Xeljanz; Xeljanz Xr — Tofacitinib drug label

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS See full prescribing information for complete boxed warning. • Increased risk of serious bacterial, fungal, viral, and opportunistic infections, including tuberculosis (TB), leading to hospitalization or death. Interrupt XELJANZ/XELJANZ XR treatment 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 (CV) 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 major adverse CV events (defined as CV 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 INFECTIONS Patients treated with XELJANZ (tablets and oral solution) or XELJANZ XR (extended-release tablets) are at increased risk for developing serious bacterial, fungal, viral, and opportunistic infections, including tuberculosis (TB), that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Reported infections included: • Active TB, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent TB before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR 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 XELJANZ/XELJANZ XR treatment 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 XELJANZ/XELJANZ XR treatment, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled [see Warnings and Precautions (5.1) ] . MORTALITY In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing XELJANZ tablets 5 mg or 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ tablets 5 mg or 10 mg twice a day [see Warnings and Precautions (5.2) ] . XELJANZ 10 mg twice daily and XELJANZ XR 22 mg once daily dosages are not recommended for the treatment of RA, psoriatic arthritis (PsA), ankylosing spondylitis (AS), or polyarticular course juvenile idiopathic arthritis (pcJIA) [see Dosage and Administration (2.3, 2.4) ] . MALIGNANCIES Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ tablets 5 mg or 10 mg twice a day compared with TNF blockers [see Warnings and Precautions (5.3) ] . Lymphomas and lung cancers were observed at a higher rate in patients treated with XELJANZ tablets 5 mg or 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. MAJOR ADVERSE CARDIOVASCULAR EVENTS RA patients 50 years of age and older with at least one cardiovascular risk factor, treated with XELJANZ tablets 5 mg or 10 mg twice daily, had a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ/XELJANZ XR in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions (5.4) ] . THROMBOSIS Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ/XELJANZ XR in patients at risk. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis [see Warnings and Precautions (5.5) ] .

1 INDICATIONS AND USAGE XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) are Janus kinase (JAK) inhibitors. XELJANZ tablets and XELJANZ XR are 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. • Active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. • Active ankylosing spondylitis (AS), who have had an inadequate response or intolerance to one or more TNF blockers. • Moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers. XELJANZ (tablets and oral solution) are indicated for the treatment of pediatric patients 2 years of age and older with: • Active PsA, who have had an inadequate response or intolerance to one or more TNF blockers. • Active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use : • Use of XELJANZ/XELJANZ XR for RA, AS, PsA, or pcJIA in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.1 , 1.2 , 1.3 , 1.4 ) • Use of XELJANZ tablets and XELJANZ XR for UC in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. ( 1.5 ) 1.1 Rheumatoid Arthritis XELJANZ tablets and XELJANZ XR (extended-release tablets) are 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 tablets or 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 (tablets and oral solution) is indicated for the treatment of adult and pediatric patients 2 years of age and older with active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. XELJANZ XR (extended-release tablets) is indicated for the treatment of adults with active PsA who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of XELJANZ or XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.3 Ankylosing Spondylitis XELJANZ tablets and XELJANZ XR (extended-release tablets) are 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 tablets or XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.4 Polyarticular Course Juvenile Idiopathic Arthritis XELJANZ (tablets and oral solution) are indicated for the treatment of pediatric patients 2 years of age and older with of active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.5 Ulcerative Colitis XELJANZ tablets and XELJANZ XR (extended-release tablets) are 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 tablets or XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS • Serious Infections : Avoid use of XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) during an active serious infection, including localized infections. ( 5.1 ) • Gastrointestinal Perforations : Promptly evaluate patients at increased risk for gastrointestinal perforation who present with new onset abdominal symptoms. ( 5.6 ) • Hypoglycemia in Patients with Diabetes : Consider increased monitoring of blood glucose; advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia. ( 5.8 ) • Laboratory Monitoring : Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. ( 5.9 ) • Vaccinations : Avoid use of live vaccines concurrently with XELJANZ or XELJANZ XR. ( 5.10 ) 5.1 Serious Infections Serious and sometimes fatal infections may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). 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, urinary tract infection, cellulitis, herpes zoster, bronchitis, septic shock, diverticulitis, gastroenteritis, appendicitis, and sepsis . Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multi-dermatomal 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, treatment with XELJANZ tablets 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ tablets 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 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 in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a 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. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. Interrupt XELJANZ/XELJANZ XR if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with XELJANZ/XELJANZ XR, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy, and monitor the patients closely. Caution is also recommended in patients with a 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 (2.3 , 2.4 , 2.5) ]. Tuberculosis Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR. Consider anti-TB therapy prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients closely for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Treat patients with latent TB with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea. 5.2 Increased Risk of Mortality Increased risk of mortality may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Adult patients with rheumatoid arthritis (RA), 50 years of age and older, with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 1.23 for XELJANZ tablets 10 mg twice a day, 0.88 for XELJANZ tablets 5 mg twice a 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 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA [see Dosage and Administration (2.3 , 2.4) ] . 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 (2.5) ] . 5.3 Malignancy and Lymphoproliferative Disorders Malignancies and lymphoproliferative disorders may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Malignancies, including lymphomas and solid cancers, were observed in clinical studies of XELJANZ [see Adverse Reactions (6.1) ]. Other malignancies were observed in XELJANZ clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ tablets 5 mg or 10 mg twice a day compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for XELJANZ tablets 10 mg twice a day, 1.13 for XELJANZ tablets 5 mg twice a 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 a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with XELJANZ tablets 5 mg twice a day and XELJANZ tablets 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.11 for XELJANZ tablets 10 mg twice a day, 0.07 for XELJANZ tablets 5 mg twice a day, and 0.02 for TNF blockers. The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.59 for XELJANZ tablets 10 mg twice a day, 0.48 for XELJANZ tablets 5 mg twice a 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, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA [see Dosage and Administration (2.3 , 2.4) ] . Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ tablets. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ tablets 10 mg twice daily was associated with greater risk of NMSC than treatment with placebo. 5.4 Major Adverse Cardiovascular Events Major adverse cardiovascular events may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). In RA Safety Study 1, patients with RA who were 50 years of age and older with at least one cardiovascular risk factor and treated with XELJANZ tablets 5 mg or 10 mg twice daily had a 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 1.11 for XELJANZ tablets 10 mg twice a day, 0.91 for XELJANZ tablets 5 mg twice a day, and 0.79 for TNF blockers. The incidence rate of fatal or non-fatal myocardial infarction per 100 patient-years was 0.39 for XELJANZ tablets 10 mg twice a day, 0.36 for XELJANZ tablets 5 mg twice a day, and 0.2 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, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue XELJANZ/XELJANZ XR in patients that have experienced a MI or stroke. XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA [see Dosage and Administration (2.3 , 2.4) ] . 5.5 Thrombosis Thrombosis may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). 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 RA 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ tablets 5 mg or 10 mg twice daily compared to TNF blockers in RA Safety Study 1 had an observed increase in incidence of these thrombotic events. The incidence rate of DVT per 100 patient-years was 0.28 for XELJANZ tablets 10 mg twice a day, 0.22 for XELJANZ tablets 5 mg twice a day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.49 for XELJANZ tablets 10 mg twice a day, 0.18 for XELJANZ tablets 5 mg twice a day, and 0.05 for TNF blockers [see Clinical Studies (14.6) ] . XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosages are not recommended for the treatment of RA, PsA, AS, or pcJIA [see Dosage and Administration (2.3 , 2.4) ] . In a 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 a patient with advanced cancer. Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ/XELJANZ XR in patients with symptoms of thrombosis. Avoid XELJANZ/XELJANZ XR in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ tablets or XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.5) ] . 5.6 Gastrointestinal Perforations Gastrointestinal perforations may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ tablets, although the role of JAK inhibition in these events is not known. In these studies, many patients with RA received background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ tablets treatment groups in clinical trials of patients with UC, and many of them were receiving background corticosteroids. Promptly evaluate patients treated with XELJANZ/XELJANZ XR who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs) and who present with new onset abdominal symptoms for early identification of gastrointestinal perforation [see Adverse Reactions (6.1) ] . 5.7 Hypersensitivity Reactions Hypersensitivity reactions may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). 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 a serious hypersensitivity reaction occurs, promptly discontinue XELJANZ/XELJANZ XR while evaluating the potential cause or causes of the reaction [see Adverse Reactions (6.2) ] . 5 .8 Hypoglycemia in Patients with Diabetes Hypoglycemia, including severe hypoglycemia, has been reported following initiation of XELJANZ/XELJANZ XR and other JAK inhibitors in patients with diabetes. During treatment with XELJANZ/XELJANZ XR, consider increased monitoring of blood glucose as clinically indicated in patients with diabetes. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia. 5.9 Laboratory Abnormalities Laboratory abnormalities may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Lymphocyte Abnormalities Treatment with XELJANZ tablets was associated with initial lymphocytosis at one month of XELJANZ tablets treatment followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm 3 in these patients were associated with an increased incidence of treated and serious infections. • Monitor lymphocyte counts at baseline and every 3 months thereafter. • Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm 3 ). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm 3 , treatment with XELJANZ/XELJANZ XR is not recommended. Neutropenia Treatment with XELJANZ tablets was associated with an increased incidence of neutropenia (less than 2000 cells/mm 3 ) compared to treatment with placebo. • Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. • Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm 3 ). For patients who develop a persistent ANC of 500 to 1000 cells/mm 3 , interrupt dosing until ANC is greater than or equal to 1000 cells/mm 3 . In patients who develop an ANC less than 500 cells/mm 3 , treatment with XELJANZ/XELJANZ XR is not recommended. Anemia • Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. • Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Interrupt treatment with XELJANZ/XELJANZ XR in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment until hemoglobin values have normalized. Liver Enzyme Elevations Treatment with XELJANZ tablets was associated with an increased incidence of liver enzyme elevation compared to treatment with placebo. Most of these abnormalities occurred in studies with background DMARD therapy (primarily methotrexate). • 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, interrupt the administration of XELJANZ/XELJANZ XR until this diagnosis has been excluded. Lipid Elevations Treatment with XELJANZ tablets was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum changes in these lipid parameters were generally observed within 6 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. • Perform assessment of lipid parameters approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy. • Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. 5.10 Vaccinations Avoid use of live vaccines concurrently with XELJANZ (tablets and oral solution) or XELJANZ XR (extended-release tablets). Prior to initiating XELJANZ/XELJANZ XR therapy, update immunizations in agreement with current immunization guidelines. The interval between live vaccinations and initiation of XELJANZ/XELJANZ XR therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 5.11 Risk of Gastrointestinal Obstruction with XELJANZ XR - A Non-Deformable Extended-Release Formulation Gastrointestinal obstruction may occur with XELJANZ XR (extended-release tablets). Avoid use of XELJANZ XR in 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 a non-deformable extended-release formulation.

2 DOSAGE AND ADMINISTRATION Recommended Evaluations and Immunization Prior to Treatment Initiation • Prior to initiating XELJANZ/XELJANZ XR, consider performing an active and latent TB evaluation, viral hepatitis screening, a complete blood count, and updating immunizations. Avoid XELJANZ or XELJANZ XR initiation if absolute lymphocyte count <500 cells/mm 3 , an absolute neutrophil count (ANC) <1000 cells/mm 3 or hemoglobin <9 g/dL. ( 2.1 ) Important Administration Instructions • XELJANZ XR (extended-release tablets) is not substitutable with XELJANZ (tablets and oral solution). ( 2.2 ) • Switching between XELJANZ and XELJANZ XR should be made by the healthcare provider. ( 2.2 ) Recommended Dosage Adult Patients with RA, PsA or AS • XELJANZ tablets 5 mg twice daily or XELJANZ XR (extended-release tablets) 11 mg once daily. ( 2.3 ) Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Who Weigh At Least 10 kg • XELJANZ (tablets or oral solution) 5 mg twice daily for those ≥40 kg or weight-based equivalent twice daily for those <40 kg. ( 2.4 ) Adult Patients with UC • Induction: XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily for a maximum of 16 weeks. Discontinue XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. ( 2.5 ) • Maintenance: XELJANZ tablets 5 mg twice daily or XELJANZ XR 11 mg once daily. For patients with loss of response during maintenance treatment, XELJANZ tablets 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. ( 2.5 ) Dosage in Patients with Renal Impairment or Hepatic Impairment • Use of XELJANZ (tablets and oral solution) or XELJANZ XR in patients with severe HI is not recommended. ( 2.3 , 2.4 , 2.5 , 8.7 ) • See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI. ( 2.3 , 2.4 , 2.5 , 8.6 , 8.7 ) Dosage Modification See the full prescribing information for dosage modification by indication for patients who concomitantly use CYP2C19 and/or CYP3A4 inhibitors and patients with lymphopenia, neutropenia, or anemia. ( 2.3 , 2.4 , 2.5 , 7 ) 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating XELJANZ (tablets and oral solution) or XELJANZ XR (extended-release tablets), consider performing the following: • Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to XELJANZ/XELJANZ XR treatment [see Warnings and Precautions (5.1) ] . • Viral hepatitis screening in accordance with clinical guidelines [see Warnings and Precautions (5.1) ] . • A complete blood count: Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a lymphocyte count less than 500 cells/mm 3 , absolute neutrophil count less than 1000 cells/mm 3 , or hemoglobin level less than 9 g/dL [see Warnings and Precautions (5.9) ] . • Baseline hepatic function evaluation: XELJANZ/XELJANZ XR is not recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . • Update immunizations according to current immunization guidelines. The interval between live vaccinations and initiation of XELJANZ/XELJANZ XR should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Warnings and Precautions (5.10) ] . 2.2 Important Administration Instructions • XELJANZ XR (extended-release tablets) is not substitutable with XELJANZ (tablets and oral solution). Switching between XELJANZ and XELJANZ XR should be made by the healthcare provider. • Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions (5.9) and Adverse Reactions (6.1) ] . • Interrupt use of XELJANZ/XELJANZ XR if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions (5.1) ] . • Take XELJANZ/XELJANZ XR with or without food [see Clinical Pharmacology (12.3) ] . • Swallow XELJANZ XR whole and intact. Do not crush, split, or chew the extended-release tablets [see Clinical Pharmacology (12.3) ] . 2.3 Recommended Dosage in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis Table 1 displays the recommended dosage of XELJANZ tablets and XELJANZ XR (extended-release tablets) for adults with RA, PsA, and AS [see Indication and Usage (1.1 , 1.2 , 1.3) ] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations (8.6 , 8.7 )] . The table also displays the recommended dosage modifications for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] , and patients with lymphopenia, neutropenia, or anemia. Table 1: Recommended Dosage of XELJANZ Tablets and XELJANZ XR in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis Adults XELJANZ Tablets XELJANZ XR (extended-release tablets) Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ tablets/XELJANZ XR with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3 , ANC <1000 cells/mm 3 , or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. 5 mg twice daily 11 mg once daily Recommended Dosage in Patients with Renal Impairment (RI) Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft‑Gault equation: CLcr >80 mL/min (normal renal function); >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); <30 mL/min (severe renal impairment). Mild RI (CLcr >50 and ≤80 mL/min) 5 mg twice daily 11 mg once daily Moderate RI (CLcr ≥30 and ≤50 mL/min) 5 mg once daily XELJANZ tablets 5 mg once daily Severe RI (CLcr <30 mL/min) 5 mg once daily XELJANZ tablets 5 mg once daily For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) 5 mg twice daily 11 mg once daily Moderate HI (Child-Pugh B) 5 mg once daily XELJANZ tablets 5 mg once daily Severe HI (Child-Pugh C) Use of XELJANZ tablets/XELJANZ XR is not recommended. Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) 5 mg twice daily 11 mg once daily Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) 5 mg once daily XELJANZ tablets 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. Patients with ANC less than 500 cells/mm 3 Discontinue dosing. Patients with ANC 500 to 1000 cells/mm 3 Interrupt dosing. When ANC is greater than 1000, resume 5 mg twice daily. Interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily. Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets Patients treated with XELJANZ tablets 5 mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets 5 mg. 2.4 Recommended Dosage in Pediatric Patients 2 Years of Age and Older with Psoriatic Arthritis or Polyarticular Course Juvenile Idiopathic Arthritis Table 2 displays the recommended body weight-based dosages for XELJANZ tablets and XELJANZ oral solution in pediatric patients 2 years of age and older with PsA or pcJIA [see Indication and Usage (1.2 , 1.4) ] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations (8.6 , 8.7) ] . The table also includes recommended dosage modification for pediatric patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] , and pediatric patients with lymphopenia, neutropenia, or anemia. Administer XELJANZ oral solution using the included press-in bottle adapter and oral dosing syringe [see Instructions for Use ] . Table 2: Recommended Dosage of XELJANZ Tablets and XELJANZ Oral Solution in Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Pediatric Patients 2 Years of Age and Older XELJANZ tablets and XELJANZ oral solution Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ (tablets and oral solution) with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3 , ANC <1000 cells/mm 3 , or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. • 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 5 mg tablet or 5 mL oral solution) twice daily Patients treated with XELJANZ oral solution 5 mL may be switched to XELJANZ tablets 5 mg. Recommended Dosage in Patients with Renal Impairment (RI) Mild RI Same as patients with normal renal function. Moderate RI • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily Severe RI • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI Same as patients with normal hepatic function. Moderate HI • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily Severe HI Use of XELJANZ tablets/XELJANZ oral solution is not recommended. Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended. Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) • 10 kg ≤ body weight <20 kg: 3.2 mg once daily • 20 kg ≤ body weight <40 kg: 4 mg once daily • Body weight ≥40 kg: 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. Patients with ANC less than 500 cells/mm 3 Discontinue dosing. Patients with ANC 500 to 1000 cells/mm 3 Interrupt dosing until ANC is greater than 1000 cells/mm 3 . Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. 2.5 Recommended Dosage in Adults with Ulcerative Colitis Table 3 displays the recommended dosage of XELJANZ tablets and XELJANZ XR (extended-release tablets) in adult patients with ulcerative colitis (UC) [see Indications and Usage (1.5) ] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations (8.6 , 8.7) ] . Table 4 displays the recommended dosage modification for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] , and patients with lymphopenia, neutropenia, or anemia. Table 3: Recommended Dosage of XELJANZ Tablets and XELJANZ XR in Adults with Ulcerative Colitis With and Without Renal Impairment or Hepatic Impairment Adults XELJANZ tablets XELJANZ XR (extended-release tablets) Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ tablets/XELJANZ XR with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3 , ANC <1000 cells/mm 3 , or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. Induction: 10 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 10 mg twice daily for a maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 22 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 22 mg once daily for a maximum of 16 weeks. Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg twice daily. For patients with loss of response during maintenance treatment, may consider a dosage of 10 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: 11 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 22 mg once daily (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. Recommended Dosage in Patients with Renal Impairment (RI) Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft‑Gault equation: CLcr >80 mL/min (normal renal function); CLcr >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); <30 mL/min (severe renal impairment). Mild RI (CLcr >50 and ≤80 mL/min) Same as patients with normal renal function. Moderate RI (CLcr ≥30 and ≤50 mL/min) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Severe RI (CLcr <30 mL/min) Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Maintenance: XELJANZ XR is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate or Severe RI. For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) Same as patients with normal hepatic function. Moderate HI (Child-Pugh B) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: XELJANZ XR is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate HI. Severe HI (Child-Pugh C) Use of XELJANZ tablets/XELJANZ XR is not recommended. Table 4: Dosage Modifications of XELJANZ Tablets and XELJANZ XR Due to Drug Interactions and for Lymphopenia, Neutropenia or Anemia in Adults with Ulcerative Colitis Adults XELJANZ Tablets XELJANZ XR (extended-release tablets) Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended. Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Induction: 5 mg twice daily for at least 8 weeks [see Clinical Studies (14.5) ] ; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Strong CYP3A4 inhibitor(s) Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: XELJANZ XR is not recommended. see Maintenance Dosage for XELJANZ tablets for Strong CYP3A4 inhibitors. Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. ANC less than 500 cells/mm 3 Discontinue dosing. ANC 500 to 1000 cells/mm 3 If taking: • 10 mg twice daily, reduce to 5 mg twice daily. When ANC is greater than 1000, increase to 10 mg twice daily based on clinical response. • 5 mg twice daily, interrupt dosing. When ANC is greater than 1000, resume 5 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. • 11 mg once daily, interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily. Hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets Patients treated with XELJANZ tablets: • 5 mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets 5 mg. • 10 mg twice daily may be switched to XELJANZ XR extended-release tablets 22 mg once daily the day following the last dose of XELJANZ tablets 10 mg.

3 DOSAGE FORMS AND STRENGTHS • XELJANZ tablets: 5 mg, 10 mg ( 3 ) • XELJANZ XR extended-release tablets: 11 mg, 22 mg ( 3 ) • XELJANZ oral solution: 1 mg/mL ( 3 ) XELJANZ tablets: o 5 mg of tofacitinib: White, round, immediate-release film-coated tablets, debossed with “Pfizer” on one side, and “JKI 5” on the other side. o 10 mg of tofacitinib: Blue, round, immediate-release film-coated tablets, debossed with “Pfizer” on one side, and “JKI 10” on the other side. XELJANZ XR extended-release tablets: o 11 mg of tofacitinib: Pink, oval, extended-release film-coated tablets with a drilled hole at one end of the tablet band and “JKI 11” printed on one side of the tablet. o 22 mg of tofacitinib: Beige, oval, extended-release film-coated tablets with a drilled hole at one end of the tablet band and “JKI 22” printed on one side of the tablet. XELJANZ oral solution: 1 mg/mL of tofacitinib: Clear, colorless oral solution.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions (5.1) ] • Increased Risk of 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 Reactions [see Warnings and Precautions (5.7) ] • Hypoglycemia in Patients with Diabetes [see Warnings and Precautions (5.8) ] • Laboratory Abnormalities [see Warnings and Precautions (5.9) ] Most common adverse reactions are: • RA, PsA, and AS : Reported in ≥2% of adult patients treated with XELJANZ tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache. ( 6.1 ) • PcJIA : Consistent with common adverse reactions reported in adult patients with RA. ( 6.1 ) • UC : Reported in ≥ 5% of adult patients treated with either XELJANZ tablets and ≥1% greater than reported in patients treated with placebo: nasopharyngitis, elevated cholesterol levels, headache, URI, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. ( 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 . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The clinical studies described in this subsection were conducted using XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) and/or XELJANZ oral solution. Adverse Reactions in Adults with Rheumatoid Arthritis In RA Safety Study 1, 1,455 adults were treated with XELJANZ 5 mg twice daily, 1,456 adults were treated with 10 mg twice daily, and 1,451 adults were treated with a TNF blocker for a median of 4 years [see Clinical Studies (14.6) ] . A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA because of increased risks [see Dosage and Administration (2.3) and Warnings and Precautions (5) ] . For the treatment of adults with moderately to severely active RA [see Indications and Usage (1.1) ] , the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily. The safety of XELJANZ was also evaluated in two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials in patients with RA. In these trials, adults were randomized to receive: • XELJANZ (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), • In combination with DMARDs (including methotrexate), XELJANZ 5 mg twice daily (1044 patients) or 10 mg twice daily (1043 patients and • Placebo (809 patients). All seven trials included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a 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 a given interval. Comparisons between placebo and XELJANZ groups were based on the first 3 months of exposure, and comparisons between XELJANZ 5 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 adults with RA who participated in a 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 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for XELJANZ-treated patients and 3% for placebo-treated patients. Overall Infections In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the XELJANZ 5 mg twice daily and XELJANZ 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 Infections: In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 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 XELJANZ 5 mg twice daily and 10 mg twice daily group minus placebo. In the seven placebo-controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received XELJANZ 10 mg twice daily. 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 XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection [see Warnings and Precautions (5.1) ] . Tuberculosis: In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, tuberculosis (TB) was not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily. In the seven placebo-controlled trials, during the 0 to 12 months exposure, TB was reported in 0 patients who received XELJANZ 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received XELJANZ 10 mg twice daily. 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 XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. Cases of disseminated TB were also reported. The median XELJANZ exposure prior to diagnosis of TB 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 in patients with RA, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, XELJANZ 5 mg twice daily, or XELJANZ 10 mg twice daily. In the seven placebo-controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received XELJANZ 10 mg twice daily. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) [see Warnings and Precautions (5.1) ]. Malignancies In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 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 XELJANZ 5 mg and 10 mg twice daily group minus placebo. In the seven placebo-controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received XELJANZ 5 mg twice daily and 7 patients (0.6 events per 100 patient-years) who received XELJANZ 10 mg twice daily. 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 XELJANZ 10 mg twice daily minus XELJANZ 5 mg twice daily. One of these malignancies was a case of lymphoma that occurred during the 0-to-12-month period in a patient treated with XELJANZ 10 mg twice daily. The most common types of malignancy, including malignancies observed during the long-term extension in XELJANZ-treated patients, 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 Lymphopenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in absolute lymphocyte counts below 500 cells/mm 3 occurred in 0.04% of patients for the XELJANZ 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure. Confirmed lymphocyte counts less than 500 cells/mm 3 were associated with an increased incidence of treated and serious infections [see Warnings and Precautions (5.9) ] . Neutropenia: In the placebo-controlled clinical trials in patients with RA, confirmed decreases in ANC below 1,000 cells/mm 3 occurred in 0.07% of patients for the XELJANZ 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure. There were no confirmed decreases in ANC below 500 cells/mm 3 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 (5.9) ]. Liver Enzyme Elevations: Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients with RA 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 dosage, 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 5 mg, and 10 mg twice daily groups. In the placebo-controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients who received placebo, XELJANZ 5 mg, and 10 mg twice daily, respectively. One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× ULN, which required hospitalizations and a liver biopsy. Lipid Elevations: In the placebo-controlled clinical trials in patients with RA, 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 3 months of exposure in the placebo-controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm. • Mean HDL cholesterol increased by 10% in the XELJANZ 5 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 a 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. Serum Creatinine Elevations: In the placebo-controlled clinical trials in patients with RA, 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. Common Adverse Reactions Table 5 displays adverse reactions that occurred in 2% or more of patients on XELJANZ 5 mg or 10 mg twice daily and at least 1% greater than in XELJANZ-treated patients that observed in placebo-treated patients with or without DMARD in the RA trials. Table 5: Common Adverse Reactions reported 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 in Adults With or Without Concomitant DMARDs (0–3 Months) Preferred Term Placebo XELJANZ 5 mg Twice Daily XELJANZ 10 mg Twice Daily The recommended dose of XELJANZ for the treatment of RA is 5 mg twice daily [see Dosage and Administration (2) ] . N = 809 (%) N = 1336 (%) N = 1349 (%) N reflects randomized and treated patients from the seven placebo-controlled clinical trials. Upper respiratory tract infection 3 4 4 Nasopharyngitis 3 4 3 Diarrhea 2 4 3 Headache 2 4 3 Hypertension 1 2 2 Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients [see Clinical Studies (14) ] . The safety experience in these patients was consistent with Studies RA-I through V. Adverse Reactions in Adults with Psoriatic Arthritis The safety of XELJANZ was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA): • Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months. • Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period. In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of PsA. For the treatment of adults with active PsA [see Indications and Usage (1.2) ] , the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily [see Dosage and Administration (2.3) ]. All patients in the clinical trials in patients with PsA were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (10%) patients aged 65 years or older and 66 (14%) patients with diabetes at baseline. During the 2 PsA controlled clinical trials, there were: • 3 malignancies (excluding NMSC) in 474 patients who received XELJANZ plus non-biologic DMARD (6 to 12 months exposure) • 0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and • 0 malignancies in 106 patients in patients who received 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 patients with PsA treated with XELJANZ. The safety profile observed in adults with active PsA treated with XELJANZ was consistent with the safety profile observed in adults with RA. Adverse Reactions in Adults with Ankylosing Spondylitis The safety of XELJANZ was evaluated in adults with active ankylosing spondylitis (AS) in a double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II). • Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily. • Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily. A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of AS. For the treatment of adults with active AS [see Indications and Usage (1.3) ] , the recommended dosage of XELJANZ is 5 mg twice daily and the recommended dosage for XELJANZ XR is 11 mg once daily [see Dosage and Administration (2.3) ] . In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either XELJANZ 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ 5 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%) patients aged 65 years or older and 18 (4%) patients with diabetes at baseline. The safety profile observed in adults with AS treated with XELJANZ was consistent with the safety profile observed in adults with RA and PsA. Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis XELJANZ tablets and XELJANZ oral solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 pediatric patients from 2 years to 17 years of age in Study pcJIA-I [see Clinical Studies (14.4) ] and one open-label extension study (Study A3921145). The total patient exposure (defined as patients who received at least one dose of XELJANZ tablets or XELJANZ oral solution) was 105.6 patient-years in Study pcJIA-I and 777.5 patient-years in Study A3921145. In general, the types of adverse reactions in pediatric patients 2 years of age and older with pcJIA, were consistent with those seen in adults with RA and PsA (see Adverse Reactions in Adults with Rheumatoid Arthritis and Adverse Reactions in Adults with Psoriatic Arthritis ) . Adverse Reactions in Adults with Ulcerative Colitis The safety of XELJANZ has been evaluated in adults with moderately to severely active UC in 4 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 (14.5) ] . Adverse reactions reported in ≥5% of patients treated with either XELJANZ 5 mg or 10 mg twice daily and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials of patients with UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. Induction Trials in Adults with UC Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater in XELJANZ-treated patients than placebo-treated patients in the 3 induction trials of patients with UC (Studies UC-I, UC-II, and UC-V) were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia. Maintenance Trial in Adults with UC Common adverse reactions reported in ≥4% of patients treated with either dosage of XELJANZ and ≥1% greater than reported in patients treated with placebo in the maintenance trial of patients with UC (Study UC-III) are shown in Table 6. Table 6: Common Adverse Reactions Reported in ≥4% of patients treated with either XELJANZ dosage and ≥1% greater in XELJANZ-treated patients than placebo-treated patients. in Adults with UC During the 52-Week Maintenance Trial (Study UC-III) Preferred Term Placebo XELJANZ 5 mg Twice Daily XELJANZ 10 mg Twice Daily N = 198 (%) N = 198 (%) N = 196 (%) Nasopharyngitis 6 10 14 Elevated cholesterol levels Includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased. 1 5 9 Headache 6 9 3 Upper respiratory tract infection 4 7 6 Increased blood creatine phosphokinase 2 3 7 Rash 4 3 6 Diarrhea 3 2 5 Herpes zoster 1 1 5 Gastroenteritis 3 3 4 Anemia 2 4 2 Nausea 3 1 4 Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 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 1,220 patients, 0 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 5 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 a patient with advanced cancer [see Warnings and Precautions (5.5) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed) Metabolism and nutrition disorders: Hypoglycemia Skin and subcutaneous tissue disorders: Acne

7 DRUG INTERACTIONS Table 7 includes drugs with clinically significant drug interactions when concomitantly used with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) and instructions for preventing or managing them. Table 7: Clinically Significant Interactions Affecting XELJANZ/XELJANZ XR When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with XELJANZ/XELJANZ XR is not recommended [see Clinical Pharmacology, Figure 3 (12.3) ] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; concomitant use of XELJANZ/XELJANZ XR with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, AS, UC, or pcJIA. Intervention Concomitant use with XELJANZ/XELJANZ XR is not recommended [see Indications and Usage (1) , Clinical Pharmacology, Figure 3 (12.3) ] See FPI for clinically significant drug interactions. ( 2 , 7 )

8.1 Pregnancy Risk Summary The available data with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug‑associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy (see Clinical Considerations ) . In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data ) . The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 grams) infants, and small for gestational age at birth. Data Animal Data: In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats). In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits). In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

8.4 Pediatric Use The safety and effectiveness of XELJANZ (tablets and oral solution) in pediatric patients for indications, other than in patients with active pcJIA and PsA, have not been established. The safety and effectiveness of XELJANZ have not been established in pediatric patients less than 2 years of age. The safety and effectiveness of XELJANZ XR (extended-release tablets) in pediatric patients have not been established. Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA) The safety and effectiveness of XELJANZ (tablets and oral solution) for the treatment of active pcJIA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Use of XELJANZ for this indication is supported by evidence from adequate and well-controlled studies of XELJANZ tablets in adults with RA, pharmacokinetic (PK) data from adult patients with RA, and with additional safety, efficacy, and PK data from a clinical trial of XELJANZ in pediatric patients 2 years and older with active pcJIA (Study pcJIA-I) [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.4) ] . Adverse reactions observed in pediatric patients with pcJIA who received XELJANZ were consistent with those reported in adults with RA [see Adverse Reactions (6.1) ] . Psoriatic Arthritis The safety and effectiveness of XELJANZ (tablets and oral solution) for the treatment of active PsA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Use of XELJANZ for this indication is supported by evidence from well-controlled studies of XELJANZ tablets in adults with PsA, PK data from adults with PsA, and PK data from a clinical trial of XELJANZ in 225 pediatric patients with JIA, and safety data from 280 pediatric patients 2 years of age and older with JIA [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Following administration of the recommended XELJANZ dosage in pediatric patients 2 years of age and older with PsA, tofacitinib plasma exposures are predicted to be comparable to those observed in adults with PsA based on population PK modeling and simulation [see Clinical Pharmacology (12.3) ] . Systemic Juvenile Idiopathic Arthritis The safety and effectiveness of XELJANZ for the treatment of pediatric patients with systemic juvenile idiopathic arthritis (sJIA) have not been established. The results from a two-part study (an open-label, run-in phase, followed by a double-blind, placebo-controlled, randomized event-driven withdrawal phase) in 100 patients 2 years to 17 years of age with sJIA with active systemic features did not demonstrate that XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) was efficacious in the treatment of sJIA with active systemic features. Of the 100 patients enrolled in the open-label run-in phase, 59 (59%) patients achieved a clinical response and were eligible for the double-blind withdrawal phase. There were 28 patients randomized to XELJANZ and 31 patients to placebo. The study data were insufficient to demonstrate efficacy and, therefore, XELJANZ is not recommended for the treatment of sJIA. Adverse reactions observed in pediatric patients with sJIA receiving XELJANZ/XELJANZ oral solution were consistent with those reported in pcJIA and RA patients [see Adverse Reactions (6.1) ] .

8.5 Geriatric Use Of the 3315 adults who were enrolled in clinical trials with RA (Studies RA-I to V), a total of 505 patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ tablets-treated patients 65 years of age and older was higher than among those adults under the age of 65. Of the 1156 XELJANZ tablet-treated patients in clinical trials of patients with UC, a total of 77 patients (7%) were 65 years of age or older. Clinical studies of XELJANZ in patients with UC did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger adult patients. Of the 783 XELJANZ tablet-treated patients in clinical trials of patients with PsA, a total of 72 (9.2%) patients were 65 years of age and older, including 2 (0.3%) patients 75 years and older. These clinical studies did not include sufficient numbers of patients aged 65 years and older with PsA to determine if they respond differently from younger adult patients. Of the 420 XELJANZ tablet-treated patients in clinical trials of patients with AS, a total of 12 (2.9%) patients were 65 years of age and older, including 1 (0.2%) patient 75 years and older. These clinical studies did not include sufficient numbers of patients aged 65 years and older with AS to determine if they respond differently from younger adult patients.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary The available data with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug‑associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy (see Clinical Considerations ) . In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data ) . The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 grams) infants, and small for gestational age at birth. Data Animal Data: In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats). In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits). In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats). 8.2 Lactation Risk Summary Based on published data, tofacitinib is present in human milk. Data on the effects of tofacitinib on the breastfed infant is limited to a small number of cases with no reported adverse effects. There are no data on the effects on milk production. Given the serious adverse reactions seen in patients treated with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets), 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 or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives). Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum and were approximately 2 times higher in milk relative to maternal serum at all time points measured. 8.3 Females and Males of Reproductive Potential Contraception Females In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dosage of 5 mg twice daily and 6.3 times the maximum recommended dosage 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 dosage. Consider pregnancy planning and prevention for females of reproductive potential. Infertility Females Based on findings in rats, treatment with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) 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 (tablets and oral solution) in pediatric patients for indications, other than in patients with active pcJIA and PsA, have not been established. The safety and effectiveness of XELJANZ have not been established in pediatric patients less than 2 years of age. The safety and effectiveness of XELJANZ XR (extended-release tablets) in pediatric patients have not been established. Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA) The safety and effectiveness of XELJANZ (tablets and oral solution) for the treatment of active pcJIA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Use of XELJANZ for this indication is supported by evidence from adequate and well-controlled studies of XELJANZ tablets in adults with RA, pharmacokinetic (PK) data from adult patients with RA, and with additional safety, efficacy, and PK data from a clinical trial of XELJANZ in pediatric patients 2 years and older with active pcJIA (Study pcJIA-I) [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.4) ] . Adverse reactions observed in pediatric patients with pcJIA who received XELJANZ were consistent with those reported in adults with RA [see Adverse Reactions (6.1) ] . Psoriatic Arthritis The safety and effectiveness of XELJANZ (tablets and oral solution) for the treatment of active PsA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Use of XELJANZ for this indication is supported by evidence from well-controlled studies of XELJANZ tablets in adults with PsA, PK data from adults with PsA, and PK data from a clinical trial of XELJANZ in 225 pediatric patients with JIA, and safety data from 280 pediatric patients 2 years of age and older with JIA [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Following administration of the recommended XELJANZ dosage in pediatric patients 2 years of age and older with PsA, tofacitinib plasma exposures are predicted to be comparable to those observed in adults with PsA based on population PK modeling and simulation [see Clinical Pharmacology (12.3) ] . Systemic Juvenile Idiopathic Arthritis The safety and effectiveness of XELJANZ for the treatment of pediatric patients with systemic juvenile idiopathic arthritis (sJIA) have not been established. The results from a two-part study (an open-label, run-in phase, followed by a double-blind, placebo-controlled, randomized event-driven withdrawal phase) in 100 patients 2 years to 17 years of age with sJIA with active systemic features did not demonstrate that XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) was efficacious in the treatment of sJIA with active systemic features. Of the 100 patients enrolled in the open-label run-in phase, 59 (59%) patients achieved a clinical response and were eligible for the double-blind withdrawal phase. There were 28 patients randomized to XELJANZ and 31 patients to placebo. The study data were insufficient to demonstrate efficacy and, therefore, XELJANZ is not recommended for the treatment of sJIA. Adverse reactions observed in pediatric patients with sJIA receiving XELJANZ/XELJANZ oral solution were consistent with those reported in pcJIA and RA patients [see Adverse Reactions (6.1) ] . 8.5 Geriatric Use Of the 3315 adults who were enrolled in clinical trials with RA (Studies RA-I to V), a total of 505 patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ tablets-treated patients 65 years of age and older was higher than among those adults under the age of 65. Of the 1156 XELJANZ tablet-treated patients in clinical trials of patients with UC, a total of 77 patients (7%) were 65 years of age or older. Clinical studies of XELJANZ in patients with UC did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger adult patients. Of the 783 XELJANZ tablet-treated patients in clinical trials of patients with PsA, a total of 72 (9.2%) patients were 65 years of age and older, including 2 (0.3%) patients 75 years and older. These clinical studies did not include sufficient numbers of patients aged 65 years and older with PsA to determine if they respond differently from younger adult patients. Of the 420 XELJANZ tablet-treated patients in clinical trials of patients with AS, a total of 12 (2.9%) patients were 65 years of age and older, including 1 (0.2%) patient 75 years and older. These clinical studies did not include sufficient numbers of patients aged 65 years and older with AS to determine if they respond differently from younger adult patients. 8.6 Renal Impairment Moderate and Severe Renal Impairment XELJANZ-treated patients with moderate renal impairment (RI) (CLcr ≥30 and ≤50 mL/minute) or severe RI (<30 mL/minute) had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function (CLcr >80 mL/minute). The recommended dosage of XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) in patients with moderate or severe RI (including those with severe RI who are undergoing hemodialysis) is lower than the recommended dosage in patients with normal renal function [see Dosage and Administration (2.3 , 2.4 , 2.5) ] . Mild Renal Impairment The recommended dosage in patients with mild RI (CLcr >50 and ≤80 mL/minute) is the same as patients with normal renal function. 8.7 Hepatic Impairment Severe Hepatic Impairment XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) has not been studied in patients with severe hepatic impairment (HI) (Child-Pugh C); therefore, use of XELJANZ/XELJANZ XR in patients with severe HI is not recommended. Moderate Hepatic Impairment XELJANZ-treated patients with moderate hepatic impairment (Child-Pugh B) 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. The recommended XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) dosage in patients with moderate HI is lower than the recommended dosage in patients with normal hepatic function [see Dosage and Administration (2.3 , 2.4 , 2.5 )] . Mild Hepatic Impairment The recommended dosage of XELJANZ/XELJANZ XR in patients with mild hepatic impairment (Child-Pugh A) is the same as patients with normal hepatic function. Hepatitis B or C Serology The safety and efficacy of XELJANZ/XELJANZ XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

10 OVERDOSAGE There is no specific antidote for overdose with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets). In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. In a study in patients 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. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.