TOFACITINIB

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS SERIOUS INFECTIONS Patients treated with tofacitinib oral solution 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 tofacitinib oral solution use and during therapy. Treatment for latent infection should be initiated prior to tofacitinib oral solution use. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens. The risks and benefits of tofacitinib oral solution 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 tofacitinib oral solution 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 tofacitinib oral solution 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) ] . A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of psoriatic arthritis (PsA), or polyarticular course juvenile idiopathic arthritis (pcJIA) [see Dosage and Administration (2.4) ] . MALIGNANCIES Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ tablets 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 tofacitinib oral solution in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions (5.4) ] . THROMBOSIS Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with XELJANZ tablets 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 tofacitinib oral solution in patients at risk. Discontinue tofacitinib oral solution and promptly evaluate patients with symptoms of thrombosis [see Warnings and Precautions (5.5) ] . 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 tofacitinib oral solution 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 )

5 WARNINGS AND PRECAUTIONS Serious Infections : Avoid use of tofacitinib oral solution 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 tofacitinib. ( 5. 10) 5.1 Serious Infections Serious and sometimes fatal infections may occur with tofacitinib oral solution. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The most common serious infections reported with tofacitinib 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 tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of tofacitinib oral solution in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib oral solution 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 tofacitinib oral solution. Interrupt tofacitinib oral solution if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with tofacitinib oral solution, 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 (2.4) ]. Tuberculosis Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of tofacitinib oral solution. Consider anti-TB therapy prior to administration of tofacitinib oral solution 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 tofacitinib oral solution. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with tofacitinib. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib. The impact of tofacitinib oral solution 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 tofacitinib oral solution. The risk of herpes zoster is increased in patients treated with tofacitinib oral solution and appears to be higher in patients treated with tofacitinib in Japan and Korea. 5.2 Increased Risk of Mortality Increased risk of mortality may occur with tofacitinib oral solution. 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 tofacitinib oral solution. A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4) ] . 5.3 Malignancy and Lymphoproliferative Disorders Malignancies and lymphoproliferative disorders may occur with tofacitinib oral solution. Malignancies, including lymphomas and solid cancers, were observed in clinical studies of tofacitinib [see Adverse Reactions (6.1) ]. Other malignancies were observed in tofacitinib 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 tofacitinib oral solution, 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. A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (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. 5.4 Major Adverse Cardiovascular Events Major adverse cardiovascular events may occur with tofacitinib oral solution. 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 tofacitinib oral solution, 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 tofacitinib oral solution in patients that have experienced a MI or stroke. A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4) ] . 5.5 Thrombosis Thrombosis may occur with tofacitinib oral solution. Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with tofacitinib 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) ] . A tofacitinib oral solution 10 mg twice daily dosage is not recommended for the treatment of PsA or pcJIA [see Dosage and Administration (2.4) ] . Promptly evaluate patients with symptoms of thrombosis and discontinue tofacitinib oral solution in patients with symptoms of thrombosis. Avoid tofacitinib oral solution in patients that may be at increased risk of thrombosis. 5.6 Gastrointestinal Perforations Gastrointestinal perforations may occur with tofacitinib oral solution. 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 tofacitinib oral solution 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 tofacitinib oral solution. Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving tofacitinib oral solution. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib oral solution 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 tofacitinib oral solution and other JAK inhibitors in patients with diabetes. During treatment with tofacitinib oral solution, 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 tofacitinib oral solution. 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 tofacitinib oral solution 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 tofacitinib oral solution is not recommended. Neutropenia Treatment with XELJANZ tablets was associated with an increased incidence of neutropenia (less than 2,000 cells/mm 3 ) compared to treatment with placebo. Monitor neutrophil counts at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter. Avoid initiation of tofacitinib oral solution treatment in patients with a low neutrophil count (i.e., ANC less than 1,000 cells/mm 3 ). For patients who develop a persistent ANC of 500 to 1,000 cells/mm 3 , interrupt dosing until ANC is greater than or equal to 1,000 cells/mm 3 . In patients who develop an ANC less than 500 cells/mm 3 , treatment with tofacitinib oral solution is not recommended. Anemia Monitor hemoglobin at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter. Avoid initiation of tofacitinib oral solution treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Interrupt treatment with tofacitinib oral solution 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 tofacitinib oral solution 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 to 8 weeks following initiation of tofacitinib oral solution 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 tofacitinib oral solution. Prior to initiating tofacitinib oral solution therapy, update immunizations in agreement with current immunization guidelines. The interval between live vaccinations and initiation of tofacitinib oral solution therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

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: PsA: 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc., at 1-800-818-4555 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 tablets” in this subsection of labeling) and/or tofacitinib oral solution. Adverse Reactions in Adults with Rheumatoid Arthritis In RA Safety Study 1, 1,455 adults were treated with XELJANZ tablets 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) ] . The safety of XELJANZ tablets 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 tablets (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), In combination with DMARDs (including methotrexate), XELJANZ tablets 5 mg twice daily (1,044 patients) or 10 mg twice daily (1,043 patients and Placebo (809 patients). All seven trials included provisions for patients taking placebo to receive treatment with XELJANZ tablets 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 tablets in both the placebo and XELJANZ tablets group of a given interval. Comparisons between placebo and XELJANZ tablets groups were based on the first 3 months of exposure, and comparisons between XELJANZ tablets 5 mg twice daily and XELJANZ tablets 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 tablets 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 tablets-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 tablets 5 mg twice daily and XELJANZ tablets 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with XELJANZ tablets 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 tablets 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 tablets 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 tablets 5 mg twice daily and 33 patients (2.7 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 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 tablets 5 mg twice daily, or XELJANZ tablets 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 tablets 5 mg twice daily and 6 patients (0.5 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 5 mg twice daily. Cases of disseminated TB were also reported. The median XELJANZ tablets 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 tablets 5 mg twice daily, or XELJANZ tablets 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 tablets 5 mg twice daily and 4 patients (0.3 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 5 mg twice daily. The median XELJANZ tablets 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 tablets 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 tablets 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 tablets 5 mg twice daily and 7 patients (0.6 events per 100 patient-years) who received XELJANZ tablets 10 mg twice daily. The rate difference between XELJANZ tablets doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for XELJANZ tablets 10 mg twice daily minus XELJANZ tablets 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 tablets 10 mg twice daily. The most common types of malignancy, including malignancies observed during the long-term extension in XELJANZ tablets-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 tablets 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 tablets 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 (3x ULN) were observed in patients with RA treated with XELJANZ tablets. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ tablets, or reduction in XELJANZ tablets dosage, resulted in decrease or normalization of liver enzymes. In the placebo-controlled monotherapy trials (0 to 3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ tablets 5 mg, and 10 mg twice daily groups. In the placebo-controlled background DMARD trials (0 to 3 months), ALT elevations greater than 3x ULN were observed in 1%, 1.3% and 1.2% of patients who received placebo, XELJANZ tablets 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients who received placebo, XELJANZ tablets 5 mg, and 10 mg twice daily, respectively. One case of drug-induced liver injury was reported in a patient treated with XELJANZ tablets 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and 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 tablets 5 mg twice daily arm and 19% in the XELJANZ tablets 10 mg twice daily arm. Mean HDL cholesterol increased by 10% in the XELJANZ tablets 5 mg twice daily arm and 12% in the XELJANZ tablets 10 mg twice daily arm. Mean LDL/HDL ratios were essentially unchanged in XELJANZ tablets -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 tablets 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 tablets 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 tablets 5 mg or 10 mg twice daily and at least 1% greater than in XELJANZ tablets -treated patients that observed in placebo-treated patients with or without DMARD in the RA trials. Table 5: Common Adverse Reactions * in Clinical Trials of XELJANZ tablets for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0 to 3 Months) Preferred Term Placebo XELJANZ Tablets 5 mg Twice Daily XELJANZ Tablets 10 mg Twice Daily ** N = 809 (%) N = 1,336 (%) N = 1,349 (%) Upper respiratory tract infection 3 4 4 Nasopharyngitis 3 4 3 Diarrhea 2 4 3 Headache 2 4 3 Hypertension 1 2 2 N reflects randomized and treated patients from the seven placebo-controlled clinical trials. * reported in ≥ 2% of patients treated with either dose of XELJANZ tablets and ≥ 1% greater than that reported for placebo. ** The recommended dose of XELJANZ tablets for the treatment of RA is 5 mg twice daily [see Dosage and Administration (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 Adverse Reactions in Adults with Psoriatic Arthritis The safety of XELJANZ tablets 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 tablets 5 mg twice daily and 236 patients were randomized and treated with XELJANZ tablets 10 mg twice daily. A dosage of XELJANZ tablets 10 mg twice daily is not recommended for the treatment of PsA. 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 tablets (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 tablets 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 tablets. The safety profile observed in adults with active PsA treated with XELJANZ tablets was consistent with the safety profile observed in adults with RA. Adverse Reactions in Pediatric Patients 2 Years of Age and Older with Polyarticular Course Juvenile Idiopathic Arthritis XELJANZ tablets or tofacitinib 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 tofacitinib 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) . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of XELJANZ tablets/tofacitinib 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

<table width="100%" border="1" cellspacing="0" cellpadding="0"><tbody><tr><td rowspan="2"><paragraph><content styleCode="bold">Preferred Term</content></paragraph><paragraph/></td><td><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td><paragraph><content styleCode="bold">XELJANZ Tablets 5 mg Twice Daily</content></paragraph></td><td><paragraph><content styleCode="bold">XELJANZ Tablets 10 mg Twice Daily ^**</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">N = 809</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td><paragraph><content styleCode="bold">N = 1,336</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td><paragraph><content styleCode="bold">N = 1,349</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td></tr><tr><td><paragraph>Upper respiratory tract infection</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>4</paragraph></td></tr><tr><td><paragraph>Nasopharyngitis</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>3</paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>2</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>3</paragraph></td></tr><tr><td><paragraph>Headache</paragraph></td><td><paragraph>2</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>3</paragraph></td></tr><tr><td><paragraph>Hypertension</paragraph></td><td><paragraph>1</paragraph></td><td><paragraph>2</paragraph></td><td><paragraph>2</paragraph></td></tr></tbody></table>