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Serious Infections: Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunomodulatory agents, including biologic DMARDs and XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infections, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and rheumatoid arthritis patients were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids which, in addition to rheumatoid arthritis may predispose them to infections. Other serious infections that were not reported in clinical studies, may also occur (e.g., coccidioidomycosis).
In the UC population, XELJANZ treatment with 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 10 mg twice daily.
XELJANZ should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients with chronic or recurrent infections, or those who have been exposed to tuberculosis, or with a history of a serious or an opportunistic infection, or have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or have underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes (see Dosage & Administration). Caution is also recommended in patients with a history of chronic lung disease as they may be more prone to infections. Events of interstitial lung disease (some of which had a fatal outcome) have been reported in patients treated with XELJANZ, a Janus-kinase (JAK) inhibitor, in clinical trials and in the post-marketing setting although the role of JAK inhibition in these events is not known.
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 discussed in Dosage & Administration.
Tuberculosis: Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ.
Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ.
Antituberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a healthcare professional with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating antituberculosis therapy is appropriate for an individual patient.
Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Viral Reactivation: Viral reactivation has been reported with DMARD treatment and cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. Post-marketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. The risk of herpes zoster appears to be higher in Japanese and Korean patients treated with XELJANZ.
Venous Thromboembolism: Venous thromboembolism (VTE) has been observed in patients taking XELJANZ in clinical trials and post-marketing reporting. In one large ongoing randomized post authorization safety surveillance (PASS) study in RA patients who were 50 years or older with at least one cardiovascular risk factor, patients were treated with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily or a TNF inhibitor. A dose dependent increase in pulmonary embolism (PE) events was observed in patients treated with tofacitinib compared to TNF inhibitors (see Adverse Reactions). Many of these PE events were serious and some resulted in death. PE events were reported more frequently in this study in patients taking tofacitinib relative to other studies across the tofacitinib program (see Adverse Reactions).
Deep vein thrombosis (DVT) events were observed in all three treatment groups in this study (see Adverse Reactions).
Assess patients for VTE risk factors before starting treatment and periodically during treatment. Use XELJANZ with caution in patients in whom risk factors are identified (see Dosage & Administration). Urgently evaluate patients with signs and symptoms of VTE. Discontinue tofacitinib while evaluating suspected VTE, regardless of dose or indication.
Mortality: Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study.
A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA (see Dosage & Administration).
For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response (see Dosage & Administration).
Malignancy and Lymphoproliferative Disorder (Excluding Non-melanoma Skin Cancer [NMSC]): Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. The possibility exists for XELJANZ to affect host defenses against malignancies.
Lymphomas have been observed in patients treated with XELJANZ. Patients with rheumatoid arthritis, particularly those with highly active disease may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. The role of XELJANZ, in the development of lymphoma is uncertain.
Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer and pancreatic cancer.
The role of treatment with XELJANZ on the development and course of malignancies is not known.
Recommendations for non-melanoma skin cancer are presented as follows.
Rheumatoid Arthritis: In controlled Phase 3 clinical studies in rheumatoid arthritis patients, 26 malignancies (excluding NMSC) including 5 lymphoma were diagnosed in 26 patients receiving XELJANZ/XELJANZ plus DMARD, compared to 0 malignancies (excluding NMSC) in patients in the placebo/placebo plus DMARD and 2 in 2 patients in the adalimumab group, 1 in 1 patient in the methotrexate group. 3800 patients (3942 patient-years of observation) were treated with XELJANZ for durations up to 2 years while 681 patients (203 patient-years of observation) were treated with placebo for a maximum of 6 months and 204 patients (179 patient-years of observation) were treated with adalimumab for 12 months. The exposure-adjusted incidence rate for malignancies and lymphoma was 0.66 and 0.13 events per 100 patient-years, respectively, in the XELJANZ groups.
In the long-term safety population (4867 patients), in rheumatoid arthritis studies, the rate of malignancies (excluding NMSC) and lymphoma was 0.97 and 0.09 events per 100 patient-years respectively, consistent with the rate observed in the controlled period.
Psoriatic Arthritis: During the 2 PsA controlled clinical studies there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic 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.
Ulcerative Colitis: All information provided in this section for the ulcerative colitis indication is applicable to XELJANZ 5 mg and 10 mg twice daily as they contain the same active ingredient (tofacitinib).
In the placebo-controlled induction and maintenance studies for ulcerative colitis, there were no malignancies (excluding NMSC) in any XELJANZ group. In the entire XELJANZ treatment experience for ulcerative colitis, malignancies (excluding NMSC) have been reported with an overall incidence rate of 0.5 events per 100 patient-years.
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.
Thrombosis: Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Patients with rheumatoid arthritis 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death (see Precautions).
A dosage of XELJANZ 10 mg twice daily is not recommended for the treatment of RA (see Dosage & Administration).
In a long-term extension study in patients with UC, four 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 in patients with symptoms of thrombosis.
Avoid XELJANZ in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response (see Dosage & Administration).
Gastrointestinal Perforations: Events of gastrointestinal perforation have been reported in clinical trials. The role of JAK inhibition in these events is not known. Events were primarily reported as diverticular perforation, peritonitis, abdominal abscess and appendicitis. In the rheumatoid arthritis clinical trials, the incidence rate of gastrointestinal perforation across all studies (Phase 1, Phase 2, Phase 3 and long-term extension) for all treatments groups all doses was 0.11 events per 100 patient-years with XELJANZ therapy. Rheumatoid arthritis patients who developed gastrointestinal perforations were taking concomitant non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids. The relative contribution of these concomitant medications vs. XELJANZ to the development of gastrointestinal perforations is not known.
XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids.
Hypersensitivity: Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ. Some events were serious. Many of these events occurred in patients that have a history of multiple allergies. If a serious hypersensitivity reaction occurs, promptly discontinue XELJANZ while evaluating the potential cause or causes of the reaction.
Laboratory Parameters: Lymphocytes: Lymphocyte counts <500 cells/mm3 were associated with an increased incidence of treated and serious infections. It is not recommended to initiate XELJANZ treatment in patients with a low lymphocyte count (i.e., <500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count <500 cells/mm3 treatment with XELJANZ is not recommended. Lymphocytes should be monitored at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts (see Dosage & Administration).
Neutrophils: Treatment with XELJANZ was associated with an increased incidence of neutropenia (<2000 cells/mm3) compared to placebo. It is not recommended to initiate XELJANZ treatment in patients with a low neutrophil count (i.e., ANC <1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, reduce XELJANZ dose or interrupt XELJANZ dosing until ANC is >1000 cells/mm3. In patients who develop a confirmed absolute neutrophil count <500 cells/mm3, treatment with XELJANZ is not recommended. Neutrophils should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter (see Dosage & Administration and Adverse Reactions).
Hemoglobin: It is not recommended to initiate XELJANZ treatment in patients with low hemoglobin values (i.e., <9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels <8 g/dL or whose hemoglobin level drops >2 g/dL on treatment. Hemoglobin should be monitored at baseline and after 4 - 8 weeks of treatment and every 3 months thereafter (see Dosage & Administration and Adverse Reactions).
Lipids: Treatment with XELJANZ was associated with increases in lipid parameters such as total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assessment of lipid parameters should be performed approximately 4 - 8 weeks following initiation of XELJANZ therapy. Patients should be managed according to current local clinical guidelines for the management of hyperlipidemia. Increase in total and LDL cholesterol associated with XELJANZ may be decreased to pre-treatment levels with statin therapy.
In the clinical trials in psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis changes in lymphocytes, neutrophils, and lipids observed with XELJANZ treatment were similar to the changes observed in clinical trials in rheumatoid arthritis.
Vaccinations: No data are available on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. It is recommended that live vaccines not be given concurrently with XELJANZ. It is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy. The interval between live vaccinations and initiation of XELJANZ therapy should be in accordance with current vaccination guidelines regarding immunomodulatory agents. Consistent with these guidelines, if live zoster vaccine is administered, it should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus. Vaccination should occur at least 2 weeks but preferably 4 weeks before initiating immunomodulatory agents such as XELJANZ.
A controlled study in patients with rheumatoid arthritis on background methotrexate evaluated the humoral and cell-mediated responses to immunization with a live attenuated virus vaccine (Zostavax) indicated for prevention of herpes zoster. The immunization occurred 2 to 3 weeks before initiating a 12-week treatment with XELJANZ 5 mg twice daily or placebo. Six weeks after immunization with the zoster vaccine, XELJANZ and placebo recipients exhibited similar humoral and cell-mediated responses (mean fold change of VZV IgG antibodies 2.11 in XELJANZ 5 mg twice daily and 1.74 in placebo twice daily; VZV IgG fold-rise ≥1.5 in 57% of XELJANZ recipients and in 43% of placebo recipients; mean fold change of VZV T-cell ELISPOT Spot Forming Cells 1.5 in XELJANZ 5 mg twice daily and 1.29 in placebo twice daily). These responses were similar to those observed in healthy volunteers aged 50 years and older.
In this study one patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. XELJANZ was discontinued and the subject recovered after treatment with standard doses of antiviral medication. Subsequent testing showed that this patient made robust anti-varicella T-cell and antibody responses to the vaccine approximately 6 weeks post-vaccination, but not at 2 weeks post-vaccination, as expected for a primary infection.
Effects on ability to drive and use machines: No formal studies have been conducted on the effects on the ability to drive and use machines.
