Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

XELJANZ (NDA-213082)

(TOFACITINIB CITRATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

03/06/2026 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Infections

Additions and/or revisions underlined:

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.

. . .

10/16/2025 (SUPPL-11)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

 

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS

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)].

5 Warnings and Precautions

Extensive changes; please refer to label for complete information.

6 Adverse Reactions

Extensive changes; please refer to label for complete information.

7 Drug Interactions

Additions and/or revisions underlined:

Table 7 includes drugs with clinically significant drug interactions when concomitantly used with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) and instructions for preventing or managing them.

Table 7: Clinically Significant Interactions Affecting XELJANZ/XELJANZ XR When Concomitantly Used with Other Drugs

Extensive changes to table, please refer to label for complete information.

8 Use in Specific Populations

Extensive changes; please refer to label for complete information.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about XELJANZ/XELJANZ XR/XELJANZ oral solution?

XELJANZ/XELJANZ XR/XELJANZ oral solution may cause serious side effects including:

. . .

4. Increased risk of major cardiovascular events such as heart attack, stroke or death in people 50 years of age and older who have at least 1 heart disease (cardiovascular) risk factor and are taking XELJANZ 5 mg or 10 mg twice daily, especially if you are a current or past smoker.

Get emergency help right away if you have any symptoms of a heart attack or stroke while taking XELJANZ/XELJANZ XR/XELJANZ oral solution, including:

. . .

What is XELJANZ/XELJANZ XR/XELJANZ oral solution?

. . .

• XELJANZ/XELJANZ XR is used to treat adults and XELJANZ/XELJANZ oral solution is used to treat children 2 years of age and older with active psoriatic arthritis when 1 or more TNF blocker medicines have been used, and did not work well or cannot be tolerated.

. . .

• XELJANZ/XELJANZ oral solution is used to treat children 2 years of age and older with active polyarticular course juvenile arthritis when 1 or more TNF blocker medicines have been used, and did not work well or cannot be tolerated.

It is not known if XELJANZ/XELJANZ XR/XELJANZ oral solution is safe and effective in people with Hepatitis B or C.

XELJANZ/XELJANZ XR/XELJANZ oral solution is not recommended for people with severe liver problems.

It is not known if XELJANZ/XELJANZ oral solution is safe and effective in children for treatment other than active polyarticular course juvenile arthritis and psoriatic arthritis.

. . .

How should I take XELJANZ/XELJANZ XR/XELJANZ oral solution?

. . .

• For the treatment of psoriatic arthritis, take XELJANZ/XELJANZ XR/XELJANZ oral solution in combination with methotrexate, sulfasalazine or leflunomide as instructed by your healthcare provider.

. . .

Common side effects of XELJANZ/XELJANZ XR/XELJANZ oral solution in people with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis include:

• upper respiratory tract infections (common cold, sinus infections)
• headache
• diarrhea
• nasal congestion, sore throat, and runny nose (nasopharyngitis)
• high blood pressure (hypertension)
• acne

. . .

Common side effects of XELJANZ/XELJANZ oral solution in children with polyarticular course juvenile arthritis and psoriatic arthritis include:

• upper respiratory tract infections (common cold, sinus infections)
• nasal congestion, sore throat, and runny nose (nasopharyngitis)
• headache
• fever
• nausea
• vomiting
• acne

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

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 [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)].

. . .

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)].

. . .

02/21/2025 (SUPPL-10)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA)

The safety and effectiveness of XELJANZ/XELJANZ Oral Solution for the treatment of active pcJIA have been established in patients 2 years to 17 years of age. Use of XELJANZ/XELJANZ Oral Solution for the treatment of pediatric patients with active pcJIA in this age group is supported by evidence from adequate and well-controlled studies of XELJANZ in adult RA patients with additional data from a clinical trial of XELJANZ/XELJANZ Oral Solution in pediatric patients (2 years to 17 years of age) with active pcJIA consisting of an 18-week, open label, run-in period followed by a 26-week placebo-controlled, randomized withdrawal period [see Clinical Studies (14.5)]. The safety and effectiveness of XELJANZ/XELJANZ Oral Solution have not been established in pcJIA patients less than 2 years of age.

Adverse reactions observed in pediatric patients with pcJIA receiving XELJANZ/XELJANZ Oral Solution were consistent with those reported in RA patients [see Adverse Reactions (6.1)].

Systemic Juvenile Idiopathic Arthritis (sJIA)

The safety and effectiveness of XELJANZ/XELJANZ Oral Solution in the treatment of pediatric patients with 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 with sJIA with active systemic features (2 years to 17 years of age) did not demonstrate that XELJANZ/XELJANZ Oral Solution (dosed at 5 mg twice daily or body weight-based equivalent twice daily) is 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/XELJANZ Oral Solution and 31 patients to placebo. The study data are insufficient to demonstrate efficacy and, therefore, XELJANZ/XELJANZ Oral Solution is not recommended for pediatric use in 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)].

09/27/2024 (SUPPL-8)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

The available data with XELJANZ/XELJANZ XR/XELJANZ Oral Solution from a pregnancy exposure registry that enrolled 11 exposed patients, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy (see Clinical Considerations). In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).

…

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Based on published data, tofacitinib is present in human milk. Data on the effects of tofacitinib on the breastfed infant is limited to a small number of cases with no reported adverse effects. There are no data on the effects on milk production. Given the serious adverse reactions seen in patients treated with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ/XELJANZ Oral Solution or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives).

Data

Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.

05/14/2024 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Skin and subcutaneous tissue disorders: Acne

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Common side effects of XELJANZ/XELJANZ Oral Solution in people with polyarticular course juvenile arthritis include:

…

• acne

  …

12/14/2021 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Ankylosing Spondylitis

XELJANZ 5 mg twice daily was studied in patients with active ankylosing spondylitis (AS) in a confirmatory double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a

dose-ranging Phase 2 clinical trial (Study AS-II).

Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.

Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg, 5 mg, 10 mg, or placebo twice daily.

In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either XELJANZ 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (less than or equal to10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.

The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients.

…

7 Drug Interactions

Addition of ankylosing spondylitis to Clinical Impact under Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) in Table 6.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

…

What is XELJANZ/XELJANZ XR/XELJANZ Oral Solution?

…

• XELJANZ/XELJANZ XR is used to treat adults with active ankylosing spondylitis when 1 or more TNF blocker medicines have been used and did not work well or cannot be tolerated.

  …

  What are the possible side effects of XELJANZ/XELJANZ XR/XELJANZ Oral Solution? XELJANZ/XELJANZ XR/XELJANZ Oral Solution may cause serious side effects, including:

  …

  Common side effects of XELJANZ/XELJANZ XR in people with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis include:

• upper respiratory tract infections (common cold, sinus infections)

• headache

• diarrhea

• nasal congestion, sore throat, and runny nose (nasopharyngitis)

•  high blood pressure (hypertension)

  …

12/02/2021 (SUPPL-4)

Approved Drug Label (PDF)

Boxed Warning

Box Warning has been revised; see full information below:

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), AND THROMBOSIS

See full prescribing information for complete boxed warning.

• Increased risk of serious bacterial, fungal, viral, and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Interrupt treatment with XELJANZ/XELJANZ XR/XELJANZ Oral Solution if serious infection occurs until the infection is controlled. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. (5.1)

• Higher rate of all-cause mortality, including sudden cardiovascular death with XELJANZ vs. TNF blockers in rheumatoid arthritis (RA) patients. (5.2)

• Malignancies have occurred in patients treated with XELJANZ. Higher rate of lymphomas and lung cancers with XELJANZ vs. TNF blockers in RA patients. (5.3)

• Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with XELJANZ vs. TNF blockers in RA patients. (5.4)

• Thrombosis has occurred in patients treated with XELJANZ. Increased incidence of pulmonary embolism, venous and arterial thrombosis with XELJANZ vs. TNF blockers in RA patients. (5.5)

5 Warnings and Precautions

5.2 Mortality

Additions and/or revisions underlined:

Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice a day or XELJANZ 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 0.88 for XELJANZ 5 mg twice a day, 1.23 for XELJANZ 10 mg twice a day, and 0.69 for TNF blockers [see Clinical Studies (14.5)]. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution.

A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].

5.3 Malignancy and Lymphoproliferative Disorders

Additions and/or revisions underlined:

Malignancies, including lymphomas and solid cancers, were observed in clinical studies of XELJANZ [see Adverse Reactions (6.1)].

In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day as compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for XELJANZ 5 mg twice a day, 1.13 for XELJANZ 10 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 (14.5)].

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. The incidence rate of lymphomas per 100 patient-years was 0.07 for XELJANZ 5 mg twice a day, 0.11 for XELJANZ 10 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 0.48 for XELJANZ 5 mg twice a day,

0.59 for XELJANZ 10 mg twice a day, and 0.27 for TNF blockers [see Clinical Studies (14.5)].

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, particularly in patients with 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 XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of

111 patients treated with cyclosporine.

Other malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.

Non-Melanoma Skin Cancer

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC.

5.4 Major Adverse Cardiovascular Events

Newly added subsection:

In RA Safety Study 1, RA patients who were 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 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 0.91 for XELJANZ 5 mg twice a day, 1.11 for XELJANZ 10 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 0.36 for XELJANZ 5 mg twice a day, 0.39 for XELJANZ 10 mg twice a day, and 0.20 for TNF blockers [see Clinical Studies (14.5)]. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ/XELJANZ XR/XELJANZ Oral Solution, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that have experienced a myocardial infarction or stroke. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

5.5 Thrombosis

Additions and/or revisions underlined:

Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death [see Warnings and Precautions (5.2)].

Patients with rheumatoid arthritis 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ at both 5 mg or 10 mg twice daily compared to TNF blockers in RA Safety Study 1 had an observed increase in incidence of these events. The incidence rate of DVT per 100 patient-years was 0.22 for XELJANZ 5 mg twice a day, 0.28 for XELJANZ 10 mg twice a day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.18 for XELJANZ 5 mg twice a day, 0.49 for XELJANZ 10 mg twice a day, and 0.05 for TNF blockers [see Clinical Studies (14.5)].

A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA [see Dosage and Administration (2.2)].

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/XELJANZ Oral Solution in patients with symptoms of thrombosis.

Avoid XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response [see Dosage and Administration (2.3)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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.

Rheumatoid Arthritis

The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not a recommended regimen for the treatment of rheumatoid arthritis [see Dosage and Administration (2.2)]. In RA Safety Study 1, 1455 patients were treated with XELJANZ 5 mg twice daily, 1456 patients were treated with 10 mg twice daily, and 1451 patients were treated with a TNF blocker for a median of

4.0 years [see Clinical Studies (14.5)].

…

During the 2 PsA controlled clinical trials, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus non-biologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ.

…

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily [see Warnings and Precautions (5.3)]. Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer [see Warnings and Precautions (5.5)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Serious Infections

Inform patients that XELJANZ/XELJANZ XR/XELJANZ Oral Solution may lower the ability of their immune system to fight infections. Advise patients not to start taking XELJANZ/XELJANZ XR/XELJANZ Oral Solution if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order to ensure rapid evaluation and appropriate treatment [see Warnings and Precautions (5.1)].

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

Malignancies and Lymphoproliferative Disorders

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

Major Adverse Cardiovascular Events

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

Thrombosis

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

Hypersensitivity

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

Important Information on Laboratory Abnormalities

Inform patients that XELJANZ/XELJANZ XR/XELJANZ Oral Solution may affect certain lab test results, and that blood tests are required before and during

XELJANZ/XELJANZ XR/XELJANZ Oral Solution treatment [see Warnings and Precautions (5.8)].

Pregnancy

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy. Inform patients that Pfizer has a registry for pregnant women who have taken

XELJANZ/XELJANZ XR/XELJANZ Oral Solution during pregnancy. Advise patients to contact the registry at 1-877-311-8972 to enroll [see Use in Specific Populations (8.1)].

Lactation

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

Infertility

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

Residual Tablet 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.