10)Inflammation is the mean of two patient-reported stiffness self-assessments in BASDAI. . Figure 6. Other Health-Related OutcomesPatients treated with XELJANZ mg twice daily achieved greater improvements from baseline in Ankylosing Spondylitis Quality of Life (ASQoL) (-4.0 vs -2.0) compared to placebo-treated patients at Week 16.. 14.4 Ulcerative Colitis. Induction Trials (Study UC-I [NCT01465763] and Study UC-II [NCT01458951])In two identical induction trials (UC-I and UC-II), 1139 patients were randomized (598 and 541 patients, respectively) to XELJANZ 10 mg twice daily or placebo with 4:1 treatment allocation ratio. These trials included adult patients with moderately to severely active UC (total Mayo score of to 12, with an endoscopy subscore of at least 2, and rectal bleeding subscore of at least 1) and who had failed or were intolerant to at least of the following treatments: oral or intravenous corticosteroids, azathioprine, 6-MP or TNF blocker. XELJANZ is indicated for patients who have an inadequate response or intolerance to one or more TNF blockers [see Indications and Usage (1)].The disease activity was assessed by Mayo scoring index (0 to 12) which consists of four subscores (0 to for each subscore): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of was defined by marked erythema, absent vascular pattern, any friability, and erosions; an endoscopy subscore of was defined by spontaneous bleeding and ulceration.Patients were permitted to use stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent). Concomitant immunosuppressants (oral immunomodulators or biologic therapies) were not permitted for UC patients during these studies.A total of 52%, 73% and 72% of patients had previously failed or were intolerant to TNF blockers (51% in Study UC-1 and 52% in Study UC-II), corticosteroids (75% in Study UC-I and 71% in Study UC-II), and/or immunosuppressants (74% in Study UC-I and 70% in Study UC-II), respectively.Oral corticosteroids were received as concomitant treatment for UC by 47% of patients (45% in Study UC-I and 48% in Study UC-II) and 71% were receiving concomitant aminosalicylates as treatment for UC (71% in Study UC-I, and 72% in Study UC-II). The baseline clinical characteristics were generally similar between the XELJANZ treated patients and patients receiving placebo.The primary endpoint of Study UC-I and Study UC-II was the proportion of patients in remission at Week 8, and the key secondary endpoint was the proportion of patients with improvement of endoscopic appearance of the mucosa at Week 8.The efficacy results of Study UC-I and Study UC-II based on the centrally read endoscopy results are shown in Table 19.Table 19: Proportion of Patients Meeting Primary and Key Secondary Efficacy Endpoints at Week (Induction Study UC-I and Study UC-II, Central Endoscopy Read)CI Confidence interval; = number of patients in the analysis set; TNF tumor necrosis factorStudy UC-IEndpointPlaceboXELJANZ10 mgTwice DailyTreatment Difference versus Placebo(95% CI)Remission at Week 8Remission was defined as clinical remission (a Mayo score <=2 with no individual subscore >1) and rectal bleeding subscore of 0. Total PopulationN=122N=47610%p-value <0.01, (4.3, 16.3)8%18% With Prior TNF Blocker FailurePrior TNF blocker failure was defined in this program as inadequate response, loss of response, or intolerance to TNF blocker therapy. N=64N=2432%11% Without Prior TNF Blocker FailurePatients in this group had failed one or more conventional therapies (corticosteroid, azathioprine, 6-mercaptopurine) but did not have history of prior failure of TNF blocker therapy. N=58N=23316%26%Improvement of endoscopic appearance of the mucosa at Week 8Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of (normal or inactive disease) or (erythema, decreased vascular pattern). Total PopulationN=122N=47616%p-value <0.001. (8.1, 23.4)16%31% With Prior TNF Blocker Failure N=64N=2436%23% Without Prior TNF Blocker Failure N=58N=23326%40%Study UC-IIEndpointPlaceboXELJANZ10 mgTwice DailyTreatment Difference(95% CI)Remission at Week Total PopulationN=112N=42913% (8.1, 17.9)4%17% With Prior TNF Blocker Failure N=60N=2220%12% Without Prior TNF Blocker Failure N=52N=2078%22%Improvement of endoscopic appearance of the mucosa at Week Total PopulationN=112N-42917% (9.5, 24.1)12%28% With Prior TNF Blocker Failure N=60N=2227%22% Without Prior TNF Blocker Failure N=52N=20717%36%. Clinical Response at Week 8Clinical response was defined as decrease from baseline in Mayo score of >=3 points and >=30%, with an accompanying decrease in the subscore for rectal bleeding of >=1 point or absolute subscore for rectal bleeding of or 1.Clinical response was observed in 60% of patients treated with XELJANZ 10 mg twice daily compared to 33% of placebo patients in Study UC-I and 55% compared to 29% in Study UC-II.. Normalization of the Endoscopic Appearance of the Mucosa at Week 8Normalization of endoscopic appearance of the mucosa was defined as Mayo endoscopic subscore of and was observed in 7% of patients treated with XELJANZ 10 mg twice daily compared to 2% of placebo patients in both Studies UC-I and UC-II.. Rectal Bleeding and Stool FrequencyDecreases in rectal bleeding and stool frequency subscores were observed as early as Week in patients treated with XELJANZ.. Maintenance Trial (Study UC-III [NCT01458574])A total of 593 patients who completed the induction trials (UC-I or UC-II) and achieved clinical response were re-randomized with 1:1:1 treatment allocation ratio to XELJANZ mg twice daily, XELJANZ 10 mg twice daily, or placebo for 52 weeks in Study UC-III. XELJANZ mg twice daily is the recommended dosage for maintenance therapy; limit use of XELJANZ 10 mg twice daily beyond induction to those with loss of response and should be used for the shortest duration [see Dosage and Administration (2.3)]. As in the induction trials, patients were permitted to use stable doses of oral aminosalicylates; however, corticosteroid tapering was required upon entrance into this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (oral immunomodulators or biologic therapies) were not permitted.At baseline of Study UC-III:179 (30%) patients were in remission289 (49%) patients were receiving oral corticosteroids265 (45%), 445 (75%), and 413 (70%) patients had previously failed or were intolerant to TNF blocker therapy, corticosteroids, and immunosuppressants, respectively.The primary endpoint was the proportion of patients in remission at Week 52. There were key secondary endpoints: the proportion of patients with improvement of endoscopic appearance at Week 52, and the proportion of patients with sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline of Study UC-III.The efficacy results of Study UC-III based on the centrally read endoscopy results are summarized in Table 20.Table 20: Proportion of Patients Meeting Primary and Key Secondary Efficacy Endpoints in Maintenance Study UC-III (Central Endoscopy Read)Treatment Difference versus Placebo(95% CI)EndpointPlaceboXELJANZ mg Twice DailyXELJANZ 10 mg Twice DailyXELJANZ mg Twice DailyXELJANZ 10 mg Twice DailyCI Confidence interval; = number of patients in the analysis set; TNF tumor necrosis factor.Remission at Week 52Remission was defined as clinical remission (a Mayo score <=2 with no individual subscore >1) and rectal bleeding subscore of 0. Total PopulationN=198N=198N=19723%p-value <0.0001. (15.3, 31.2)30% (21.4, 37.6)11%34%41% With Prior TNF Blocker FailurePrior TNF blocker failure was defined in this program as inadequate response, loss of response, or intolerance to TNF blocker therapy. N=89N=83N=9311%24%37% Without Prior TNF Blocker FailurePatients in this group had failed one or more conventional therapies (corticosteroid, azathioprine, 6-mercaptopurine) but did not have history of prior failure of TNF blocker therapy. N=109N=115N=10411%42%44%Improvement of endoscopic appearance of the mucosa at Week 52Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of (normal or inactive disease) or (erythema, decreased vascular pattern). Total PopulationN=198N=198N=19724% (16.0, 32.5)33% (24.2, 41.0)13%37%46% With Prior TNF Blocker Failure N=89N=83N=9312%30%40% Without Prior TNF Blocker Failure N=109N=115N=10414%43%51%Sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baselineSustained corticosteroid-free remission was defined as being in remission and not taking corticosteroids for at least weeks prior to the visit at both Week 24 and Week 52. Total PopulationN=59N=65N=5530% (17.4, 43.2)42% (27.9, 56.5)5%35%47% With Prior TNF Blocker Failure N=21N=18N=185%22%39% Without Prior TNF Blocker Failure N=38N=47N=375%40%51%. 179 (30%) patients were in remission. 289 (49%) patients were receiving oral corticosteroids. 265 (45%), 445 (75%), and 413 (70%) patients had previously failed or were intolerant to TNF blocker therapy, corticosteroids, and immunosuppressants, respectively.. Maintenance of Clinical ResponseMaintenance of clinical response was defined as the proportion of patients who met the definition of clinical response (defined as decrease from the induction study (UC-I, UC-II) baseline Mayo score of >=3 points and >=30%, with an accompanying decrease in the rectal bleeding subscore of >=1 point or rectal bleeding subscore of or 1) at both Baseline and Week 52 of Study UC-III.Maintenance of clinical response was observed in 52% in the XELJANZ mg twice daily group and 62% in the XELJANZ 10 mg twice daily group compared to 20% of placebo patients.. Maintenance of Remission (Among Patients in Remission at Baseline)In the 179 patients who were in remission at baseline of Study UC-III (N 59 for placebo, = 65 for XELJANZ mg twice daily, = 55 for XELJANZ 10 mg twice daily), 46% in the XELJANZ mg twice daily group and 56% in the XELJANZ 10 mg twice daily group maintained remission at Week 52 compared to 10% of placebo patients.. Normalization of the Endoscopic Appearance of the MucosaNormalization of endoscopic appearance of the mucosa was defined as Mayo endoscopic subscore of and was observed at Week 52 in 15% of patients in the XELJANZ mg twice daily group and 17% of patients in the XELJANZ 10 mg twice daily group compared to 4% of placebo patients.. Open-label Extension Study (Study UC-IV [NCT01470612])In Study UC-IV, 914 patients were treated of which 156 received mg twice daily and 758 received 10 mg twice daily.Of the 905 patients who were assigned to XELJANZ 10 mg twice daily in the 8-week induction studies (Study UC-I or Study UC-II), 322 patients completed the induction studies but did not achieve clinical response. Of these 322 patients, 291 continued to receive XELJANZ 10 mg twice daily (unblinded) and had available data after an additional weeks in Study UC-IV. After additional weeks (a total of 16 weeks treatment), 148 patients achieved clinical response, and 25 patients achieved remission (based on central endoscopy read). Among those 143 patients who achieved clinical response by 16 weeks and had available data at Week 52, 66 patients achieved remission (based on local endoscopy read) after continued treatment with XELJANZ 10 mg twice daily for 52 weeks.. 14.5 Polyarticular Course Juvenile Idiopathic Arthritis. The efficacy of XELJANZ/XELJANZ Oral Solution for pcJIA was assessed in Study pcJIA-I (NCT02592434), 44-week, two-part study (consisting of an 18-week, open-label, run-in phase, followed by 26-week double-blind, placebo-controlled, randomized withdrawal phase) in patients years to 17 years of age with active RF negative polyarthritis, RF positive polyarthritis, extended oligoarthritis, and systemic JIA without systemic manifestations who had an inadequate response or intolerance to at least one DMARD which could have included MTX or biologic agents; the study also included patients ages years to 17 years of age with active juvenile psoriatic arthritis (JPsA) and enthesitis-related arthritis (ERA) who had an inadequate response to NSAIDs.Patients received XELJANZ/XELJANZ Oral Solution (dosed at mg twice daily or body weight-based equivalent twice daily) for 18 weeks (run-in phase) followed by randomization to either XELJANZ/XELJANZ Oral Solution (dosed at mg twice daily or body weight-based equivalent twice daily) or placebo for 26 weeks (double-blind phase). Only patients who achieved at least JIA ACR30 response at the end of the run-in phase were randomized (1:1) to the double-blind phase. Treatment with stable dose of MTX was permitted but was not required during the study. Concurrent use of biologics or DMARDs other than MTX was not permitted in the study.A total of 225 JIA patients (56 male and 169 female) with active polyarthritis were enrolled in the run-in phase including RF negative (104), RF positive (39), extended oligoarthritis (28), systemic JIA without systemic manifestations (13), JPsA (20), and ERA (21). Patients had mean (SD) disease duration of 3.8 +- 3.5 years, and mean (SD) number of active joints of 12.2 +- 8.1.Of the 225 patients, 173 (76.9%) patients achieved JIA ACR30 response at Week 18 and were randomized into the double-blind phase to either active XELJANZ/XELJANZ Oral Solution (n=88) or placebo (n=85). At the conclusion of the 18-week, open-label, run-in phase, pediatric ACR 30/50/70 responses were 77%, 70%, and 49%, respectively.In both the run-in and double-blind phases, approximately one-third of the patients were taking concomitant oral corticosteroids, and approximately two-thirds were taking concomitant MTX. The primary endpoint was the occurrence of disease flare at Week 44 relative to the double-blind phase baseline at Week 18. Disease flare was defined (according to Pediatric Rheumatology Collaborative Study Group (PRCSG)/Pediatric Rheumatology International Trials Organization (PRINTO) Disease Flare criteria) as worsening of >=30% in or more of the JIA core response variables with no more than of the remaining JIA core response variables improving by >=30%.XELJANZ/XELJANZ Oral Solution treated patients experienced significantly fewer disease flares at Week 44 compared to placebo-treated patients (31% [27/88] vs. 55% [47/85]; difference in proportions -25% [95% CI: -39%, -10%]; p=0.0007). The occurrence of disease flare by visit in Study pcJIA-I is shown in Figure 7.Figure 7: Occurrence of Disease Flare by Visit in the Double-Blind Phase in Study pcJIA-IBID twice daily; SE standard error; = total number of subjects.The 26-week double-blind phase is from Week 18 through Week 44 on and after randomization day.. Figure 7. 14.6 Safety Study. randomized open-label trial (RA Safety Study 1; NCT02092467) was conducted to evaluate safety with XELJANZ at two doses, mg twice daily (N=1455) and 10 mg twice daily (N=1456), versus the TNF-blocker control (N=1451) in RA patients 50 years of age and older with at least one cardiovascular risk factor. The co-primary endpoints were adjudicated MACE (defined as cardiovascular death, non-fatal MI, and non-fatal stroke) and adjudicated malignancy (excluding non-melanoma skin cancer); the study was designed to exclude prespecified risk margin of 1.8 for the hazard ratio of combined XELJANZ regimens versus the TNF-blocker control for each co-primary endpoint. An independent committee conducted blinded evaluation of the co-primary endpoints according to predefined criteria (adjudication). The study was event driven and patients were followed until sufficient number of primary outcome events accrued. Other endpoints included mortality, serious infections, and thromboembolic events. The median on-study follow-up time was 4.0 years.The mean age of the population was 61 years (range: 50 to 88 years). Most patients were female (78%) and Caucasian (77%). Patients had diagnosis of RA for mean of 10 years, and median swollen and tender joint count of 11 and 15 respectively. Cardiovascular risk factors included cigarette smoking (current or past) (48%), hypertension (66%), high density lipoprotein 40 mg/dL (12%), diabetes mellitus (17%), family history of premature coronary heart disease (15%), extra-articular disease associated with RA (37%), and history of coronary artery disease (11%).The non-inferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNF blockers since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8 (for MACE, the upper limit of the 95% CI was 1.94; for malignancies excluding NMSC, the upper limit of the 95% CI was 2.09).Table 21 shows the study results for each of the co-primary endpoints, and other endpoints. There was an increased risk of death, MACE, malignancies, serious infections, and thromboembolic events associated with both doses of XELJANZ.Table 21: Results of RA Safety Study 1EndpointXELJANZ mg Twice Daily N=1455 PY=5490XELJANZ 10 mg Twice Daily N=1456 PY=5298TNF Blocker N=1451 PY=5468Note: XELJANZ 10 mg twice daily was discontinued by the Data Monitoring Committee due to safety concerns, and ongoing patients switched from XELJANZ 10 mg to XELJANZ mg. The column XELJANZ 10 mg Twice Daily includes all events and follow-up for patients randomized to XELJANZ 10 mg twice daily.A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)]. indicates number of patients; indicates number of patients with events. IR indicates incidence rate per 100 person-year (PY).NMSC: Non-melanoma Skin Cancer; MACE: Major Adverse Cardiac Events; HR: Hazard Ratio; DVT: Deep Vein Thrombosis; PE: Pulmonary Embolism; VTE: Venous Thromboembolism, first occurrence of VTE, defined as the composite of adjudicated DVT and adjudicated PE; ATE: Arterial Thromboembolism; TE: Thromboembolism, first occurrence of TE, defined as the composite of adjudicated VTE and unadjudicated ATE.MACE, [IR]50 [0.91]59 [1.11]43 [0.79] HR (95% CI)HR (95%) CI for XELJANZ vs. TNF Blocker (Univariate Cox Proportional Hazard Model). 1.16 (0.77, 1.74)1.41 (0.95, 2.10) MI,MI and Stroke include fatal and non-fatal events. [IR]20 [0.36]21 [0.39]11 [0.20] HR (95% CI) 1.81 (0.87, 3.79)1.97 (0.95, 4.09) Stroke, [IR]18 [0.33]21 [0.39]20 [0.36] HR (95% CI) 0.89 (0.47, 1.69)1.08 (0.59, 2.00) Cardiovascular Death, [IR]18 [0.32]25 [0.47]15 [0.27] HR (95% CI) 1.20 (0.60, 2.37)1.71 (0.90, 3.24)Malignancies Excl. NMSC, [IR]62 [1.13]60 [1.13]42 [0.77] HR (95% CI) 1.47 (1.00, 2.18)1.48 (1.00, 2.19) Malignancies Excl. NMSC (among current and past smokers)Data and analyses for Malignancies excluding NMSC for current and ex-smokers are included. There were 720 current and ex-smokers randomized to XELJANZ mg, 704 to XELJANZ 10 mg, and 679 to TNF blockers. 41 [1.53]48 [1.91]25 [0.99] HR (95% CI) 1.55 (0.94, 2.55)1.94 (1.19, 3.14)All Death49 [0.88]66 [1.23]38 [0.69] HR (95% CI) 1.29 (0.84, 1.96)1.79 (1.20, 2.66)Serious Infections155 [2.95]184 [3.65]133 [2.52] HR (95% CI) 1.17 (0.93, 1.47)1.44 (1.15, 1.80)DVT12 [0.22]15 [0.28]9 [0.16] HR (95% CI) 1.33 (0.56, 3.15)1.72 (0.75, 3.92)PE10 [0.18]26 [0.49]3 [0.05] HR (95% CI) 3.32 (0.91, 12.08)8.95 (2.71, 29.56)VTE18 [0.33]36 [0.68]12 [0.22] HR (95% CI) 1.50 (0.72, 3.10)3.10 (1.61, 5.96)ATE51 [0.93]55 [1.04]45 [0.83] HR (95% CI) 1.13 (0.76, 1.69)1.26 (0.85, 1.87)TE67 [1.23]86 [1.65]56 [1.03] HR (95% CI) 1.19 (0.84, 1.70)1.60 (1.14, 2.23)Lymphomas and lung cancers, which are subset of all malignancies in RA Safety Study 1, were observed at higher rate in patients treated with XELJANZ mg twice day and XELJANZ 10 mg twice day compared to those treated with TNF blockers. Lymphoma was reported for patients receiving XELJANZ mg twice day, patients receiving XELJANZ 10 mg twice day, and patient receiving TNF blockers (Incidence Rate [IR] of 0.07, 0.11, and 0.02 per 100 patient-years, respectively). Among current and past smokers, lung cancer was reported for 13 patients receiving XELJANZ mg twice day, 15 patients receiving XELJANZ 10 mg twice day, and patients receiving TNF blockers (IR of 0.48, 0.59, and 0.27 per 100 patient-years, respectively).A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: December 2021MEDICATION GUIDEXELJANZ (ZEL JANS)(tofacitinib)tablets, for oral useXELJANZ XR (ZEL JANS EKS-AHR)(tofacitinib)extended-release tablets, for oral useXELJANZ (ZEL JANS)(tofacitinib)Oral SolutionWhat is the most important information should know about XELJANZ/XELJANZ XR/XELJANZ Oral SolutionXELJANZ/XELJANZ XR/XELJANZ Oral Solution may cause serious side effects including:1.Serious infections. XELJANZ/XELJANZ XR/XELJANZ Oral Solution is medicine that affects your immune system. XELJANZ/XELJANZ XR/XELJANZ Oral Solution can lower the ability of your immune system to fight infections. Some people can have serious infections while taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your healthcare provider should test you for TB before starting XELJANZ/XELJANZ XR/XELJANZ Oral Solution and during treatment.Your healthcare provider should monitor you closely for signs and symptoms of TB infection during treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution.You should not start taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution if you have any kind of infection unless your healthcare provider tells you it is okay. You may be at higher risk of developing shingles (herpes zoster).People with ulcerative colitis taking the higher dose of XELJANZ (10 mg twice daily) or XELJANZ XR (22 mg one time each day) have higher risk of serious infections and shingles.Before starting XELJANZ/XELJANZ XR/XELJANZ Oral Solution, tell your healthcare provider if you:think you have an infection or have symptoms of an infection such as: fever, sweating, or chillscoughblood in phlegmwarm, red, or painful skin or sores on your bodyburning when you urinate or urinating more often than normalmuscle achesshortness of breathweight lossdiarrhea or stomach painfeeling very tiredare being treated for an infection.get lot of infections or have infections that keep coming back.have diabetes, chronic lung disease, HIV, or weak immune system. People with these conditions have higher chance for infections.have TB, or have been in close contact with someone with TB.live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you take XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.have or have had hepatitis or C.After starting XELJANZ/XELJANZ XR/XELJANZ Oral Solution, call your healthcare provider right away if you have any symptoms of an infection. XELJANZ/XELJANZ XR/XELJANZ Oral Solution can make you more likely to get infections or make worse any infection that you have.2.Increased risk of death in people 50 years of age and older who have at least heart disease (cardiovascular) risk factor and are taking XELJANZ mg twice daily or XELJANZ 10 mg twice daily.3.Cancer and immune system problems. XELJANZ/XELJANZ XR/XELJANZ Oral Solution may increase your risk of certain cancers by changing the way your immune system works. Lymphoma and other cancers including skin cancers can happen in people taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution. People taking XELJANZ mg twice daily or XELJANZ 10 mg twice daily have higher risk of certain cancers including lymphoma and lung cancer, especially if you are current or past smoker. People with ulcerative colitis taking the higher dose of XELJANZ (10 mg twice daily) or XELJANZ XR (22 mg one time each day) have higher risk of skin cancers. Tell your healthcare provider if you have ever had any type of cancer.Some people who have taken XELJANZ with certain other medicines to prevent kidney transplant rejection have had problem with certain white blood cells growing out of control (Epstein Barr Virus-associated post-transplant lymphoproliferative disorder). 4.Increased risk of major cardiovascular events such as heart attack, stroke or death in people 50 years of age and older who have at least heart disease (cardiovascular) risk factor and are taking XELJANZ mg twice daily or XELJANZ 10 mg twice daily, especially if you are current or past smoker. Get emergency help right away if you have any symptoms of heart attack or stroke while taking XELJANZ, including:discomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes backsevere tightness, pain, pressure, or heaviness in your chest, throat, neck, or jawpain or discomfort in your arms, back, neck, jaw, or stomachshortness of breath with or without chest discomfortbreaking out in cold sweatnausea or vomitingfeeling lightheadedweakness in one part or on one side of your bodyslurred speech5.Blood clots in the lungs, veins of the legs or arms, and arteries. Blood clots in the lungs (pulmonary embolism, PE), veins of the legs (deep vein thrombosis, DVT) and arteries (arterial thrombosis) have happened more often in people who are 50 years of age and older and with at least heart disease (cardiovascular) risk factor taking XELJANZ mg twice daily or XELJANZ 10 mg twice daily. Blood clots in the lungs have also happened in people with ulcerative colitis. Some people have died from these blood clots.Stop taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution and tell your healthcare provider right away if you develop signs and symptoms of blood clot, such as sudden shortness of breath or difficulty breathing, chest pain, swelling of the leg or arm, leg pain or tenderness, or redness or discoloration in the leg or arm. 6.Tears (perforation) in the stomach or intestines.Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution can get tears in their stomach or intestines. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and change in your bowel habits. 7.Allergic reactions.Symptoms such as swelling of your lips, tongue, or throat, or hives (raised, red patches of skin that are often very itchy) that may mean you are having an allergic reaction have been seen in people taking XELJANZ/XELJANZ XR. Some of these reactions were serious. If any of these symptoms occur while you are taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, stop XELJANZ/XELJANZ XR/XELJANZ Oral Solution and call your healthcare provider right away.8.Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution and while you take XELJANZ/XELJANZ XR/XELJANZ Oral Solution to check for the following side effects:changes in lymphocyte counts. Lymphocytes are white blood cells that help the body fight off infections.low neutrophil counts. Neutrophils are white blood cells that help the body fight off infections.low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired.Your healthcare provider should routinely check certain liver tests.You should not take XELJANZ/XELJANZ XR/XELJANZ Oral Solution if your lymphocyte count, neutrophil count, or red blood cell count is too low or your liver tests are too high.Your healthcare provider may stop your XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment for period of time if needed because of changes in these blood test results.You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels to weeks after you start taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, and as needed after that. Normal cholesterol levels are important to good heart health.See What are the possible side effects of XELJANZ/XELJANZ XR/XELJANZ Oral Solution for more information about side effects.What is XELJANZ/XELJANZ XR/XELJANZ Oral SolutionXELJANZ/XELJANZ XR/XELJANZ Oral Solution is prescription medicine called Janus kinase (JAK) inhibitor. XELJANZ/XELJANZ XR is used to treat adults with moderately to severely active rheumatoid arthritis when or more medicines called tumor necrosis factor (TNF) blockers have been used and did not work well or cannot be tolerated.XELJANZ/XELJANZ XR is used to treat adults with active psoriatic arthritis when or more TNF blocker medicines have been used, and did not work well or cannot be tolerated.XELJANZ/XELJANZ XR is used to treat adults with active ankylosing spondylitis when or more TNF blocker medicines have been used and did not work well or cannot be tolerated.XELJANZ/XELJANZ XR is used to treat adults with moderately to severely active ulcerative colitis when or more TNF blocker medicines have been used, and did not work well or cannot be tolerated.XELJANZ/XELJANZ Oral Solution is used to treat people years of age and older with active polyarticular course juvenile arthritis when or more TNF blocker medicines have been used, and did not work well or cannot be tolerated. It is not known if XELJANZ/XELJANZ XR is safe and effective in people with Hepatitis or C. XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended for people with severe liver problems. It is not known if XELJANZ/XELJANZ Oral Solution is safe and effective in children for treatment other than active polyarticular course juvenile arthritis.It is not known if XELJANZ XR is safe and effective in children.What should tell my healthcare provider before taking XELJANZ/XELJANZ XR/XELJANZ Oral SolutionBefore taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, tell your healthcare provider about all of your medical conditions, including if you:have an infection. See What is the most important information should know about XELJANZ/XELJANZ XR/XELJANZ Oral Solutionare current or past smoker.have had any type of cancer.have had heart attack, other heart problems or stroke. have had blood clots in the veins of your legs, arms, or lungs, or clots in the arteries in the past.have liver problems.have kidney problems.have any stomach area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines.have had reaction to tofacitinib or any of the ingredients in XELJANZ/XELJANZ XR/XELJANZ Oral Solution.have recently received or are scheduled to receive vaccine. People who take XELJANZ/XELJANZ XR/XELJANZ Oral Solution should not receive live vaccines. People taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution can receive non-live vaccines.plan to become pregnant or are pregnant. XELJANZ/XELJANZ XR/XELJANZ Oral Solution may affect the ability of females to get pregnant. It is not known if this will change after stopping XELJANZ/XELJANZ XR/XELJANZ Oral Solution. It is not known if XELJANZ/XELJANZ XR/XELJANZ Oral Solution will harm an unborn baby. Pregnancy Registry: Pfizer has registry for pregnant women who take XELJANZ/XELJANZ XR/XELJANZ Oral Solution. The purpose of this registry is to check the health of the pregnant mother and her baby. If you are pregnant or become pregnant while taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, talk to your healthcare provider about how you can join this pregnancy registry or you may contact the registry at 1-877-311-8972 to enroll. plan to breastfeed or are breastfeeding. You and your healthcare provider should decide if you will take XELJANZ/XELJANZ XR/XELJANZ Oral Solution or breastfeed. You should not do both. After you stop your treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution do not start breastfeeding again until:18 hours after your last dose of XELJANZ/XELJANZ Oral Solution or36 hours after your last dose of XELJANZ XR Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XELJANZ/XELJANZ XR/XELJANZ Oral Solution and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: any other medicines to treat your rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis or polyarticular course juvenile arthritis. You should not take tocilizumab (Actemra), etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), rituximab (Rituxan), abatacept (Orencia), anakinra (Kineret), certolizumab (Cimzia), golimumab (Simponi), ustekinumab (Stelara), secukinumab (Cosentyx), vedolizumab (Entyvio), ixekizumab (Taltz), azathioprine, cyclosporine, or other immunosuppressive drugs while you are taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution with these medicines may increase your risk of infection.medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take XELJANZ/XELJANZ XR/XELJANZ Oral Solution Take XELJANZ/XELJANZ XR/XELJANZ Oral Solution exactly as your healthcare provider tells you to take it.Take XELJANZ/XELJANZ Oral Solution times day with or without food.Take XELJANZ XR time day with or without food.Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.When you take XELJANZ XR, you may see something in your stool that looks like tablet. This is the empty shell from the tablet after the medicine has been absorbed by your body.If you take too much XELJANZ/XELJANZ XR/XELJANZ Oral Solution, call your healthcare provider or go to the nearest hospital emergency room right away.For the treatment of psoriatic arthritis, take XELJANZ/XELJANZ XR in combination with methotrexate, sulfasalazine or leflunomide as instructed by your healthcare provider.XELJANZ XR should not be used instead of XELJANZ Oral Solution. What are the possible side effects of XELJANZ/XELJANZ XR/XELJANZ Oral SolutionXELJANZ/XELJANZ XR/XELJANZ Oral Solution may cause serious side effects, including:See What is the most important information should know about XELJANZ/XELJANZ XR/XELJANZ Oral SolutionHepatitis or activation infection in people who carry the virus in their blood. If you are carrier of the hepatitis or virus (viruses that affect the liver), the virus may become active while you use XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Your healthcare provider may do blood tests before you start treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution and while you are taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Tell your healthcare provider if you have any of the following symptoms of possible hepatitis or infection:feel very tiredlittle or no appetiteclay-colored bowel movementschillsmuscle achesskin rashskin or eyes look yellowvomitingfeversstomach discomfortdark urineCommon side effects of XELJANZ/XELJANZ XR in people with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis include: upper respiratory tract infections (common cold, sinus infections)headachediarrheanasal congestion, sore throat, and runny nose (nasopharyngitis)high blood pressure (hypertension)Common side effects of XELJANZ/XELJANZ XR in people with ulcerative colitis include: nasal congestion, sore throat, and runny nose (nasopharyngitis)increased cholesterol levelsheadacheupper respiratory tract infections (common cold, sinus infections)increased muscle enzyme levelsrashdiarrheashingles (herpes zoster)Common side effects of XELJANZ/XELJANZ Oral Solution in people with polyarticular course juvenile arthritis include:upper respiratory tract infections (common cold, sinus infections)nasal congestion, sore throat, and runny nose (nasopharyngitis)headachefevernauseavomitingTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of XELJANZ/XELJANZ XR/XELJANZ Oral Solution. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer at 1-800-438-1985. How should store XELJANZ/XELJANZ XR/XELJANZ Oral SolutionStore XELJANZ/XELJANZ XR at room temperature between 68F to 77F (20C to 25C).Store XELJANZ Oral Solution at room temperature between 68F to 77F (20C to 25C) in the original bottle and carton to protect from light.Safely throw away XELJANZ Oral Solution that is out of date or no longer needed. Use XELJANZ Oral Solution within 60 days of opening the bottle. Throw away (discard) remaining oral solution after 60 days.Keep XELJANZ/XELJANZ XR/XELJANZ Oral Solution and all medicines out of the reach of children.General information about the safe and effective use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use XELJANZ/XELJANZ XR/XELJANZ Oral Solution for condition for which it was not prescribed. Do not give XELJANZ/XELJANZ XR/XELJANZ Oral Solution to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about XELJANZ/XELJANZ XR/XELJANZ Oral Solution. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about XELJANZ/XELJANZ XR/XELJANZ Oral Solution that is written for health professionals.What are the ingredients in XELJANZ mgActive ingredient: tofacitinib citrate Inactive ingredients: croscarmellose sodium, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. What are the ingredients in XELJANZ 10 mg Active ingredient: tofacitinib citrate Inactive ingredients: croscarmellose sodium, FD&C Blue 1/Brilliant Blue FCF Aluminum Lake, FD&C Blue 2/Indigo Carmine Aluminum Lake, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. What are the ingredients in XELJANZ XR 11 mg Active ingredient: tofacitinib citrate Inactive ingredients: cellulose acetate, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide, and triacetin. Printing ink contains ammonium hydroxide, ferrosoferric oxide/black iron, propylene glycol, and shellac glaze. What are the ingredients in XELJANZ XR 22 mg Active ingredient: tofacitinib citrate Inactive ingredients: cellulose acetate, copovidone, FD&C Blue Aluminum Lake, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide, triacetin, and yellow iron oxide. Printing ink contains ammonium hydroxide, ferrosoferric oxide/black iron oxide, propylene glycol, and shellac glaze. What are the ingredients in XELJANZ Oral Solution Active ingredient: tofacitinib citrate Inactive ingredients: grape flavor (natural), hydrochloric acid, lactic acid, purified water, sodium benzoate, sucralose, and xylitol. LAB-0535-13.0 Your healthcare provider should test you for TB before starting XELJANZ/XELJANZ XR/XELJANZ Oral Solution and during treatment.. Your healthcare provider should monitor you closely for signs and symptoms of TB infection during treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution.. think you have an infection or have symptoms of an infection such as:. fever, sweating, or chills. cough. blood in phlegm. warm, red, or painful skin or sores on your body. burning when you urinate or urinating more often than normal. muscle aches. shortness of breath. weight loss. diarrhea or stomach pain. feeling very tired. are being treated for an infection.. get lot of infections or have infections that keep coming back.. have diabetes, chronic lung disease, HIV, or weak immune system. People with these conditions have higher chance for infections.. have TB, or have been in close contact with someone with TB.. live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you take XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.. have or have had hepatitis or C.. Lymphoma and other cancers including skin cancers can happen in people taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution. People taking XELJANZ mg twice daily or XELJANZ 10 mg twice daily have higher risk of certain cancers including lymphoma and lung cancer, especially if you are current or past smoker. People with ulcerative colitis taking the higher dose of XELJANZ (10 mg twice daily) or XELJANZ XR (22 mg one time each day) have higher risk of skin cancers. Tell your healthcare provider if you have ever had any type of cancer.. Some people who have taken XELJANZ with certain other medicines to prevent kidney transplant rejection have had problem with certain white blood cells growing out of control (Epstein Barr Virus-associated post-transplant lymphoproliferative disorder).. discomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes back. severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw. pain or discomfort in your arms, back, neck, jaw, or stomach. shortness of breath with or without chest discomfort. breaking out in cold sweat. nausea or vomiting. feeling lightheaded. weakness in one part or on one side of your body. slurred speech. Stop taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution and tell your healthcare provider right away if you develop signs and symptoms of blood clot, such as sudden shortness of breath or difficulty breathing, chest pain, swelling of the leg or arm, leg pain or tenderness, or redness or discoloration in the leg or arm.. Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution can get tears in their stomach or intestines. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and change in your bowel habits. Symptoms such as swelling of your lips, tongue, or throat, or hives (raised, red patches of skin that are often very itchy) that may mean you are having an allergic reaction have been seen in people taking XELJANZ/XELJANZ XR. Some of these reactions were serious. If any of these symptoms occur while you are taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, stop XELJANZ/XELJANZ XR/XELJANZ Oral Solution and call your healthcare provider right away.. changes in lymphocyte counts. Lymphocytes are white blood cells that help the body fight off infections.. low neutrophil counts. Neutrophils are white blood cells that help the body fight off infections.. low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired.. XELJANZ/XELJANZ XR/XELJANZ Oral Solution is prescription medicine called Janus kinase (JAK) inhibitor. XELJANZ/XELJANZ XR is used to treat adults with moderately to severely active rheumatoid arthritis when or more medicines called tumor necrosis factor (TNF) blockers have been used and did not work well or cannot be tolerated.. XELJANZ/XELJANZ XR is used to treat adults with active psoriatic arthritis when or more TNF blocker medicines have been used, and did not work well or cannot be tolerated.. XELJANZ/XELJANZ XR is used to treat adults with active ankylosing spondylitis when or more TNF blocker medicines have been used and did not work well or cannot be tolerated.. XELJANZ/XELJANZ XR is used to treat adults with moderately to severely active ulcerative colitis when or more TNF blocker medicines have been used, and did not work well or cannot be tolerated.. XELJANZ/XELJANZ Oral Solution is used to treat people years of age and older with active polyarticular course juvenile arthritis when or more TNF blocker medicines have been used, and did not work well or cannot be tolerated. have an infection. See What is the most important information should know about XELJANZ/XELJANZ XR/XELJANZ Oral Solution. are current or past smoker.. have had any type of cancer.. have had heart attack, other heart problems or stroke. have had blood clots in the veins of your legs, arms, or lungs, or clots in the arteries in the past.. have liver problems.. have kidney problems.. have any stomach area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines.. have had reaction to tofacitinib or any of the ingredients in XELJANZ/XELJANZ XR/XELJANZ Oral Solution.. have recently received or are scheduled to receive vaccine. People who take XELJANZ/XELJANZ XR/XELJANZ Oral Solution should not receive live vaccines. People taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution can receive non-live vaccines.. plan to become pregnant or are pregnant. XELJANZ/XELJANZ XR/XELJANZ Oral Solution may affect the ability of females to get pregnant. It is not known if this will change after stopping XELJANZ/XELJANZ XR/XELJANZ Oral Solution. It is not known if XELJANZ/XELJANZ XR/XELJANZ Oral Solution will harm an unborn baby. Pregnancy Registry: Pfizer has registry for pregnant women who take XELJANZ/XELJANZ XR/XELJANZ Oral Solution. The purpose of this registry is to check the health of the pregnant mother and her baby. If you are pregnant or become pregnant while taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, talk to your healthcare provider about how you can join this pregnancy registry or you may contact the registry at 1-877-311-8972 to enroll. Pregnancy Registry: Pfizer has registry for pregnant women who take XELJANZ/XELJANZ XR/XELJANZ Oral Solution. The purpose of this registry is to check the health of the pregnant mother and her baby. If you are pregnant or become pregnant while taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution, talk to your healthcare provider about how you can join this pregnancy registry or you may contact the registry at 1-877-311-8972 to enroll.. plan to breastfeed or are breastfeeding. You and your healthcare provider should decide if you will take XELJANZ/XELJANZ XR/XELJANZ Oral Solution or breastfeed. You should not do both. After you stop your treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution do not start breastfeeding again until:18 hours after your last dose of XELJANZ/XELJANZ Oral Solution or36 hours after your last dose of XELJANZ XR 18 hours after your last dose of XELJANZ/XELJANZ Oral Solution or. 36 hours after your last dose of XELJANZ XR. any other medicines to treat your rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis or polyarticular course juvenile arthritis. You should not take tocilizumab (Actemra), etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), rituximab (Rituxan), abatacept (Orencia), anakinra (Kineret), certolizumab (Cimzia), golimumab (Simponi), ustekinumab (Stelara), secukinumab (Cosentyx), vedolizumab (Entyvio), ixekizumab (Taltz), azathioprine, cyclosporine, or other immunosuppressive drugs while you are taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution with these medicines may increase your risk of infection.. medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these.. Take XELJANZ/XELJANZ Oral Solution times day with or without food.. Take XELJANZ XR time day with or without food.. Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.. When you take XELJANZ XR, you may see something in your stool that looks like tablet. This is the empty shell from the tablet after the medicine has been absorbed by your body.. If you take too much XELJANZ/XELJANZ XR/XELJANZ Oral Solution, call your healthcare provider or go to the nearest hospital emergency room right away.. For the treatment of psoriatic arthritis, take XELJANZ/XELJANZ XR in combination with methotrexate, sulfasalazine or leflunomide as instructed by your healthcare provider.. XELJANZ XR should not be used instead of XELJANZ Oral Solution.. See What is the most important information should know about XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Hepatitis or activation infection in people who carry the virus in their blood. If you are carrier of the hepatitis or virus (viruses that affect the liver), the virus may become active while you use XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Your healthcare provider may do blood tests before you start treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution and while you are taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Tell your healthcare provider if you have any of the following symptoms of possible hepatitis or infection:. feel very tired. little or no appetite. clay-colored bowel movements. chills. muscle aches. skin rash. skin or eyes look yellow. vomiting. fevers. stomach discomfort. dark urine. upper respiratory tract infections (common cold, sinus infections). headache. diarrhea. nasal congestion, sore throat, and runny nose (nasopharyngitis). high blood pressure (hypertension). nasal congestion, sore throat, and runny nose (nasopharyngitis). increased cholesterol levels. headache. upper respiratory tract infections (common cold, sinus infections). increased muscle enzyme levels. rash. diarrhea. shingles (herpes zoster). upper respiratory tract infections (common cold, sinus infections). nasal congestion, sore throat, and runny nose (nasopharyngitis). headache. fever. nausea. vomiting. Store XELJANZ/XELJANZ XR at room temperature between 68F to 77F (20C to 25C).. Store XELJANZ Oral Solution at room temperature between 68F to 77F (20C to 25C) in the original bottle and carton to protect from light.. Safely throw away XELJANZ Oral Solution that is out of date or no longer needed. Use XELJANZ Oral Solution within 60 days of opening the bottle. Throw away (discard) remaining oral solution after 60 days.. Logo.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Serious Infections [see Warnings and Precautions (5.1)] Mortality [see Warnings and Precautions (5.2)] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3)] Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)] Thrombosis [see Warnings and Precautions (5.5)] Gastrointestinal Perforations [see Warnings and Precautions (5.6)] Hypersensitivity [see Warnings and Precautions (5.7)] Laboratory Abnormalities [see Warnings and Precautions (5.8)] Serious Infections [see Warnings and Precautions (5.1)] Mortality [see Warnings and Precautions (5.2)] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3)] Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)] Thrombosis [see Warnings and Precautions (5.5)] Gastrointestinal Perforations [see Warnings and Precautions (5.6)] Hypersensitivity [see Warnings and Precautions (5.7)] Laboratory Abnormalities [see Warnings and Precautions (5.8)] Most common adverse reactions are:Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis: Reported during the first months in rheumatoid arthritis placebo-controlled clinical trials and occurring in >=2% of patients treated with XELJANZ monotherapy or in combination with DMARDs: upper respiratory tract infection, nasopharyngitis, diarrhea, and headache. (6.1)Ulcerative Colitis: Reported in >=5% of patients treated with either mg or 10 mg twice daily of XELJANZ and >=1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. (6.1)Polyarticular Course Juvenile Idiopathic Arthritis: Consistent with common adverse reactions reported in adult rheumatoid arthritis patients. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis: Reported during the first months in rheumatoid arthritis placebo-controlled clinical trials and occurring in >=2% of patients treated with XELJANZ monotherapy or in combination with DMARDs: upper respiratory tract infection, nasopharyngitis, diarrhea, and headache. (6.1). Ulcerative Colitis: Reported in >=5% of patients treated with either mg or 10 mg twice daily of XELJANZ and >=1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. (6.1). Polyarticular Course Juvenile Idiopathic Arthritis: Consistent with common adverse reactions reported in adult rheumatoid arthritis patients. (6.1). 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in broader patient population in clinical practice.. Rheumatoid ArthritisThe clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended regimen for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)]. In RA Safety Study 1, 1455 patients were treated with XELJANZ mg twice daily, 1456 patients were treated with 10 mg twice daily, and 1451 patients were treated with TNF blocker for median of 4.0 years [see Clinical Studies (14.6)].The following data includes two Phase and five Phase double-blind, placebo-controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven placebo-controlled protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month or Month either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of given interval. Comparisons between placebo and XELJANZ were based on the first months of exposure, and comparisons between XELJANZ mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.The long-term safety population includes all patients who participated in double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)].The proportion of patients who discontinued treatment due to any adverse reaction during the to months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.. Overall InfectionsIn the seven placebo-controlled trials, during the to months exposure, the overall frequency of infections was 20% and 22% in the mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).. Serious InfectionsIn the seven placebo-controlled trials, during the to months exposure, serious infections were reported in patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined mg twice daily and 10 mg twice daily XELJANZ group minus placebo.In the seven placebo-controlled trials, during the to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ.The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1)].. TuberculosisIn the seven placebo-controlled trials, during the to months exposure, tuberculosis was not reported in patients who received placebo, mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.In the seven placebo-controlled trials, during the to 12 months exposure, tuberculosis was reported in patients who received mg twice daily of XELJANZ and patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ.Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) [see Warnings and Precautions (5.1)]. Opportunistic Infections (excluding tuberculosis)In the seven placebo-controlled trials, during the to months exposure, opportunistic infections were not reported in patients who received placebo, mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.In the seven placebo-controlled trials, during the to 12 months exposure, opportunistic infections were reported in patients (0.3 events per 100 patient-years) who received mg twice daily of XELJANZ and patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ.The median XELJANZ exposure prior to diagnosis of an opportunistic infection was months (range from 41 to 698 days) [see Warnings and Precautions (5.1)]. MalignancyIn the seven placebo-controlled trials, during the to months exposure, malignancies excluding NMSC were reported in patients who received placebo and patients (0.3 events per 100 patient-years) who received either XELJANZ mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined mg and 10 mg twice daily XELJANZ group minus placebo.In the seven placebo-controlled trials, during the to 12 months exposure, malignancies excluding NMSC were reported in patients (0.4 events per 100 patient-years) who received mg twice daily of XELJANZ and patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ. One of these malignancies was case of lymphoma that occurred during the to 12 month period in patient treated with XELJANZ 10 mg twice daily.The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma [see Warnings and Precautions (5.3)]. Laboratory Abnormalities. LymphopeniaIn the placebo-controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the mg twice daily and 10 mg twice daily XELJANZ groups combined during the first months of exposure.Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.8)]. NeutropeniaIn the placebo-controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the mg twice daily and 10 mg twice daily XELJANZ groups combined during the first months of exposure.There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.There was no clear relationship between neutropenia and the occurrence of serious infections.In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials [see Warnings and Precautions (5.8)]. Liver Enzyme ElevationsConfirmed increases in liver enzymes greater than times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.In the placebo-controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ mg, and 10 mg twice daily groups.In the placebo-controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, mg, and 10 mg twice daily, respectively.One case of drug-induced liver injury was reported in patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and liver biopsy.. Lipid ElevationsIn the placebo-controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first months of exposure in the placebo-controlled clinical trials are summarized below:Mean LDL cholesterol increased by 15% in the XELJANZ mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.Mean HDL cholesterol increased by 10% in the XELJANZ mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.In placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.. Mean LDL cholesterol increased by 15% in the XELJANZ mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.. Mean HDL cholesterol increased by 10% in the XELJANZ mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.. Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.. Serum Creatinine ElevationsIn the placebo-controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.. Other Adverse ReactionsAdverse reactions occurring in 2% or more of patients on mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.Table 4: Common Adverse Reactionsreported in >=2% of patients treated with either dose of XELJANZ and >=1% greater than that reported for placebo. in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0-3 Months)Preferred TermXELJANZ5 mg Twice DailyXELJANZ10 mg Twice Dailythe recommended dose of XELJANZ for the treatment of rheumatoid arthritis is mg twice daily [see Dosage and Administration (2)]. PlaceboN 1336(%)N 1349(%)N 809(%)N reflects randomized and treated patients from the seven placebo-controlled clinical trials.Upper respiratory tract infection443Nasopharyngitis433Diarrhea432Headache432Hypertension221Other adverse reactions occurring in placebo-controlled and open-label extension studies included:Blood and lymphatic system disorders: AnemiaInfections and infestations: DiverticulitisMetabolism and nutrition disorders: DehydrationPsychiatric disorders: InsomniaNervous system disorders: ParesthesiaRespiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal)Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nauseaHepatobiliary disorders: Hepatic steatosisSkin and subcutaneous tissue disorders: Rash, erythema, pruritusMusculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swellingNeoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancersGeneral disorders and administration site conditions: Pyrexia, fatigue, peripheral edema. Clinical Experience in Methotrexate-Naive PatientsStudy RA-VI was an active-controlled clinical trial in methotrexate-naive patients [see Clinical Studies (14)]. The safety experience in these patients was consistent with Studies RA-I through V.. Psoriatic ArthritisXELJANZ mg twice daily and 10 mg twice daily were studied in double-blind Phase clinical trials in patients with active psoriatic arthritis (PsA). Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of PsA [see Dosage and Administration (2.2)]. Study PsA-I (NCT01877668) had duration of 12 months and enrolled patients who had an inadequate response to nonbiologic DMARD and who were naive to treatment with TNF blocker. Study PsA-I included 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every weeks for 12 months.Study PsA-II (NCT01882439) had duration of months and enrolled patients who had an inadequate response to at least one approved TNF blocker. This clinical trial included 3-month placebo-controlled period.In these combined Phase clinical trials, 238 patients were randomized and treated with XELJANZ mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with stable dose of nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline. During the PsA controlled clinical trials, there were malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus non-biologic DMARD (6 to 12 months exposure) compared with malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and malignancies in 106 patients in the adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ.The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in rheumatoid arthritis patients.. Ankylosing SpondylitisXELJANZ mg twice daily was studied in patients with active ankylosing spondylitis (AS) in confirmatory double-blind placebo-controlled Phase clinical trial (Study AS-I) and in dose-ranging Phase clinical trial (Study AS-II).Study AS-I (NCT03502616) had duration of 48 weeks and enrolled patients who had an inadequate response to at least NSAIDs. Study AS-I included 16-week double-blind period in which patients received XELJANZ mg or placebo twice daily and 32-week open-label treatment period in which all patients received XELJANZ mg twice daily.Study AS-II (NCT01786668) had duration of 16 weeks and enrolled patients who had an inadequate response to at least NSAIDs. This clinical trial included 12-week treatment period in which patients received either XELJANZ mg, mg, 10 mg, or placebo twice daily.In the combined Phase and Phase clinical trials, total of 420 patients were treated with either XELJANZ mg, mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (<=10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients.. Ulcerative ColitisXELJANZ has been studied in patients with moderately to severely active UC in randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV) [see Clinical Studies (14.4)].Adverse reactions reported in >=5% of patients treated with either mg or 10 mg twice daily of XELJANZ and >=1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.. Induction Trials (Study UC-I, UC-II, and UC-V):Common adverse reactions reported in >=2% of patients treated with XELJANZ 10 mg twice daily and >=1% greater than that reported in patients receiving placebo in the induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.. Maintenance Trial (Study UC-III)Common adverse reactions reported in >=4% of patients treated with either dose of XELJANZ and >=1% greater than reported in patients receiving placebo are shown in Table 5.Table 5: Common Adverse Reactionsreported in >=4% of patients treated with either dose of XELJANZ and >=1% greater than reported for placebo. in -UC Patients during the Maintenance Trial (Study UC-III) Preferred TermXELJANZ5 mg Twice DailyXELJANZ10 mg Twice DailyPlaceboN 198(%)N 196(%)N 198(%)Nasopharyngitis10146Elevated cholesterol levelsincludes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased. 591Headache936Upper respiratory tract infection764Increased blood creatine phosphokinase372Rash364Diarrhea253Herpes zoster151Gastroenteritis343Anemia422Nausea143Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC [see Warnings and Precautions (5.1, 5.3)]. During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, cases of solid cancer or lymphoma were observed in XELJANZ-treated patients.In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ mg and 10 mg twice daily [see Warnings and Precautions (5.3)]. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in patient with advanced cancer [see Warnings and Precautions (5.5)].. Polyarticular Course Juvenile Idiopathic ArthritisXELJANZ/XELJANZ Oral Solution mg twice daily or weight-based equivalent twice daily was studied in 225 patients from years to 17 years of age in Study pcJIA-I [see Clinical Studies (14.5)] and one open-label extension study. The total patient exposure (defined as patients who received at least one dose of XELJANZ/XELJANZ Oral Solution) was 351 patient-years.In general, the types of adverse drug reactions in patients with pcJIA were consistent with those seen in adult RA patients [see Adverse Reactions (6.1)].. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of XELJANZ/XELJANZ XR. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed).

BOXED WARNING SECTION.

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS. WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), AND THROMBOSISSee full prescribing information for complete boxed warning.Increased risk of serious bacterial, fungal, viral, and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Interrupt treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution if serious infection occurs until the infection is controlled. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. (5.1)Higher rate of all-cause mortality, including sudden cardiovascular death with XELJANZ vs. TNF blockers in rheumatoid arthritis (RA) patients. (5.2)Malignancies have occurred in patients treated with XELJANZ. Higher rate of lymphomas and lung cancers with XELJANZ vs. TNF blockers in RA patients. (5.3)Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with XELJANZ vs. TNF blockers in RA patients. (5.4) Thrombosis has occurred in patients treated with XELJANZ. Increased incidence of pulmonary embolism, venous and arterial thrombosis with XELJANZ vs. TNF blockers in RA patients. (5.5). Increased risk of serious bacterial, fungal, viral, and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Interrupt treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution if serious infection occurs until the infection is controlled. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. (5.1). Higher rate of all-cause mortality, including sudden cardiovascular death with XELJANZ vs. TNF blockers in rheumatoid arthritis (RA) patients. (5.2). Malignancies have occurred in patients treated with XELJANZ. Higher rate of lymphomas and lung cancers with XELJANZ vs. TNF blockers in RA patients. (5.3). Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with XELJANZ vs. TNF blockers in RA patients. (5.4) Thrombosis has occurred in patients treated with XELJANZ. Increased incidence of pulmonary embolism, venous and arterial thrombosis with XELJANZ vs. TNF blockers in RA patients. (5.5). SERIOUS INFECTIONSPatients 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 serious infection develops, interrupt XELJANZ/XELJANZ XR/XELJANZ Oral Solution until the infection is controlled.Reported infections include: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. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.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)].. 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. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.. Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.. MORTALITYIn 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 mg twice day or XELJANZ 10 mg twice day to tumor necrosis factor (TNF) blockers, higher rate of all-cause mortality, including sudden cardiovascular death, was observed with XELJANZ mg twice day or XELJANZ 10 mg twice day [see Warnings and Precautions (5.2)]. XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].. MALIGNANCIESMalignancies, 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, higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ mg twice day or XELJANZ 10 mg twice day compared with TNF blockers [see Warnings and Precautions (5.3)].Lymphomas and lung cancers were observed at higher rate in patients treated with XELJANZ mg twice day or XELJANZ 10 mg twice 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 EVENTSRA patients 50 years of age and older with at least one cardiovascular risk factor, treated with XELJANZ mg twice daily or XELJANZ 10 mg twice daily, had 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 myocardial infarction or stroke [see Warnings and Precautions (5.4)].. THROMBOSISThrombosis, 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 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)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately times the recommended dose of mg twice daily, and approximately times the 10 mg twice daily dose (on an AUC basis at oral doses of mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels times the recommended dose of mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of mg/kg twice daily).The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the recommended dose of mg twice daily, and approximately 17 times the 10 mg twice daily dose (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the recommended dose of mg twice daily, and approximately 21 times the 10 mg twice daily dose on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.In rats, tofacitinib at exposure levels approximately 17 times the recommended dose of mg twice daily, and approximately 8.3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the recommended dose of mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of mg/kg/day). Tofacitinib exposure levels at approximately 133 times the recommended dose of mg twice daily, and approximately 67 times the 10 mg twice daily dose (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tofacitinib is Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.. 12.2 Pharmacodynamics. Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within weeks after discontinuation, indicating longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.Similar changes in cells, cells, and serum CRP have been observed in patients with active psoriatic arthritis although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active psoriatic arthritis.. 12.3 Pharmacokinetics. XELJANZ/XELJANZ Oral SolutionFollowing oral administration of XELJANZ/XELJANZ Oral Solution, peak plasma concentrations are reached within 0.5-1 hour, elimination half-life is about hours and dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.. XELJANZ XRFollowing oral administration of XELJANZ XR, peak plasma concentrations are reached at hours and half-life is about to hours. Steady state concentrations are achieved within 48 hours with negligible accumulation after once daily administration.Table 7: Pharmacokinetic Parameters of XELJANZ/ XELJANZ XR Following Multiple Oral DosingPK ParametersValues represent the geometric mean, except max, for which is the median (range) is shown. (CV%)XELJANZXELJANZ XRDosing Regimen5 mgTwice Daily10 mgTwice Daily11 mgOnce Daily22 mgOnce DailyAbbreviations: AUC24 area under the concentration-time profile from time to 24 hours; Cmax maximum plasma concentration; Cmin minimum plasma concentration; Tmax time to Cmax; CV Coefficient of variation.AUC24 (ng.hr/mL)263.4 (15)539.6 (22)269.0 (18)596.6 (19)Cmax (ng/mL)42.7 (26)84.7 (18)38.2 (15)83.8 (25)Cmin (ng/mL)1.41 (40)3.10 (54)1.07 (69)3.11 (43)Tmax (hours)1.0(0.5 to14.0Values beyond 12 hours were after the evening dose which was administered 12 hours after the morning dose of twice-daily XELJANZ)0.8(0.5 to 14.0)4.0(3.0 to 4.0)4.0(2.0 to 4.0). Absorption. XELJANZThe absolute oral bioavailability of XELJANZ is 74%. Coadministration of XELJANZ with high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals [see Dosage and Administration (2.1)].. XELJANZ XRCoadministration of XELJANZ XR 11 and 22 mg with high-fat meal resulted in no changes in AUC while Cmax was increased by 27% and 19% respectively. Tmax was extended by approximately hour for both XELJANZ XR 11 and 22 mg.. DistributionAfter intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to 1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.. Metabolism and ExcretionClearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.. Pharmacokinetics in Patient PopulationsPopulation pharmacokinetic analyses indicated that pharmacokinetic characteristics were similar between patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and UC. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 8).Table 8: XELJANZ Exposure in Patient Populations at mg Twice Daily and 10 mg Twice Daily DosesPharmacokinetic ParametersPharmacokinetic parameters estimated based on population pharmacokinetic analysis. Geometric Mean (CV%)XELJANZ mg Twice DailyXELJANZ 10 mg Twice DailyRheumatoid ArthritisPsoriatic ArthritisAnkylosing SpondylitisUlcerative ColitisUlcerative ColitisAbbreviations: AUC0-24,ss=area under the plasma concentration-time curve over 24 hours at steady state; CV=coefficient of variation.AUC0-24,ss (ngh/mL)504(22.0%)419(34.1%)381 (25.4%)423(22.6%)807(24.6%). Specific PopulationsCovariate evaluation as part of population PK analyses in adult patient populations indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant.Covariate evaluation as part of population PK analyses in pcJIA patients identified body weight significantly impacting tofacitinib exposure, which supports weight-based dosing in this population. No additional dose adjustment is needed based on age, gender, race, or disease severity in pcJIA patients.The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.Figure 1: Impact of Intrinsic Factors on Tofacitinib PharmacokineticsNote: Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function. Refer to Dosage and Administration (2.2, 2.3, 2.4) for dosage adjustment in RA, PsA, AS, UC, and pcJIA patients.In subjects with ESRD maintained on hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib. Dose adjustment is recommended in RA, PsA, AS, UC, and pcJIA patients with ESRD maintained on hemodialysis [see Dosage and Administration (2.2, 2.3, 2.4)].. Figure 1. Drug Interaction Studies. Potential for XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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 corresponding to the steady state Cmax of 10 mg twice daily dose. These in vitro results were confirmed by human drug interaction study showing no changes in the pharmacokinetics of midazolam, highly sensitive CYP3A4 substrate, when coadministered with XELJANZ. 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 Cmax of 10 mg twice daily dose.In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.Dosing recommendations for coadministered drugs following administration with XELJANZ/XELJANZ XR/XELJANZ Oral Solution are shown in Figure 2.Figure 2: Impact of Tofacitinib on the Pharmacokinetics of Other DrugsNote: Reference group is administration of concomitant medication alone; OCT Organic Cationic Transporter; MATE Multidrug and Toxic Compound Extrusion.. Figure 2. Potential for Other Drugs to Influence the Pharmacokinetics of TofacitinibSince tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the pharmacokinetics of tofacitinib (see Figure 3).Figure 3: Impact of Other Drugs on the Pharmacokinetics of TofacitinibNote: Reference group is administration of tofacitinib alone. [see Dosage and Administration (2.2, 2.3, 2.4), Drug Interactions (7)]. Figure 3.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in broader patient population in clinical practice.. Rheumatoid ArthritisThe clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended regimen for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)]. In RA Safety Study 1, 1455 patients were treated with XELJANZ mg twice daily, 1456 patients were treated with 10 mg twice daily, and 1451 patients were treated with TNF blocker for median of 4.0 years [see Clinical Studies (14.6)].The following data includes two Phase and five Phase double-blind, placebo-controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven placebo-controlled protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month or Month either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of given interval. Comparisons between placebo and XELJANZ were based on the first months of exposure, and comparisons between XELJANZ mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.The long-term safety population includes all patients who participated in double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)].The proportion of patients who discontinued treatment due to any adverse reaction during the to months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.. Overall InfectionsIn the seven placebo-controlled trials, during the to months exposure, the overall frequency of infections was 20% and 22% in the mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).. Serious InfectionsIn the seven placebo-controlled trials, during the to months exposure, serious infections were reported in patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined mg twice daily and 10 mg twice daily XELJANZ group minus placebo.In the seven placebo-controlled trials, during the to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ.The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1)].. TuberculosisIn the seven placebo-controlled trials, during the to months exposure, tuberculosis was not reported in patients who received placebo, mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.In the seven placebo-controlled trials, during the to 12 months exposure, tuberculosis was reported in patients who received mg twice daily of XELJANZ and patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ.Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) [see Warnings and Precautions (5.1)]. Opportunistic Infections (excluding tuberculosis)In the seven placebo-controlled trials, during the to months exposure, opportunistic infections were not reported in patients who received placebo, mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.In the seven placebo-controlled trials, during the to 12 months exposure, opportunistic infections were reported in patients (0.3 events per 100 patient-years) who received mg twice daily of XELJANZ and patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ.The median XELJANZ exposure prior to diagnosis of an opportunistic infection was months (range from 41 to 698 days) [see Warnings and Precautions (5.1)]. MalignancyIn the seven placebo-controlled trials, during the to months exposure, malignancies excluding NMSC were reported in patients who received placebo and patients (0.3 events per 100 patient-years) who received either XELJANZ mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined mg and 10 mg twice daily XELJANZ group minus placebo.In the seven placebo-controlled trials, during the to 12 months exposure, malignancies excluding NMSC were reported in patients (0.4 events per 100 patient-years) who received mg twice daily of XELJANZ and patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus mg twice daily XELJANZ. One of these malignancies was case of lymphoma that occurred during the to 12 month period in patient treated with XELJANZ 10 mg twice daily.The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma [see Warnings and Precautions (5.3)]. Laboratory Abnormalities. LymphopeniaIn the placebo-controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the mg twice daily and 10 mg twice daily XELJANZ groups combined during the first months of exposure.Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.8)]. NeutropeniaIn the placebo-controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the mg twice daily and 10 mg twice daily XELJANZ groups combined during the first months of exposure.There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.There was no clear relationship between neutropenia and the occurrence of serious infections.In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials [see Warnings and Precautions (5.8)]. Liver Enzyme ElevationsConfirmed increases in liver enzymes greater than times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.In the placebo-controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ mg, and 10 mg twice daily groups.In the placebo-controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, mg, and 10 mg twice daily, respectively.One case of drug-induced liver injury was reported in patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and liver biopsy.. Lipid ElevationsIn the placebo-controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first months of exposure in the placebo-controlled clinical trials are summarized below:Mean LDL cholesterol increased by 15% in the XELJANZ mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.Mean HDL cholesterol increased by 10% in the XELJANZ mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.In placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.. Mean LDL cholesterol increased by 15% in the XELJANZ mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.. Mean HDL cholesterol increased by 10% in the XELJANZ mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.. Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.. Serum Creatinine ElevationsIn the placebo-controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.. Other Adverse ReactionsAdverse reactions occurring in 2% or more of patients on mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.Table 4: Common Adverse Reactionsreported in >=2% of patients treated with either dose of XELJANZ and >=1% greater than that reported for placebo. in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0-3 Months)Preferred TermXELJANZ5 mg Twice DailyXELJANZ10 mg Twice Dailythe recommended dose of XELJANZ for the treatment of rheumatoid arthritis is mg twice daily [see Dosage and Administration (2)]. PlaceboN 1336(%)N 1349(%)N 809(%)N reflects randomized and treated patients from the seven placebo-controlled clinical trials.Upper respiratory tract infection443Nasopharyngitis433Diarrhea432Headache432Hypertension221Other adverse reactions occurring in placebo-controlled and open-label extension studies included:Blood and lymphatic system disorders: AnemiaInfections and infestations: DiverticulitisMetabolism and nutrition disorders: DehydrationPsychiatric disorders: InsomniaNervous system disorders: ParesthesiaRespiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal)Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nauseaHepatobiliary disorders: Hepatic steatosisSkin and subcutaneous tissue disorders: Rash, erythema, pruritusMusculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swellingNeoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancersGeneral disorders and administration site conditions: Pyrexia, fatigue, peripheral edema. Clinical Experience in Methotrexate-Naive PatientsStudy RA-VI was an active-controlled clinical trial in methotrexate-naive patients [see Clinical Studies (14)]. The safety experience in these patients was consistent with Studies RA-I through V.. Psoriatic ArthritisXELJANZ mg twice daily and 10 mg twice daily were studied in double-blind Phase clinical trials in patients with active psoriatic arthritis (PsA). Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of PsA [see Dosage and Administration (2.2)]. Study PsA-I (NCT01877668) had duration of 12 months and enrolled patients who had an inadequate response to nonbiologic DMARD and who were naive to treatment with TNF blocker. Study PsA-I included 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every weeks for 12 months.Study PsA-II (NCT01882439) had duration of months and enrolled patients who had an inadequate response to at least one approved TNF blocker. This clinical trial included 3-month placebo-controlled period.In these combined Phase clinical trials, 238 patients were randomized and treated with XELJANZ mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with stable dose of nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline. During the PsA controlled clinical trials, there were malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus non-biologic DMARD (6 to 12 months exposure) compared with malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and malignancies in 106 patients in the adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ.The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in rheumatoid arthritis patients.. Ankylosing SpondylitisXELJANZ mg twice daily was studied in patients with active ankylosing spondylitis (AS) in confirmatory double-blind placebo-controlled Phase clinical trial (Study AS-I) and in dose-ranging Phase clinical trial (Study AS-II).Study AS-I (NCT03502616) had duration of 48 weeks and enrolled patients who had an inadequate response to at least NSAIDs. Study AS-I included 16-week double-blind period in which patients received XELJANZ mg or placebo twice daily and 32-week open-label treatment period in which all patients received XELJANZ mg twice daily.Study AS-II (NCT01786668) had duration of 16 weeks and enrolled patients who had an inadequate response to at least NSAIDs. This clinical trial included 12-week treatment period in which patients received either XELJANZ mg, mg, 10 mg, or placebo twice daily.In the combined Phase and Phase clinical trials, total of 420 patients were treated with either XELJANZ mg, mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (<=10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients.. Ulcerative ColitisXELJANZ has been studied in patients with moderately to severely active UC in randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV) [see Clinical Studies (14.4)].Adverse reactions reported in >=5% of patients treated with either mg or 10 mg twice daily of XELJANZ and >=1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.. Induction Trials (Study UC-I, UC-II, and UC-V):Common adverse reactions reported in >=2% of patients treated with XELJANZ 10 mg twice daily and >=1% greater than that reported in patients receiving placebo in the induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.. Maintenance Trial (Study UC-III)Common adverse reactions reported in >=4% of patients treated with either dose of XELJANZ and >=1% greater than reported in patients receiving placebo are shown in Table 5.Table 5: Common Adverse Reactionsreported in >=4% of patients treated with either dose of XELJANZ and >=1% greater than reported for placebo. in -UC Patients during the Maintenance Trial (Study UC-III) Preferred TermXELJANZ5 mg Twice DailyXELJANZ10 mg Twice DailyPlaceboN 198(%)N 196(%)N 198(%)Nasopharyngitis10146Elevated cholesterol levelsincludes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased. 591Headache936Upper respiratory tract infection764Increased blood creatine phosphokinase372Rash364Diarrhea253Herpes zoster151Gastroenteritis343Anemia422Nausea143Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC [see Warnings and Precautions (5.1, 5.3)]. During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, cases of solid cancer or lymphoma were observed in XELJANZ-treated patients.In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ mg and 10 mg twice daily [see Warnings and Precautions (5.3)]. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in patient with advanced cancer [see Warnings and Precautions (5.5)].. Polyarticular Course Juvenile Idiopathic ArthritisXELJANZ/XELJANZ Oral Solution mg twice daily or weight-based equivalent twice daily was studied in 225 patients from years to 17 years of age in Study pcJIA-I [see Clinical Studies (14.5)] and one open-label extension study. The total patient exposure (defined as patients who received at least one dose of XELJANZ/XELJANZ Oral Solution) was 351 patient-years.In general, the types of adverse drug reactions in patients with pcJIA were consistent with those seen in adult RA patients [see Adverse Reactions (6.1)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. XELJANZ/XELJANZ XR (tofacitinib) tablets and XELJANZ (tofacitinib) Oral Solution are formulated with the citrate salt of tofacitinib, JAK inhibitor.Tofacitinib citrate is white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ss-oxo-1-piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1).The solubility of tofacitinib citrate in water is 2.9 mg/mL.Tofacitinib citrate has molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and molecular formula of C16H20N6OC6H8O7. The chemical structure of tofacitinib citrate is:XELJANZ is supplied for oral administration as 5 mg white round, immediate-release film-coated tablet. Each tablet of XELJANZ contains mg tofacitinib (equivalent to 8.08 mg tofacitinib citrate) and the following inactive ingredients: croscarmellose sodium, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.XELJANZ is supplied for oral administration as 10 mg blue round, immediate-release film-coated tablet. Each 10 mg tablet of XELJANZ contains 10 mg tofacitinib (equivalent to 16.16 mg of tofacitinib citrate) and the following inactive ingredients: croscarmellose sodium, FD&C Blue 1/Brilliant Blue FCF Aluminum Lake, FD&C Blue 2/Indigo Carmine Aluminum Lake, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.XELJANZ XR is supplied for oral administration as 11 mg pink, oval, extended-release film-coated tablet with drilled hole at one end of the tablet band. Each 11 mg tablet of XELJANZ XR contains 11 mg tofacitinib (equivalent to 17.77 mg tofacitinib citrate) and the following inactive ingredients: cellulose acetate, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide and triacetin. Printing ink contains, ammonium hydroxide, ferrosoferric oxide/black iron oxide, propylene glycol, and shellac glaze.XELJANZ XR is supplied for oral administration as 22 mg beige, oval, extended-release film-coated tablet with drilled hole at one end of the tablet band. Each 22 mg tablet of XELJANZ XR contains 22 mg tofacitinib (equivalent to 35.54 mg tofacitinib citrate) and the following inactive ingredients: cellulose acetate, copovidone, FD&C Blue Aluminum Lake, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red iron oxide, sorbitol, titanium dioxide, triacetin, and yellow iron oxide. Printing ink contains ammonium hydroxide, ferrosoferric oxide/black iron oxide, propylene glycol, and shellac glaze.XELJANZ Oral Solution is supplied for oral administration as 1 mg/mL clear, colorless solution. Each mL of XELJANZ Oral Solution contains mg of tofacitinib (equivalent to 1.62 mg tofacitinib citrate) and the following inactive ingredients: grape flavor (natural), hydrochloric acid, lactic acid, purified water, sodium benzoate, sucralose, and xylitol.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administration Instructions XELJANZ XR (tofacitinib extended-release tablets) is not interchangeable or substitutable with XELJANZ Oral Solution. (2.1)Changes between XELJANZ and XELJANZ XR should be made by the healthcare provider. (2.1)Do not initiate XELJANZ/XELJANZ XR/XELJANZ Oral Solution if absolute lymphocyte count <500 cells/mm3, an absolute neutrophil count (ANC) <1000 cells/mm3 or hemoglobin <9 g/dL. (2.1)Recommended DosageRheumatoid ArthritisXELJANZ mg twice daily or XELJANZ XR 11 mg once daily. (2.2)Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is XELJANZ mg once daily. (2, 8.7, 8.8)Psoriatic Arthritis (in combination with nonbiologic DMARDs)XELJANZ mg twice daily or XELJANZ XR 11 mg once daily. (2.2)Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is XELJANZ mg once daily. (2, 8.7, 8.8)Ankylosing SpondylitisXELJANZ mg twice daily or XELJANZ XR 11 mg once daily. (2.2)Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is XELJANZ mg once daily. (2, 8.7, 8.8)Ulcerative ColitisInduction: XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily for weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily for maximum of 16 weeks. Discontinue XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. (2.3)Maintenance: XELJANZ mg twice daily or XELJANZ XR 11 mg once daily. For patients with loss of response during maintenance treatment, XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response. (2.3)Dosage adjustment is needed in patients with moderate and severe renal impairment or moderate hepatic impairment: see full prescribing information. (2.3)Polyarticular Course Juvenile Idiopathic ArthritisXELJANZ/XELJANZ Oral Solution mg twice daily or weight-based equivalent twice daily. (2.4)Dosage adjustment is needed in patients with moderate and severe renal impairment or moderate hepatic impairment: see full prescribing information. (2.4)Dosage AdjustmentSee the full prescribing information for dosage adjustments by indication for patients receiving CYP2C19 and/or CYP3A4 inhibitors; in patients with moderate or severe renal impairment or moderate hepatic impairment; and patients with lymphopenia, neutropenia, or anemia. (2.2, 2.3, 2.4, 8.7, 8.8)Use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with severe hepatic impairment is not recommended in any patient population. (2.2, 2.3, 2.4, 8.8). XELJANZ XR (tofacitinib extended-release tablets) is not interchangeable or substitutable with XELJANZ Oral Solution. (2.1). Changes between XELJANZ and XELJANZ XR should be made by the healthcare provider. (2.1). Do not initiate XELJANZ/XELJANZ XR/XELJANZ Oral Solution if absolute lymphocyte count <500 cells/mm3, an absolute neutrophil count (ANC) <1000 cells/mm3 or hemoglobin <9 g/dL. (2.1). XELJANZ mg twice daily or XELJANZ XR 11 mg once daily. (2.2). Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is XELJANZ mg once daily. (2, 8.7, 8.8). XELJANZ mg twice daily or XELJANZ XR 11 mg once daily. (2.2). Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is XELJANZ mg once daily. (2, 8.7, 8.8). XELJANZ mg twice daily or XELJANZ XR 11 mg once daily. (2.2). Recommended dosage in patients with moderate and severe renal impairment or moderate hepatic impairment is XELJANZ mg once daily. (2, 8.7, 8.8). Induction: XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily for weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily for maximum of 16 weeks. Discontinue XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. (2.3). Maintenance: XELJANZ mg twice daily or XELJANZ XR 11 mg once daily. For patients with loss of response during maintenance treatment, XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response. (2.3). Dosage adjustment is needed in patients with moderate and severe renal impairment or moderate hepatic impairment: see full prescribing information. (2.3). XELJANZ/XELJANZ Oral Solution mg twice daily or weight-based equivalent twice daily. (2.4). Dosage adjustment is needed in patients with moderate and severe renal impairment or moderate hepatic impairment: see full prescribing information. (2.4). See the full prescribing information for dosage adjustments by indication for patients receiving CYP2C19 and/or CYP3A4 inhibitors; in patients with moderate or severe renal impairment or moderate hepatic impairment; and patients with lymphopenia, neutropenia, or anemia. (2.2, 2.3, 2.4, 8.7, 8.8). Use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with severe hepatic impairment is not recommended in any patient population. (2.2, 2.3, 2.4, 8.8). 2.1 Important Administration Instructions. XELJANZ XR (tofacitinib extended-release tablets) is not interchangeable or substitutable with XELJANZ Oral Solution.Changes between XELJANZ and XELJANZ XR should be made by the healthcare provider [see Dosage and Administration (2.2)].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 g/dL.Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions (5.8), Adverse Reactions (6.1)].Interrupt use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution if patient develops serious infection until the infection is controlled [see Warnings and Precautions (5.1)].Take XELJANZ/XELJANZ XR/XELJANZ Oral Solution with or without food [see Clinical Pharmacology (12.3)].Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.. XELJANZ XR (tofacitinib extended-release tablets) is not interchangeable or substitutable with XELJANZ Oral Solution.. Changes between XELJANZ and XELJANZ XR should be made by the healthcare provider [see Dosage and Administration (2.2)].. 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 g/dL.. Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions (5.8), Adverse Reactions (6.1)].. Interrupt use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution if patient develops serious infection until the infection is controlled [see Warnings and Precautions (5.1)].. Take XELJANZ/XELJANZ XR/XELJANZ Oral Solution with or without food [see Clinical Pharmacology (12.3)].. Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.. 2.2 Recommended Dosage in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis. Table 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. Table 1: Recommended Dosage of XELJANZ and XELJANZ XR in Patients with Rheumatoid Arthritis, Psoriatic ArthritisXELJANZ/XELJANZ XR is used in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis. The efficacy of XELJANZ/XELJANZ XR as monotherapy has not been studied in psoriatic arthritis., and Ankylosing Spondylitis XELJANZ tabletXELJANZ XR extended-release tabletAdult patients5 mg twice daily11 mg once dailyPatients receiving: Strong CYP3A4 inhibitors (e.g., ketoconazole), ora moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) [see Drug Interactions (7)] mg once dailyReduce to XELJANZ mg once dailyPatients with: moderate or severe renal impairment [see Use in Specific Populations (8.7)] moderate hepatic impairment [see Use in Specific Populations (8.8)]Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. mg once dailyReduce to XELJANZ mg once dailyFor patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If 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 testingDiscontinue dosing.Patients with ANC 500 to 1000 cells/mm3 Interrupt dosing.When ANC is greater than 1000, resume mg twice daily.Interrupt dosing.When ANC is greater than 1000, resume 11 mg once daily.Patients with ANC less than 500 cells/mm3 Discontinue dosing.Patients with hemoglobin less than g/dL or decrease of more than g/dLInterrupt dosing until hemoglobin values have normalized.. Strong CYP3A4 inhibitors (e.g., ketoconazole), or. moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole). moderate or severe renal impairment [see Use in Specific Populations (8.7)] moderate hepatic impairment [see Use in Specific Populations (8.8)]Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release TabletsPatients treated with XELJANZ tablets mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ mg.. 2.3 Recommended Dosage in Ulcerative Colitis. Table 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. Table 2: Recommended Dosage of XELJANZ/XELJANZ XR in Patients with UCXELJANZ tabletXELJANZ XR extended-release tabletAdult patients Induction: 10 mg twice daily for at least 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 maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved.Maintenance: mg twice daily. For patients with loss of response during maintenance treatment, dosage of 10 mg twice daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response. Induction: 22 mg once daily for at least weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 22 mg once daily for maximum of 16 weeks. Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 11 mg once daily. For patients with loss of response during maintenance treatment, dosage of 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response.Patients receiving: Strong CYP3A4 inhibitors (e.g., ketoconazole), or moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) [see Drug Interactions (7)] If taking 10 mg twice daily, reduce to mg twice daily. If taking mg twice daily, reduce to mg once daily.If taking 22 mg once daily, reduce to 11 mg once daily. If taking 11 mg once daily, reduce to XELJANZ mg once dailyPatients with: moderate or severe renal impairment [see Use in Specific Populations (8.7)] moderate hepatic impairment [see Use in Specific Populations (8.8)]Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. If taking 10 mg twice daily, reduce to mg twice daily. If taking mg twice daily, reduce to mg once daily.If taking 22 mg once daily, reduce to 11 mg once daily. If taking 11 mg once daily, reduce to XELJANZ mg once daily.For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If 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 testingDiscontinue dosing.Patients with ANC 500 to 1000 cells/mm3 If taking 10 mg twice daily, reduce to mg twice daily. When ANC is greater than 1000, increase to 10 mg twice daily based on clinical response.If taking mg twice daily, interrupt dosing. When ANC is greater than 1000, resume mg twice daily.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.If taking 11 mg once daily, interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily.Patients with ANC less than 500 cells/mm3 Discontinue dosing.Patients with hemoglobin less than g/dL or decrease of more than g/dLInterrupt dosing until hemoglobin values have normalized.. Strong CYP3A4 inhibitors (e.g., ketoconazole), or a moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) moderate or severe renal impairment [see Use in Specific Populations (8.7)] moderate hepatic impairment [see Use in Specific Populations (8.8)]Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release TabletsPatients treated with XELJANZ 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 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.. 2.4 Recommended Dosage in Polyarticular Course Juvenile Idiopathic Arthritis. Table 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.Table 3: Recommended Dosage of XELJANZ/XELJANZ Oral Solution in Patients with pcJIAXELJANZ tablets/XELJANZ Oral SolutionpcJIA patients10 kg <= body weight <20 kg:3.2 mg (3.2 mL oral solution) twice daily20 kg <= body weight <40 kg:4 mg (4 mL oral solution) twice dailyBody weight >=40 kg:5 mg (one mg tablet or mL oral solutionPatients treated with mL XELJANZ Oral Solution may be switched to XELJANZ mg tablet.) twice dailyPatients receiving: strong CYP3A4 inhibitors (e.g., ketoconazole), or moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) [see Drug Interactions (7)] If taking 3.2 mg twice daily, reduce to 3.2 mg once daily.If taking mg twice daily, reduce to mg once daily.If taking mg twice daily, reduce to mg once daily.Patients with: moderate or severe renal impairment [see Use in Specific Populations (8.7)] moderate hepatic impairment [see Use in Specific Populations (8.8)] XELJANZ/XELJANZ Oral Solution is not recommended for patients with severe hepatic impairment. If taking 3.2 mg twice daily, reduce to 3.2 mg once daily.If taking mg twice daily, reduce to mg once daily.If taking mg twice daily, reduce to mg once daily.For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If 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 testingDiscontinue 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 g/dL or decrease of more than g/dLInterrupt 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].. 10 kg <= body weight <20 kg:3.2 mg (3.2 mL oral solution) twice daily. 20 kg <= body weight <40 kg:4 mg (4 mL oral solution) twice daily. Body weight >=40 kg:5 mg (one mg tablet or mL oral solutionPatients treated with mL XELJANZ Oral Solution may be switched to XELJANZ mg tablet.) twice daily. strong CYP3A4 inhibitors (e.g., ketoconazole), or a moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole). moderate or severe renal impairment [see Use in Specific Populations (8.7)] moderate hepatic impairment [see Use in Specific Populations (8.8)] XELJANZ/XELJANZ Oral Solution is not recommended for patients with severe hepatic impairment.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. XELJANZ Tablets: mg, 10 mg tofacitinib (3) XELJANZ XR Tablets: 11 mg, 22 mg tofacitinib (3) XELJANZ Oral Solution: mg/mL tofacitinib (3). XELJANZ Tablets: mg, 10 mg tofacitinib (3). XELJANZ XR Tablets: 11 mg, 22 mg tofacitinib (3). XELJANZ Oral Solution: mg/mL tofacitinib (3). XELJANZ Tablets:5 mg tofacitinib: White, round, immediate-release film-coated tablets, debossed with Pfizer on one side, and JKI 5 on the other side.10 mg tofacitinib: Blue, round, immediate-release film-coated tablets, debossed with Pfizer on one side, and JKI 10 on the other side.. mg tofacitinib: White, round, immediate-release film-coated tablets, debossed with Pfizer on one side, and JKI 5 on the other side.. 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:11 mg tofacitinib: Pink, oval, extended-release film-coated tablets with drilled hole at one end of the tablet band and JKI 11 printed on one side of the tablet.22 mg tofacitinib: Beige, oval, extended-release film-coated tablets with drilled hole at one end of the tablet band and JKI 22 printed on one side of the tablet.. 11 mg tofacitinib: Pink, oval, extended-release film-coated tablets with drilled hole at one end of the tablet band and JKI 11 printed on one side of the tablet.. 22 mg tofacitinib: Beige, oval, extended-release film-coated tablets with 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ/XELJANZ XR/XELJANZ Oral Solution and instructions for preventing or managing them.Table 6: Clinically Relevant Interactions Affecting XELJANZ/XELJANZ XR/XELJANZ Oral Solution When Coadministered with Other DrugsStrong CP3A4 Inhibitors (e.g., ketoconazole)Clinical ImpactIncreased exposure to tofacitinibInterventionDosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended [see Dosage and Administration (2), Clinical Pharmacology, Figure (12.3)] Moderate CYP3A4 Inhibitors Coadministered with Strong CYP2C19 Inhibitors (e.g., fluconazole)Clinical ImpactIncreased exposure to tofacitinibInterventionDosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is recommended [see Dosage and Administration (2), Clinical Pharmacology, Figure (12.3)] Strong CYP3A4 Inducers (e.g., rifampin)Clinical ImpactDecreased exposure to tofacitinib and may result in loss of or reduced clinical responseInterventionCoadministration with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended [see Clinical Pharmacology, Figure (12.3)] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine)Clinical ImpactRisk of added immunosuppression; coadministration with biologic DMARDs or potent immunosuppressants has not been studied in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, UC, or pcJIA.InterventionCoadministration with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended [see Indications and Usage (1), Clinical Pharmacology, Figure (12.3)] See full prescribing information for clinically relevant drug interactions. (2, 7).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Contraception. FemalesIn an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 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. FemalesBased 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)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 3315 patients who enrolled in rheumatoid arthritis Studies to V, 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, 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 higher incidence of infections in the elderly population in general, caution should be used when treating the elderly [see Warnings and Precautions (5.1)].

HEPATIC IMPAIRMENT SUBSECTION.

8.8 Hepatic Impairment. Severe ImpairmentXELJANZ/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 ImpairmentXELJANZ-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 ImpairmentNo dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is required in patients with mild hepatic impairment.. Hepatitis or SerologyThe safety and efficacy of XELJANZ/XELJANZ XR/XELJANZ Oral Solution have not been studied in patients with positive hepatitis virus or hepatitis virus serology.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How supplied information for XELJANZ/XELJANZ XR is shown in Table 22.Table 22: How Supplied Information for XELJANZ/XELJANZ XRBottle Size(number of tablets)NDC NumberXELJANZ5 mg tofacitinib tabletsWhite, round, immediate-release film-coated tablets, debossed with Pfizer on one side, and JKI 5 on the other side60NDC 0069-1001-01XELJANZ10 mg tofacitinib tabletsBlue, round, immediate-release film-coated tablets, debossed with Pfizer on one side, and JKI 10 on the other side60NDC 0069-1002-01XELJANZ XR11 mg tofacitinib tabletsPink, oval, extended-release film-coated tablets with drilled hole at one end of the tablet band and JKI 11 printed on one side of the tablet30NDC 0069-0501-30XELJANZ XR22 mg tofacitinib tabletsBeige, oval, extended-release film-coated tablets with drilled hole at one end of the tablet band and JKI 22 printed on one side of the tablet30NDC 0069-0502-30How supplied information for XELJANZ Oral Solution is shown in Table 23.Table 23: How Supplied Information for XELJANZ Oral SolutionBottle Fill(volume mL)NDC NumberXELJANZ Oral Solution1 mg/mL tofacitinib oral solutionClear, colorless solution240 mLNDC 0069-1029-02. XELJANZ/XELJANZ XRStore XELJANZ/XELJANZ XR at 20C to 25C (68F to 77F). [See USP Controlled Room Temperature].Do not repackage.. XELJANZ Oral SolutionXELJANZ mg/ mL oral solution is clear, colorless solution that contains mg of tofacitinib. It is packaged in HDPE bottles as follows:Each bottle is packaged with one press-in bottle adapter and one mL oral dosing syringe with 3.2 mL, mL, and mL gradations. The press-in bottle adapter and oral dosing syringe are not made with natural rubber latex.Store at 20C to 25C (68F to 77F), excursions permitted between 15C and 30C (between 59F and 86F). [See USP Controlled Room Temperature].Store in the original bottle and carton to protect from light.Use contents of bottle within 60 days of opening.Discard remaining oral solution after 60 days.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. XELJANZ/XELJANZ XR/XELJANZ Oral Solution is Janus kinase (JAK) inhibitor indicated for:Rheumatoid Arthritis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis 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. (1.1)Psoriatic Arthritis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis 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. (1.2)Ankylosing Spondylitis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active ankylosing spondylitis 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. (1.3)Ulcerative Colitis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), 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 biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.4)Polyarticular Course Juvenile Idiopathic Arthritis: XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.5). Rheumatoid Arthritis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis 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. (1.1). Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.1). Psoriatic Arthritis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis 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. (1.2). Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.2). Ankylosing Spondylitis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active ankylosing spondylitis 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. (1.3). Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.3). Ulcerative Colitis: XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), 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 biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.4). 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. (1.4). Polyarticular Course Juvenile Idiopathic Arthritis: XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.5). Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. (1.5). 1.1 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.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. 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. 1.2 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.. 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.. 1.3 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.. Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.. 1.4 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. 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.. 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.. 1.5 Polyarticular Course Juvenile Idiopathic Arthritis. XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.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.. 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).. Serious InfectionsInform patients that XELJANZ/XELJANZ XR/XELJANZ Oral Solution may lower the ability of their immune system to fight infections. Advise patients not to start taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order to ensure rapid evaluation and appropriate treatment [see Warnings and Precautions (5.1)].Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with XELJANZ/XELJANZ XR [see Warnings and Precautions (5.1)].. Malignancies and Lymphoproliferative DisordersInform patients that XELJANZ/XELJANZ XR/XELJANZ Oral Solution may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking XELJANZ. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions (5.3)].. Major Adverse Cardiovascular Events Inform patients that XELJANZ/XELJANZ XR/XELJANZ Oral Solution may increase their risk of major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.4)].. ThrombosisAdvise patients to stop taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution and to call their healthcare provider right away if they experience any symptoms of thrombosis (sudden shortness of breath, chest pain worsened with breathing, swelling of leg or arm, leg pain or tenderness, red or discolored skin in the affected leg or arm) [see Warnings and Precautions (5.5)].. HypersensitivityAdvise patients to stop taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution and to call their healthcare provider right away if they experience any symptoms of allergic reactions while taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution [see Warnings and Precautions (5.7)].. Important Information on Laboratory AbnormalitiesInform patients that XELJANZ/XELJANZ XR/XELJANZ Oral Solution may affect certain lab test results, and that blood tests are required before and during XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment [see Warnings and Precautions (5.8)].. PregnancyAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their prescriber of known or suspected pregnancy. Inform patients that Pfizer has registry for pregnant women who have taken XELJANZ/XELJANZ XR/XELJANZ Oral Solution during pregnancy. Advise patients to contact the registry at 1-877-311-8972 to enroll [see Use in Specific Populations (8.1)] . LactationAdvise women not to breastfeed during treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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 [see Use in Specific Populations (8.2)]. InfertilityAdvise females of reproductive potential that XELJANZ/XELJANZ XR/XELJANZ Oral Solution may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. It is not known if this effect is reversible.. Residual Tablet ShellPatients receiving XELJANZ XR may notice an inert tablet shell passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert tablet shell.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE. XELJANZ(R) (ZEL JANS)(tofacitinib)Oral SolutionRead this Instructions for Use before you start taking XELJANZ Oral Solution and each time you get refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.Important information about measuring XELJANZ Oral Solution:Always use the oral dosing syringe that comes with XELJANZ Oral Solution to measure and take your prescribed dose. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose if you are not sure.How should store XELJANZStore XELJANZ Oral Solution at room temperature between 68F to 77F (20C to 25C).Always store XELJANZ Oral Solution in the original bottle and carton to protect from light.Keep XELJANZ and all medicines out of the reach of children.Use XELJANZ Oral Solution within 60 days of opening the bottle. Throw away (discard) remaining XELJANZ Oral Solution after 60 days.To help you remember when to throw away your bottle of XELJANZ Oral Solution, you can write the date when you first start to use it on the carton and below:Date of first use / .Before each use:Wash your hands with soap and water and place the texts from the carton on clean, flat surface.Each carton of XELJANZ Oral Solution contains:1 press-in bottle adapter1 bottle of XELJANZ Oral Solution1 oral dosing syringeStep 1. Remove bottle from cartonOpen the carton and remove the bottle of XELJANZ Oral Solution.Step 2. Open bottleOpen the bottle by pushing down on the child-resistant cap and turning it to the left (counter-clockwise) as shown. Remove the seal off the top of the bottle (first time only).Do not throw away the child-resistant cap.Note: The bottle does not need to be shaken before use.Step 3. Insert press-in bottle adapter (first time only)Remove the press-in bottle adapter and oral dosing syringe from the plastic overwrap. With the bottle on flat surface, push the ribbed end of the press-in bottle adapter all the way into the neck of the bottle with your thumbs while holding the bottle firmly.Note: Do not remove the press-in bottle adapter from the bottle after it is inserted.Step 4. Remove air from oral dosing syringePush the oral dosing syringe plunger all the way down to the tip of the syringe barrel to remove excess air.Step 5. Insert the oral dosing syringeInsert the oral dosing syringe tip into the upright bottle through the opening of the press-in bottle adapter until it is firmly in place.Step 6. Withdraw dose from bottleWith the oral dosing syringe in place, turn the bottle upside down. Pull down on the plunger until the bottom of the plunger is even with the markings on the oral dosing syringe for your prescribed dose of oral solution.If you see air bubbles in the oral dosing syringe, fully push the plunger in so that the oral solution flows back into the bottle. Then withdraw your prescribed dose of oral solution.Step 7. Remove oral dosing syringeTurn the bottle upright and place the bottle on flat surface. Remove the oral dosing syringe from the press-in bottle adapter and bottle by pulling straight up on the oral dosing syringe barrel.Step 8. Check the doseCheck that the correct dose was drawn up into the oral dosing syringe.If the dose is not correct, insert the oral dosing syringe tip firmly into the press-in bottle adapter. Fully push in the plunger so that the oral solution flows back into the bottle. Repeat Step and Step 7.Step 9. Take the dose of XELJANZPlace the tip of the oral dosing syringe into the inside of the cheek.Slowly push the plunger all the way down to give all of the medicine in the oral dosing syringe. Make sure there is time to swallow the medicine.Step 10. Close the bottleClose the bottle tightly by turning the child-resistant cap to the right (clockwise), leaving the press-in bottle adapter in place.Place the bottle back into the carton.Close the carton to protect XELJANZ Oral Solution from light.Step 11. Clean oral dosing syringeRemove the plunger from the barrel by pulling the plunger and the barrel away from each other.Rinse both with water after each use.Allow to air dry. When the barrel and plunger are dry, put the oral dosing syringe back together by inserting the plunger into the barrel.Store the oral dosing syringe with the XELJANZ Oral Solution.Do not throw away the oral dosing syringe.LAB-1422-1.0This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: September 2020. Store XELJANZ Oral Solution at room temperature between 68F to 77F (20C to 25C).. Always store XELJANZ Oral Solution in the original bottle and carton to protect from light.. press-in bottle adapter. bottle of XELJANZ Oral Solution. oral dosing syringe. Image. Step 1. Step 2. Step 3. Step 4. Step 5. Step 6. Step 7. Step 8. Step 9. Step 10. Step 11. Logo.

LACTATION SECTION.

8.2 Lactation. Risk Summary There are no data on the presence of tofacitinib in human milk, the effects on breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When drug is present in animal milk, it is likely that the drug will be present in human milk. 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 elimination half-lives).. DataFollowing administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately times higher in milk relative to maternal serum at all time points measured.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tofacitinib is Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately times the recommended dose of mg twice daily, and approximately times the 10 mg twice daily dose (on an AUC basis at oral doses of mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels times the recommended dose of mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of mg/kg twice daily).The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the recommended dose of mg twice daily, and approximately 17 times the 10 mg twice daily dose (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the recommended dose of mg twice daily, and approximately 21 times the 10 mg twice daily dose on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.In rats, tofacitinib at exposure levels approximately 17 times the recommended dose of mg twice daily, and approximately 8.3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the recommended dose of mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of mg/kg/day). Tofacitinib exposure levels at approximately 133 times the recommended dose of mg twice daily, and approximately 67 times the 10 mg twice daily dose (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no specific antidote for overdose with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.In study in subjects with end stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus limits the value of hemodialysis for treatment of overdose with XELJANZ/XELJANZ XR/XELJANZ Oral Solution.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 5 mg Tablet Bottle Label. ALWAYS DISPENSE WITHMEDICATION GUIDEPfizerNDC 0069-1001-01Xeljanz(R)(tofacitinib) tablets5 mg60 Tablets Rx only PRINCIPAL DISPLAY PANEL 5 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of XELJANZ/XELJANZ Oral Solution for the treatment of active pcJIA have been established in patients 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 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 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 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within weeks after discontinuation, indicating longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.Similar changes in cells, cells, and serum CRP have been observed in patients with active psoriatic arthritis although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active psoriatic arthritis.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. XELJANZ/XELJANZ Oral SolutionFollowing oral administration of XELJANZ/XELJANZ Oral Solution, peak plasma concentrations are reached within 0.5-1 hour, elimination half-life is about hours and dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.. XELJANZ XRFollowing oral administration of XELJANZ XR, peak plasma concentrations are reached at hours and half-life is about to hours. Steady state concentrations are achieved within 48 hours with negligible accumulation after once daily administration.Table 7: Pharmacokinetic Parameters of XELJANZ/ XELJANZ XR Following Multiple Oral DosingPK ParametersValues represent the geometric mean, except max, for which is the median (range) is shown. (CV%)XELJANZXELJANZ XRDosing Regimen5 mgTwice Daily10 mgTwice Daily11 mgOnce Daily22 mgOnce DailyAbbreviations: AUC24 area under the concentration-time profile from time to 24 hours; Cmax maximum plasma concentration; Cmin minimum plasma concentration; Tmax time to Cmax; CV Coefficient of variation.AUC24 (ng.hr/mL)263.4 (15)539.6 (22)269.0 (18)596.6 (19)Cmax (ng/mL)42.7 (26)84.7 (18)38.2 (15)83.8 (25)Cmin (ng/mL)1.41 (40)3.10 (54)1.07 (69)3.11 (43)Tmax (hours)1.0(0.5 to14.0Values beyond 12 hours were after the evening dose which was administered 12 hours after the morning dose of twice-daily XELJANZ)0.8(0.5 to 14.0)4.0(3.0 to 4.0)4.0(2.0 to 4.0). Absorption. XELJANZThe absolute oral bioavailability of XELJANZ is 74%. Coadministration of XELJANZ with high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals [see Dosage and Administration (2.1)].. XELJANZ XRCoadministration of XELJANZ XR 11 and 22 mg with high-fat meal resulted in no changes in AUC while Cmax was increased by 27% and 19% respectively. Tmax was extended by approximately hour for both XELJANZ XR 11 and 22 mg.. DistributionAfter intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to 1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.. Metabolism and ExcretionClearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.. Pharmacokinetics in Patient PopulationsPopulation pharmacokinetic analyses indicated that pharmacokinetic characteristics were similar between patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and UC. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 8).Table 8: XELJANZ Exposure in Patient Populations at mg Twice Daily and 10 mg Twice Daily DosesPharmacokinetic ParametersPharmacokinetic parameters estimated based on population pharmacokinetic analysis. Geometric Mean (CV%)XELJANZ mg Twice DailyXELJANZ 10 mg Twice DailyRheumatoid ArthritisPsoriatic ArthritisAnkylosing SpondylitisUlcerative ColitisUlcerative ColitisAbbreviations: AUC0-24,ss=area under the plasma concentration-time curve over 24 hours at steady state; CV=coefficient of variation.AUC0-24,ss (ngh/mL)504(22.0%)419(34.1%)381 (25.4%)423(22.6%)807(24.6%). Specific PopulationsCovariate evaluation as part of population PK analyses in adult patient populations indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant.Covariate evaluation as part of population PK analyses in pcJIA patients identified body weight significantly impacting tofacitinib exposure, which supports weight-based dosing in this population. No additional dose adjustment is needed based on age, gender, race, or disease severity in pcJIA patients.The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.Figure 1: Impact of Intrinsic Factors on Tofacitinib PharmacokineticsNote: Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function. Refer to Dosage and Administration (2.2, 2.3, 2.4) for dosage adjustment in RA, PsA, AS, UC, and pcJIA patients.In subjects with ESRD maintained on hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib. Dose adjustment is recommended in RA, PsA, AS, UC, and pcJIA patients with ESRD maintained on hemodialysis [see Dosage and Administration (2.2, 2.3, 2.4)].. Figure 1. Drug Interaction Studies. Potential for XELJANZ/XELJANZ XR/XELJANZ Oral Solution 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 corresponding to the steady state Cmax of 10 mg twice daily dose. These in vitro results were confirmed by human drug interaction study showing no changes in the pharmacokinetics of midazolam, highly sensitive CYP3A4 substrate, when coadministered with XELJANZ. 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 Cmax of 10 mg twice daily dose.In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.Dosing recommendations for coadministered drugs following administration with XELJANZ/XELJANZ XR/XELJANZ Oral Solution are shown in Figure 2.Figure 2: Impact of Tofacitinib on the Pharmacokinetics of Other DrugsNote: Reference group is administration of concomitant medication alone; OCT Organic Cationic Transporter; MATE Multidrug and Toxic Compound Extrusion.. Figure 2. Potential for Other Drugs to Influence the Pharmacokinetics of TofacitinibSince tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the pharmacokinetics of tofacitinib (see Figure 3).Figure 3: Impact of Other Drugs on the Pharmacokinetics of TofacitinibNote: Reference group is administration of tofacitinib alone. [see Dosage and Administration (2.2, 2.3, 2.4), Drug Interactions (7)]. Figure 3.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of XELJANZ/XELJANZ XR. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed).

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/XELJANZ XR/XELJANZ Oral Solution during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR/XELJANZ Oral Solution pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.. Risk SummaryAvailable data with XELJANZ/XELJANZ XR/XELJANZ Oral Solution use in pregnant women are insufficient to establish drug associated risk of major birth defects, miscarriage or 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 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 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have 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 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.. Clinical Considerations. Disease-Associated Maternal and/or Embryo/Fetal RiskPublished 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 DataIn 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 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 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 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 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 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 times the recommended dose of 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 peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 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 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 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).

RECENT MAJOR CHANGES SECTION.

Boxed Warning12/2021Indications and Usage (1)12/2021Dosage and Administration (2.2)12/2021Warnings and Precautions (5.2)12/2021Warnings and Precautions (5.3)12/2021Warnings and Precautions (5.4)12/2021Warnings and Precautions (5.5)12/2021.

RENAL IMPAIRMENT SUBSECTION.

8.7 Renal Impairment. Moderate and Severe ImpairmentXELJANZ-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 impairmentNo dosage adjustment is required in patients with mild renal impairment.

SPL UNCLASSIFIED SECTION.

SERIOUS INFECTIONSPatients 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 serious infection develops, interrupt XELJANZ/XELJANZ XR/XELJANZ Oral Solution until the infection is controlled.Reported infections include: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. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.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)].. 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. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.. Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

STORAGE AND HANDLING SECTION.

XELJANZ/XELJANZ XRStore XELJANZ/XELJANZ XR at 20C to 25C (68F to 77F). [See USP Controlled Room Temperature].Do not repackage.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. All information provided in this section is applicable to XELJANZ/XELJANZ XR/XELJANZ Oral Solution as they contain the same active ingredient (tofacitinib).. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/XELJANZ XR/XELJANZ Oral Solution during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR/XELJANZ Oral Solution pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.. Risk SummaryAvailable data with XELJANZ/XELJANZ XR/XELJANZ Oral Solution use in pregnant women are insufficient to establish drug associated risk of major birth defects, miscarriage or 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 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 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have 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 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.. Clinical Considerations. Disease-Associated Maternal and/or Embryo/Fetal RiskPublished 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 DataIn 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 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 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 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 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 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 times the recommended dose of 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 peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 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 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 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).. 8.2 Lactation. Risk Summary There are no data on the presence of tofacitinib in human milk, the effects on breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When drug is present in animal milk, it is likely that the drug will be present in human milk. 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 elimination half-lives).. DataFollowing administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately times higher in milk relative to maternal serum at all time points measured.. 8.3 Females and Males of Reproductive Potential. Contraception. FemalesIn an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 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. FemalesBased 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)].. 8.4 Pediatric Use. The safety and effectiveness of XELJANZ/XELJANZ Oral Solution for the treatment of active pcJIA have been established in patients 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 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 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 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.. 8.5 Geriatric Use. Of the 3315 patients who enrolled in rheumatoid arthritis Studies to V, 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, 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 higher incidence of infections in the elderly population in general, caution should be used when treating the elderly [see Warnings and Precautions (5.1)].. 8.6 Use in Diabetics. As there is higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.. 8.7 Renal Impairment. Moderate and Severe ImpairmentXELJANZ-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 impairmentNo dosage adjustment is required in patients with mild renal impairment.. 8.8 Hepatic Impairment. Severe ImpairmentXELJANZ/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 ImpairmentXELJANZ-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 ImpairmentNo dosage adjustment of XELJANZ/XELJANZ XR/XELJANZ Oral Solution is required in patients with mild hepatic impairment.. Hepatitis or SerologyThe safety and efficacy of XELJANZ/XELJANZ XR/XELJANZ Oral Solution have not been studied in patients with positive hepatitis virus or hepatitis virus serology.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serious Infections: Avoid use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution during an active serious infection, including localized infections. (5.1)Gastrointestinal Perforations: Use with caution in patients that may be at increased risk. (5.6)Laboratory Monitoring: Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. (5.8)Immunizations: Live vaccines: Avoid use with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. (5.9). Serious Infections: Avoid use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution during an active serious infection, including localized infections. (5.1). Gastrointestinal Perforations: Use with caution in patients that may be at increased risk. (5.6). Laboratory Monitoring: Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. (5.8). Immunizations: Live vaccines: Avoid use with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. (5.9). 5.1 Serious Infections. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.In the UC population, XELJANZ treatment with 10 mg twice daily was associated with greater risk of serious infections compared to mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients: with chronic or recurrent infection who have been exposed to tuberculosis with history of serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to 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. XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be interrupted if patient develops serious infection, an opportunistic infection, or sepsis. patient who develops new infection during treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.Caution is also recommended in patients with history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and Administration (2.2, 2.3, 2.4)] . with chronic or recurrent infection. who have been exposed to tuberculosis. with history of serious or an opportunistic infection. who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or. with underlying conditions that may predispose them to infection.. Tuberculosis Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR/XELJANZ Oral Solution. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR/XELJANZ Oral Solution.. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ/XELJANZ Oral Solution. Postmarketing cases of hepatitis reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR/XELJANZ Oral Solution on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis or were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR/XELJANZ Oral Solution and appears to be higher in patients treated with XELJANZ in Japan and Korea.. 5.2 Mortality. Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ mg twice day or XELJANZ 10 mg twice day had higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 0.88 for XELJANZ mg twice day, 1.23 for XELJANZ 10 mg twice day, and 0.69 for TNF blockers [see Clinical Studies (14.6)]. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution.A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration (2.2)].For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].. 5.3 Malignancy and Lymphoproliferative Disorders Malignancies, including lymphomas and solid cancers, were observed in clinical studies of XELJANZ [see Adverse Reactions (6.1)]. In RA Safety Study 1, higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ mg twice day or XELJANZ 10 mg twice day as compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for XELJANZ mg twice day, 1.13 for XELJANZ 10 mg twice day, and 0.77 for TNF blockers. Patients who are current or past smokers are at additional increased risk [see Clinical Studies (14.6)]. Lymphomas and lung cancers, which are subset of all malignancies in RA Safety Study 1, were observed at higher rate in patients treated with XELJANZ mg twice day and XELJANZ 10 mg twice day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.07 for XELJANZ mg twice day, 0.11 for XELJANZ 10 mg twice day, and 0.02 for TNF blockers. The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.48 for XELJANZ mg twice day, 0.59 for XELJANZ 10 mg twice day, and 0.27 for TNF blockers [see Clinical Studies (14.6)].Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, particularly in patients with known malignancy (other than successfully treated NMSC), patients who develop malignancy while on treatment, and patients who are current or past smokers. XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in out of 218 patients treated with XELJANZ (2.3%) compared to out of 111 patients treated with cyclosporine.Other malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.. Non-Melanoma Skin CancerNon-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.. 5.4 Major Adverse Cardiovascular Events In RA Safety Study 1, RA patients who were 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ mg twice daily or XELJANZ 10 mg twice daily had higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, compared to those treated with TNF blockers. The incidence rate of MACE per 100 patient-years was 0.91 for XELJANZ mg twice day, 1.11 for XELJANZ 10 mg twice day, and 0.79 for TNF blockers. The incidence rate of fatal or non-fatal myocardial infarction per 100 patient-years was 0.36 for XELJANZ mg twice day, 0.39 for XELJANZ 10 mg twice day, and 0.20 for TNF blockers [see Clinical Studies (14.6)]. Patients who are current or past smokers are at additional increased risk.Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that have experienced myocardial infarction or stroke. XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].. 5.5 Thrombosis. Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death [see Warnings and Precautions (5.2)].Patients with rheumatoid arthritis 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ at both mg or 10 mg twice daily compared to TNF blockers in RA Safety Study had an observed increase in incidence of these events. The incidence rate of DVT per 100 patient-years was 0.22 for XELJANZ mg twice day, 0.28 for XELJANZ 10 mg twice day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.18 for XELJANZ mg twice day, 0.49 for XELJANZ 10 mg twice day, and 0.05 for TNF blockers [see Clinical Studies (14.6)].A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS [see Dosage and Administration (2.2)].In long-term extension study in patients with UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in patient with advanced cancer.Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with symptoms of thrombosis.Avoid XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].. 5.6 Gastrointestinal Perforations. Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids.XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with history of diverticulitis or taking NSAIDs). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)]. 5.7 Hypersensitivity. Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR. Some events were serious. If serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction [see Adverse Reactions (6.2)].. 5.8 Laboratory Abnormalities. Lymphocyte AbnormalitiesTreatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment in patients with low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended.Monitor lymphocyte counts at baseline and every months thereafter. For recommended modifications based on lymphocyte counts [see Dosage and Administration (2.2, 2.3, 2.4)].. NeutropeniaTreatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.Avoid initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment in patients with low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop persistent ANC of 500 to 1000 cells/mm3, interrupt XELJANZ/XELJANZ XR/XELJANZ Oral Solution dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution is not recommended.Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every months thereafter. For recommended modifications based on ANC results [see Dosage and Administration (2.2, 2.3)].. Anemia Avoid initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment in patients with low hemoglobin level (i.e., less than g/dL). Treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be interrupted in patients who develop hemoglobin levels less than g/dL or whose hemoglobin level drops greater than g/dL on treatment.Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every months thereafter. For recommended modifications based on hemoglobin results [see Dosage and Administration (2)].. Liver Enzyme ElevationsTreatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR/XELJANZ Oral Solution should be interrupted until this diagnosis has been excluded.. Lipid ElevationsTreatment with XELJANZ was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution therapy.Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.. 5.9 Vaccinations. Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR/XELJANZ Oral Solution. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and days after treatment start with tofacitinib mg twice daily. The patient was varicella virus naive, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR/XELJANZ Oral Solution therapy.. 5.10 Risk of Gastrointestinal Obstruction with Non-Deformable Extended-Release Formulation such as XELJANZ XR. As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing non-deformable extended-release formulation.