XELJANZ

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)].

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.

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.

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.

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.

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.

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/mm³, absolute neutrophil count less than 1000 cells/mm³, 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)].

• 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)].

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 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 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.

XELJANZ tablets:

• o5 mg of tofacitinib: White, round, immediate-release film-coated tablets, debossed with “Pfizer” on one side, and “JKI 5” on the other side.
• o10 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:

• o11 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.
• o22 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.

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) ].

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) ].

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) ].

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) ].

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) ].

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)].

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)].

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.

Laboratory abnormalities may occur with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets).

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.

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.

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.

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)

Infections and infestations: Progressive multifocal leukoencephalopathy

Metabolism and nutrition disorders: Hypoglycemia

Skin and subcutaneous tissue disorders: Acne

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)].

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.

Moderate and Severe Renal Impairment

XELJANZ-treated patients with moderate renal impairment (RI) (CLcr ≥30 mL/minute 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.

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

Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.

Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis (RA) were lower than in patients who received placebo; however, changes were small and not dose-dependent.

After treatment with XELJANZ in patients with RA, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.

Similar changes in T cells, B cells, and serum CRP have been observed in patients with active psoriatic arthritis (PsA) although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active PsA.

In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the recommended dose of 5 mg twice daily, and approximately 3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the recommended dose of 5 mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of 1 mg/kg twice daily).

The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the recommended dose of 5 mg twice daily, and approximately 17 times the 10 mg twice daily dose (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.

In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the recommended dose of 5 mg twice daily, and approximately 21 times the 10 mg twice daily dose on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.

Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.

In rats, tofacitinib at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the 10 mg twice daily dose (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the recommended dose of 5 mg twice daily, and approximately 0.5 times the 10 mg twice daily dose (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the recommended dose of 5 mg twice daily, and approximately 67 times the 10 mg twice daily dose (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.

The rheumatoid arthritis (RA) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included six randomized controlled trials in adults with moderate to severe active RA.

Trial Design

• Study RA-I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active RA who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 mg or 10 mg twice daily or placebo added to their background DMARD. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 mg or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
• Study RA-II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active RA who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 mg or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 mg or 10 mg twice daily. At the end of Month 6, all patients treated with placebo were switched to their second predetermined XELJANZ treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
• Study RA-III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active RA who had an inadequate response to methotrexate (MTX). Patients received XELJANZ 5 mg or 10 mg orally twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Patients treated with placebo were switched as in Study RA-II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
• Study RA-IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active RA who had an inadequate response to MTX received XELJANZ 5 mg or 10 mg twice daily or placebo added to background MTX. Patients treated with placebo were switched as in Study RA-II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
• Study RA-V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active RA who had an inadequate response to at least one approved TNF blocking biological product received XELJANZ 5 mg or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
• Study RA-VI (NCT01039688) was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active RA received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.

Although other dosages have been studied, the recommended dosage of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for the treatment of RA [see Dosage and Administration (2.3)].

Clinical Response

The percentages of XELJANZ-treated patients who achieved ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and V are shown in Table 10. Similar results were observed with Studies RA-II and III. In trials RA-I through V, patients treated with 5 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus patients treated with placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.

In Study RA-IV, a greater proportion of patients treated with XELJANZ 5 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 11).

The results of the components of the ACR response criteria for Study RA-IV are shown in Table 12. Similar results were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

The percent of ACR20 responders by visit for Study RA-IV is shown in Figure 4. Similar responses were observed for XELJANZ in Studies RA-I, II, III, V, and VI.

Figure 4: Percentage of ACR20 Responders by Visit Through Month 6 in Study RA-IV

Figure 4

The psoriatic arthritis (PsA) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included 2 multicenter, randomized, double-blind, placebo-controlled trials in 816 adults with active PsA (Studies PsA-I and PsA-II).

Trial Designs and Population

All patients had active PsA for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender/painful joints and at least 3 swollen joints, and active plaque psoriasis. Patients randomized and treated across the 2 clinical trials represented different PsA subtypes at screening, including <5 joints or asymmetric involvement (21%), ≥5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had a diagnosis of PsA for a mean (SD) of 7.7 (7.2) years. At baseline, 80% and 53% of patients had enthesitis and dactylitis, respectively. At baseline, all patients were required to receive treatment with a stable dose of a nonbiologic DMARD (79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other nonbiologic DMARDs). In both clinical trials, the primary endpoints were the ACR20 response and the change from baseline in HAQ-DI at Month 3.

• Study PsA-I was a 12-month clinical trial in 422 patients who had an inadequate response to a nonbiologic DMARD (67% and 33% were inadequate responders to 1 nonbiologic DMARD and ≥2 nonbiologic DMARDs, respectively) and who were naïve to treatment with a TNF blocker. Although Study PsA-1 included patients who are TNF blocker-naïve, XELJANZ and XELJANZ XR are not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.2)]. Patients were randomized in a 2:2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, all patients randomized to placebo treatment were switched in a blinded fashion to a predetermined XELJANZ dosage of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate non‑inferiority or superiority to adalimumab.
• Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNF blocker (66%, 19%, and 15% were inadequate responders to 1 TNF blocker, 2 TNF blockers and ≥3 TNF blockers, respectively). Patients were randomized in a 2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, placebo patients were switched in a blinded fashion to a predetermined XELJANZ dosage of 5 mg or 10 mg twice daily as in Study PsA-I.

Although other dosages have been studied, the recommended dosage of XELJANZ is 5 mg twice daily. XELJANZ 10 mg twice daily is not recommended for treatment of PsA [see Dosage and Administration (2.3)].

The ankylosing spondylitis (AS) clinical development program with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) included one placebo-controlled trial (Study AS-I) in adults with active AS. Patients had active disease as defined by both Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and back pain score (BASDAI question 2) of greater or equal to 4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy.

The efficacy of XELJANZ (tablets and oral solution) for pcJIA was assessed in Study pcJIA-I (NCT02592434). This was a 44-week, two-part study (that consisted of an 18-week, open-label, run-in phase, followed by a 26-week double-blind, placebo-controlled, randomized withdrawal phase) in pediatric patients 2 years to 17 years of age with active rheumatoid factor (RF) negative polyarthritis, RF positive polyarthritis, extended oligoarthritis, and systemic JIA without systemic manifestations who had an inadequate response or intolerance to at least one DMARD which could have included MTX or biologic agents. This study also included patients ages 2 years to 17 years of age with active juvenile psoriatic arthritis (jPsA) and enthesitis-related arthritis (ERA) who had an inadequate response to NSAIDs. Although the clinical studies included some patients who are TNF blocker-naïve, XELJANZ is not approved for use in TNF blocker-naïve patients [see Indications and Usage (1.4)].

Patients received XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) for 18 weeks (run-in phase) followed by randomization to either XELJANZ (dosed at 5 mg twice daily or body weight-based equivalent twice daily) or placebo for 26 weeks (double-blind phase). Only patients who achieved at least a JIA ACR30 response at the end of the run-in phase were randomized (1:1) to the double-blind phase. Treatment with a stable dose of MTX was permitted but was not required during the study. Concurrent use of biologics or DMARDs other than MTX was not permitted in the study.

Baseline Disease Characteristics

A total of 225 pediatric patients with JIA (56 male and 169 female) with active polyarthritis were enrolled in the run-in phase including RF negative (104), RF positive (39), extended oligoarthritis (28), systemic JIA without systemic manifestations (13), jPsA (20), and ERA (21). Patients had a mean (SD) disease duration of 3.8 ± 3.5 years, and a mean (SD) number of active joints of 12.2 ± 8.1.

Efficacy Results

Of the 225 patients, 173 (77%) patients achieved JIA ACR30 response at Week 18 and were randomized into the double-blind phase to either XELJANZ (n=88) or placebo (n=85). At the conclusion of the 18-week, open-label, run-in phase, pediatric ACR 30/50/70 responses were 77%, 70%, and 49%, respectively.

In both the run-in and double-blind phases, approximately one-third of the patients were taking concomitant oral corticosteroids, and approximately two-thirds were taking concomitant MTX.

The primary endpoint was the occurrence of disease flare at Week 44 relative to the double-blind phase baseline at Week 18. Disease flare was defined (according to Pediatric Rheumatology Collaborative Study Group (PRCSG)/Pediatric Rheumatology International Trials Organization (PRINTO) Disease Flare criteria) as worsening of ≥30% in 3 or more of the 6 JIA core response variables with no more than 1 of the remaining JIA core response variables improving by ≥30%.

XELJANZ-treated patients experienced significantly fewer disease flares at Week 44 compared to placebo-treated patients (31% [27/88] vs. 55% [47/85]; difference in proportions -25% [95% CI: -39%, -10%]; p=0.0007). The occurrence of disease flare by visit in Study pcJIA-I is shown in Figure 7.

Figure 7: Occurrence of Disease Flare in Pediatric Patients 2 Years of Age and Older with JIA by Visit from Week 18 to Week 44 in the Double-Blind Phase in Study pcJIA-I

BID = twice daily; SE = standard error; N = total number of patients.

The 26-week double-blind phase is from Week 18 through Week 44 on and after randomization day.

Figure 7

A randomized open-label trial (RA Safety Study 1; NCT02092467) was conducted to evaluate safety with XELJANZ tablets (referred to as “XELJANZ” in this subsection of labeling) at two doses, 5 mg twice daily (N=1455) and 10 mg twice daily (N=1456), versus the TNF-blocker control (N=1451) in RA patients 50 years of age and older with at least one cardiovascular risk factor. The co-primary endpoints were adjudicated MACE (defined as cardiovascular death, non-fatal MI, and non-fatal stroke) and adjudicated malignancy (excluding non-melanoma skin cancer). The study was designed to exclude a prespecified risk margin of 1.8 for the hazard ratio of combined XELJANZ regimens versus the TNF-blocker control for each co-primary endpoint. An independent committee conducted a blinded evaluation of the co-primary endpoints according to predefined criteria (adjudication). The study was event-driven and patients were followed until a sufficient number of primary outcome events accrued. Other endpoints included mortality, serious infections, and thromboembolic events. The median on-study follow-up time was 4 years.

The mean age of the population was 61 years (range: 50 to 88 years). Most patients were female (78%) and Caucasian (77%). Patients had a diagnosis of RA for a mean of 10 years, and a median swollen and tender joint count of 11 and 15 respectively. Cardiovascular risk factors included cigarette smoking (current or past) (48%), hypertension (66%), high density lipoprotein <40 mg/dL (12%), diabetes mellitus (17%), family history of premature coronary heart disease (15%), extra-articular disease associated with RA (37%), and history of coronary artery disease (11%).

The non-inferiority criterion was not met for the primary comparison of the combined XELJANZ dosages to TNF blockers since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8 (for MACE, the upper limit of the 95% CI was 1.94; for malignancies excluding NMSC, the upper limit of the 95% CI was 2.09).

Table 22 shows the study results for each of the co-primary endpoints, and other endpoints. There was an increased risk of death, MACE, malignancies, serious infections, thromboembolic events, and fractures associated with both dosages of XELJANZ.

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 5 mg twice a day and XELJANZ 10 mg twice a day compared to those treated with TNF blockers. Lymphoma was reported for 4 patients who received XELJANZ 5 mg twice a day, 6 patients who received XELJANZ 10 mg twice a day, and 1 patient who received TNF blockers (Incidence Rate [IR] of 0.07, 0.11, and 0.02 per 100 patient-years, respectively). Among current and past smokers, lung cancer was reported for 13 patients who received XELJANZ 5 mg twice a day, 15 patients who received XELJANZ 10 mg twice a day, and 7 patients who received TNF blockers (IR of 0.48, 0.59, and 0.27 per 100 patient-years, respectively).

Given these increased risks, XELJANZ (tablets and oral solution) 10 mg twice daily (or XELJANZ XR (extended-release tablets) 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)].

The overall fractures and osteoporotic fractures were observed at a higher rate in both XELJANZ treatment groups compared to the TNF blocker treatment group. The observed incidence rate of osteoporotic fractures was higher in women than men, and was highest in women on XELJANZ 10 mg twice daily (1.56 per 100 patient-years), followed by XELJANZ 5 mg twice daily (1.26 per 100 patient-years), and TNF blockers (1.01 per 100 patient-years).

Serious Infections

Inform patients that XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) may lower the ability of their immune system to fight infections. Advise patients not to start taking XELJANZ/XELJANZ XR if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear to ensure rapid evaluation and appropriate treatment. Instruct patients to contact their healthcare provider immediately during treatment if they, their partner, or caregiver notice new onset or worsening of neurological symptoms including general muscle weakness, disturbance of vision, changes in thinking, memory and orientation leading to confusion and personality changes as these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML) [see Warnings and Precautions (5.1)].

Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with XELJANZ/XELJANZ XR [see Warnings and Precautions (5.1)].

Malignancies and Lymphoproliferative Disorders

Inform patients that XELJANZ/XELJANZ XR may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking XELJANZ. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions (5.3)].

Major Adverse Cardiovascular Events

Inform patients that XELJANZ/XELJANZ XR may increase their risk of major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.4)].

Thrombosis

Advise patients to stop taking XELJANZ/XELJANZ XR and to call their healthcare provider right away if they experience any symptoms of thrombosis (sudden shortness of breath, chest pain worsened with breathing, swelling of leg or arm, leg pain or tenderness, red or discolored skin in the affected leg or arm) [see Warnings and Precautions (5.5)].

Hypersensitivity

Advise patients to stop taking XELJANZ/XELJANZ XR and to call their healthcare provider right away if they experience any symptoms of allergic reactions while taking XELJANZ/XELJANZ XR [see Warnings and Precautions (5.7)].

Hypoglycemia in Patients with Diabetes

Consider advising patients with diabetes to increase monitoring of blood glucose since hypoglycemia, including severe hypoglycemia, has been reported after starting XELJANZ/XELJANZ XR. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia [see Warnings and Precautions (5.8)].

Important Information on Laboratory Abnormalities

Inform patients that XELJANZ/XELJANZ XR may affect certain lab test results, and that blood tests are required before and during XELJANZ/XELJANZ XR treatment [see Warnings and Precautions (5.9)].

Pregnancy

Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with XELJANZ/XELJANZ XR and for at least 18 hours after the last dose of XELJANZ or 36 hours after the last dose of XELJANZ XR [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that XELJANZ/XELJANZ XR may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. It is not known if this effect is reversible.

Residual Tablet Shell

Patients receiving XELJANZ XR may notice an inert tablet shell passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert tablet shell.

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

LAB-0445-32.0