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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 tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, urinary tract infection, cellulitis, herpes zoster, bronchitis, septic shock, diverticulitis, gastroenteritis, appendicitis, and sepsis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infections, and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents, such as methotrexate or corticosteroids 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 one large randomized post-authorization safety study (PASS) in RA patients who were 50 years or older with at least one additional cardiovascular risk factor, a dose dependent increase in serious infections was observed in patients treated with tofacitinib compared to TNF inhibitor (see Pharmacology: Pharmacodynamics under Actions). Some of these serious infections resulted in death. Opportunistic infections were also reported in the study.
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 Adverse Reactions). 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 tofacitinib, 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 health care 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, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with tofacitinib. In one large randomized post-authorization safety study (PASS) in RA patients who were 50 years or older with at least one additional cardiovascular risk factor, an increase in herpes zoster events was observed in patients treated with tofacitinib compared to TNF inhibitor (see Pharmacology: Pharmacodynamics under Actions). Post-marketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib. 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 tofacitinib.
The incidence of herpes zoster appears to be increased in patients treated with tofacitinib 10 mg twice daily.
Venous Thromboembolism: Venous thromboembolism (VTE) has been observed in patients taking tofacitinib in clinical trials and post-marketing reporting. In one large randomized PASS in RA patients who were 50 years or older with at least one additional 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 inhibitor (see Pharmacology: Pharmacodynamics under Actions).
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 and Pharmacology: Pharmacodynamics under Actions).
Deep vein thrombosis (DVT) events were observed in all three treatment groups in this study (see Pharmacology: Pharmacodynamics under Actions).
Assess patients for VTE risk factors before starting treatment and periodically during treatment. Use XELJANZ with caution in patients 65 years of age and older and in patients in whom VTE risk factors are identified (see Dosage & Administration). Urgently evaluate patients with signs and symptoms of VTE. Discontinue XELJANZ while evaluating suspected VTE, regardless of dose or indication.
Major Adverse Cardiovascular Events (Including Myocardial Infarction): In one large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor, patients were treated with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily or a TNF inhibitor. Major adverse cardiovascular events (MACE), including events of myocardial infarction, were observed in all three treatment groups in this study. An increase in non-fatal myocardial infarctions was observed in patients treated with tofacitinib compared to TNF inhibitor (see Pharmacology: Pharmacodynamics under Actions). MACE, including events of myocardial infarction, were more common in patients 65 years of age and older, in patients who were current or past, long-time smokers, and in patients with a history of atherosclerotic cardiovascular disease (ASCVD). Caution should be used in treating patients 65 years of age and older, patients who are current or past, long-time smokers, and patients with other cardiovascular risk factors (e.g., history of ASCVD). In patients with these risk factors, an individualized benefit-risk assessment should be completed prior to a decision on treatment initiation or continuation (see Pharmacology: Pharmacodynamics under Actions).
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.
An increase in malignancies was observed in patients treated with tofacitinib compared to TNF inhibitor in a large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions). Malignancies excluding NMSC were more common in patients 65 years of age and older, and in patients who were current or past, long-time smokers. Caution should be used in treating patients 65 years of age and older, patients who are current or past, long-time smokers, and patients with other malignancy risk factors (e.g., current malignancy or history of malignancy). In patients with these risk factors, an individualized benefit-risk assessment should be completed prior to a decision on treatment initiation or continuation (see Pharmacology: Pharmacodynamics under Actions).
Lymphomas have been observed in patients treated with tofacitinib and in patients treated with tofacitinib in a large randomized PASS in RA patients who were 50 years and older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions). 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.
Lung cancers have been observed in patients treated with tofacitinib. Lung cancers were also observed in patients treated with tofacitinib in a large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor; an increase was observed in patients treated with tofacitinib 10 mg twice daily compared with TNF inhibitor (see Pharmacology: Pharmacodynamics under Actions). Of the 30 lung cancers reported in the study in patients taking tofacitinib, all but 2 were in patients who were current or past smokers. Patients with rheumatoid arthritis may be at higher risk than the general population for the development of lung cancer. The role of XELJANZ in the development of lung cancer is uncertain.
Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, breast cancer, melanoma, prostate cancer, and pancreatic cancer. The role of treatment with XELJANZ on the development and course of malignancies is not known.
Caution should be used in treating elderly patients, patients who are current or past smokers, and patients with other malignancy risk factors.
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 tofacitinib (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
Rheumatoid Arthritis: In the 5 controlled Phase 3 clinical studies in rheumatoid arthritis patients, 21 malignancies (excluding NMSC) including 2 lymphomas were diagnosed in 21 patients receiving tofacitinib/tofacitinib 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. 3030 patients (2679 patient-years of observation) were treated with tofacitinib 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 0.78 and 0.075 events per 100 patient-years, respectively, in the tofacitinib 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.
In a large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor, an increase in malignancies (excluding NMSC) was observed in patients treated with tofacitinib compared with TNF inhibitor (see Pharmacology: Pharmacodynamics under Actions). Malignancies (excluding NMSC) were more common in patients 65 years of age and older and in patients who were current or past, long-time smokers.
Psoriatic Arthritis: In 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients (298 patient-years of observation) receiving tofacitinib plus csDMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients (52.3 patient-years) in the placebo plus csDMARD group (3 months exposure) and 0 malignancies in 106 patients (91 patient-years) in the adalimumab plus csDMARD group (12 months exposure). No lymphomas were reported. The exposure-adjusted incidence rate for malignancies (excluding NMSC) was 1.95 patients with events and 0 patients with events per 100 patient-years in the tofacitinib groups that received 5 mg twice daily and 10 mg twice daily, respectively.
In the safety population comprised of the 2 controlled Phase 3 clinical trials and the long-term extension trial (783 patients) the rate of malignancies (excluding NMSC) was 0.72 patients with events per 100 patient-years.
Ulcerative Colitis: In the placebo-controlled induction and maintenance studies for ulcerative colitis, there were no malignancies (excluding NMSC) in any tofacitinib group. In the entire tofacitinib treatment experience for ulcerative colitis, malignancies (excluding NMSC) have been reported with an overall incidence rate of 0.5 events per 100 patient-years.
In Cohort 3 P2P3LTE Tofacitinib study, the IRs (95% CI) for PD tofacitinib 5 mg and PD tofacitinib 10 mg for all malignancies (excluding NMSC) were 0.00 (0.00, 1.00) and 0.62 (0.27, 1.22) patients with events per 100 Pys respectively.
Non-melanoma Skin Cancer: Non-melanoma skin cancers (NMSCs) have been reported in patients treated with tofacitinib. NMSCs were also reported in a large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor. In this study, an increase in overall NMSCs, including cutaneous squamous cell carcinomas was observed in patients treated with tofacitinib compared to TNF inhibitor (see Pharmacology: Pharmacodynamics under Actions). As there is a higher incidence of NMSC in the elderly and in patients with a prior history of NMSC, caution should be used when treating these types of patients. The risk of NMSC may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Gastrointestinal Perforations: Events of gastrointestinal perforation have been reported in clinical trials including a large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions). The role of JAK inhibition in these events is not known. In the rheumatoid arthritis clinical trials, the incidence rate of gastrointestinal perforation across all studies (Phase 1, Phase 2, Phase 3 (excluding A3921069) and long-term extension) for all treatments groups all doses was 0.12 events per 100 patient-years with tofacitinib therapy. Events were primarily reported as diverticular perforation, peritonitis, abdominal abscess and appendicitis. 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. tofacitinib to the development of gastrointestinal perforations is not known. The incidence rate in the psoriatic arthritis clinical trials (Phase 3 and long-term extension) was 0.08 patients with events per 100 patient-years with tofacitinib therapy.
In placebo-controlled induction studies for ulcerative colitis, gastrointestinal perforation (all cases) occurred in 2 (0.2%) patients treated with tofacitinib 10 mg twice daily and in 2 (0.9%) patients receiving placebo. In the Phase 3 maintenance study for ulcerative colitis, gastrointestinal perforation (all cases) was not reported in patients treated with tofacitinib and was reported in 1 patient treated with placebo.
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.
Fractures: Fractures have been observed in patients treated with XELJANZ in clinical studies and the post-marketing setting.
In controlled Phase 3 clinical studies in RA patients, during the 0 to 3 months exposure, the incidence rates for fractures for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and placebo were 2.11, 2.56 and 4.43 patients with events per 100 PYs, respectively.
In a large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor, fractures were observed across XELJANZ and TNF inhibitor treatment groups (see Pharmacology: Pharmacodynamics under Actions).
Caution should be used in patients with known risk factors for fractures such as elderly patients, female patients and patients with corticosteroid use.
Hypersensitivity: Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving tofacitinib. 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 taking XELJANZ 10 mg twice daily who develop a persistent ANC of 500-1000 cells/mm3, reduce XELJANZ dose to 5 mg twice daily until ANC is >1000 cells/mm3. For patients taking XELJANZ 5 mg twice daily who develop a persistent ANC of 500-1000 cells/mm3, interrupt 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 to 8 weeks of treatment and every 3 months thereafter (see Dosage & Administration and Adverse Reactions).
Liver Enzymes: Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.
Lipids: Treatment with tofacitinib 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. Increases of total cholesterol, LDL cholesterol, and HDL cholesterol were also reported in a large randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor (see Pharmacology: Pharmacodynamics under Actions).
Assessment of lipid parameters should be performed approximately 4 to 8 weeks following initiation of XELJANZ therapy. Patients should be managed according to clinical guidelines (e.g., National Cholesterol Educational Program) for the management of hyperlipidemia. Increases in total and LDL cholesterol associated with XELJANZ may be decreased to pretreatment levels with statin therapy.
Vaccinations: No data are available on the secondary transmission of infection by live vaccines to patients receiving tofacitinib. 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 tofacitinib 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 tofacitinib.
In a controlled clinical trial, the humoral response to concurrent vaccination with influenza and pneumococcal polysaccharide vaccines in patients with rheumatoid arthritis initiating tofacitinib 10 mg twice daily or placebo was evaluated. A similar percentage of patients achieved a satisfactory humoral response to influenza vaccine (≥4-fold increase in ≥2 of 3 antigens) in the tofacitinib (57%) and placebo (62%) treatment groups. A modest reduction in the percentage of patients who achieved a satisfactory humoral response to pneumococcal polysaccharide vaccine (≥2-fold increase in ≥6 of 12 serotypes) was observed in patients treated with tofacitinib monotherapy (62%) and methotrexate monotherapy (62%) as compared with placebo (77%), with a greater reduction in the response rate of patients receiving both tofacitinib and methotrexate (32%). The clinical significance of this is unknown.
A separate vaccine study evaluated the humoral response to concurrent vaccination with influenza and pneumococcal polysaccharide vaccines in patients receiving tofacitinib 10 mg twice daily for a median of approximately 22 months. Greater than 60% of patients treated with tofacitinib (with or without methotrexate) had satisfactory responses to influenza and pneumococcal vaccines. Consistent with the controlled trial, patients receiving both tofacitinib and MTX had a lower response rate to pneumococcal polysaccharide vaccine as compared with tofacitinib monotherapy (66% vs. 89%).
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 tofacitinib 5 mg twice daily or placebo. Six weeks after immunization with the zoster vaccine, tofacitinib and placebo recipients exhibited similar humoral and cell-mediated responses (mean fold change of VZV IgG antibodies 2.11 in tofacitinib 5 mg twice daily and 1.74 in placebo twice daily; VZV IgG fold-rise ≥1.5 in 57% of tofacitinib recipients and in 43% of placebo recipients; mean fold change of VZV T-cell ELISPOT Spot Forming Cells 1.5 in tofacitinib 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. Tofacitinib 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.
Patients with Renal Impairment: No dose adjustment is required in patients with mild renal impairment. If XELJANZ dose is 5 mg twice daily, the recommended dose in patients with severe renal impairment is XELJANZ 5 mg once daily. For specific dose adjustment recommendations for each indication, see Dosage & Administration.
In clinical trials, tofacitinib was not evaluated in patients with baseline creatinine clearance values (estimated by Cockcroft-Gault equation) <40 mL/min (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Patients with Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. If XELJANZ dose is 5 mg twice daily, the recommended dose in patients with moderate hepatic impairment, is XELJANZ 5 mg once daily. For specific dose adjustment recommendations for each indication, see Dosage & Administration.
XELJANZ should not be used in patients with severe hepatic impairment (see Dosage & Administration). In clinical trials, tofacitinib was not evaluated in patients with severe hepatic impairment, or in patients with positive HBV or HCV serology.
Combination with Other Therapies: Rheumatoid Arthritis: XELJANZ has not been studied and its use should be avoided in RA patients in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators and potent immunosuppressants, such as azathioprine and cyclosporine because of the possibility of increased immunosuppression and increased risk of infection.
Psoriatic Arthritis: XELJANZ has not been studied and its use should be avoided in patients with active psoriatic arthritis in combination with biological DMARDs such as TNF antagonists, IL-17 antagonists, and IL-12/IL-23 antagonists, and potent immunosuppressants, such as azathioprine and cyclosporine because of the possibility of increased immunosuppression and increased risk of infection.
The use of XELJANZ in combination with phosphodiesterase 4 inhibitors has not been studied in XELJANZ clinical trials.
Ulcerative Colitis: XELJANZ has not been studied and its use should be avoided in patients with ulcerative colitis in combination with biological agents such as TNF antagonists and vedolizumab, and/or potent immunosuppressants such as azathioprine, 6-mercaptopurine, tacrolimus, and cyclosporine because of the possibility of increased immunosuppression and increased risk of 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.
