Scroll for Important Safety Information and Indication

INDICATION

  • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
  • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS INFECTIONS AND MALIGNANCY

SERIOUS INFECTIONS

Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled.

Reported infections include:

  • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis 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, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ/XELJANZ XR 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 treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus—associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

SERIOUS INFECTIONS
The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, and diverticulitis. Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ/XELJANZ XR in patients:

  • with chronic or recurrent infection;
  • who have been exposed to tuberculosis (TB);
  • with a history of a serious or an opportunistic infection;
  • who have lived or traveled in areas of endemic TB or mycoses; or
  • with 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 XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

Tuberculosis
Evaluate and test patients for latent or active infection before administration of XELJANZ/XELJANZ XR. Consider anti-TB therapy prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Treat patients with latent TB with standard therapy before administering XELJANZ/XELJANZ XR.

Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (eg, herpes zoster), was observed in clinical studies with XELJANZ. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan.

MALIGNANCY and LYMPHOPROLIFERATIVE DISORDERS
Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy.

In the 7 controlled rheumatoid arthritis clinical studies, 11 solid cancers and 1 lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ.

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.

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.

GASTROINTESTINAL PERFORATIONS
Gastrointestinal perforations have been reported in XELJANZ rheumatoid arthritis clinical trials, although the role of JAK inhibition is not known. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (eg, patients with a history of diverticulitis).

LABORATORY ABNORMALITIES
Lymphocyte Abnormalities
Treatment with XELJANZ was associated with initial lymphocytosis at 1 month of exposure followed by a gradual decrease in mean lymphocyte counts of approximately 10% during 12 months of therapy. Counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia
Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia
Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations
Treatment with XELJANZ 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/XELJANZ XR should be interrupted until this diagnosis has been excluded.

Lipid Elevations
Treatment with XELJANZ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks.

Assess lipid parameters approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy, and manage patients according to clinical guidelines for the management of hyperlipidemia.

VACCINATIONS
Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy.

GENERAL
Specific to XELJANZ XR
Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. 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.

HEPATIC and RENAL IMPAIRMENT
Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.

The recommended dose in patients with moderate hepatic impairment or with moderate or severe renal impairment is XELJANZ 5 mg once daily.

ADVERSE REACTIONS
The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infections (4.5%, 3.3%), headache (4.3%, 2.1%), diarrhea (4.0%, 2.3%), and nasopharyngitis (3.8%, 2.8%).

USE IN PREGNANCY
There are no adequate and well-controlled studies in pregnant women. XELJANZ/XELJANZ XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Safety

XELJANZ: SAFETY PROFILE EXTENSIVELY STUDIED IN RA CLINICAL TRIALS1

The safety profile of XELJANZ® (tofacitinib citrate) 5 mg has been evaluated out to 8 years in long-term extension (LTE) studies1

  • Approximately 320 patients taking XELJANZ 5 mg twice dailyb have been treated for 72 months or more (324 of 1525 total enrollment; exposure ranges from 1 month to 105 months) in open-label LTE studies1

aData as of January 2016 (data from phase 1, phase 2, phase 3, and 2 LTE studies).1

bAverage daily dose.

LTE Studies Limitations

Pooled LTE analysis data from 2 open-label LTE studies in which patients from qualifying index studies (Phase 1-3) were allowed to enroll in LTE studies. The primary objectives of these analyses are safety. Limitations to interpretation of these analyses include:

  • Some patients do not qualify or choose not to enroll and some are ineligible due to prior events such as serious infections or malignancies
  • Some patients discontinue from the LTE studies for a range of possible reasons, including adverse events (AEs). Information on AEs is limited to the time that patients are taking study drug and up to 30 days after discontinuation; information on AEs that occur more than 30 days after discontinuation is often not available
  • Rates are subject to change. The number of patients and patient exposure for a specific safety event may differ, depending on the timing of censored events
  • As of January 2016, the overall discontinuation rate for the pooled LTE analyses alone (all doses) was 48%1

Based on the design of the LTE studies and the additional factors listed above, including discontinuation over time, this limits the interpretation of long-term safety data.



INCIDENCE RATES OF SERIOUS INFECTIONS OUT TO 8 YEARS IN LTE STUDIES ARE CONSISTENT WITH THE XELJANZ PHASE 3 PROGRAM1

Studies were conducted with XELJANZ 5 mg BID dosing.1,2



cIn Oral Start only.2

dXELJANZ approved November 6, 2012.

  • In the 7 controlled clinical trials, during 0 to 3 months of exposure, serious infections were reported in 1 patient (0.5 events per 100 pt-yrs) who received placebo and 11 patients (1.7 events per 100 pt-yrs) who received XELJANZ 5 mg or 10 mg twice daily2
  • In the 7 controlled clinical trials, during 0 to 12 months of exposure, serious infections were reported in 34 patients (2.7 events per 100 pt-yrs) and opportunistic infections were reported in 4 patients (0.3 events per 100 pt-yrs), who received XELJANZ 5 mg or 10 mg twice daily, respectively2
    • A serious infection was defined as an infection that required hospitalization or parenteral antimicrobial therapy or met other criteria that required it to be classified as a serious AE1
    • A patient who experienced a serious infection was to be discontinued from the study by protocol1

Some patients are ineligible to enroll in LTEs due to prior events, such as serious infections or malignancies, and some patients discontinue for a range of possible reasons. Based on these factors, this limits the interpretation of long-term safety data. Rates are subject to change. Please see full safety analysis.


  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily2

INCIDENCE RATES OF MALIGNANCIES (EXCLUDING NMSC) OUT TO 8 YEARS IN LTE STUDIES ARE CONSISTENT WITH THE XELJANZ PHASE 3 PROGRAM1

Studies were conducted with XELJANZ 5 mg BID dosing.1,2


eIn Oral Start only.2

fXELJANZ approved November 6, 2012.

  • In the 7 controlled clinical trials, 11 solid cancers and 1 lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without a DMARD. This compares with 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure to XELJANZ2
  • Lymphomas and solid cancers have also been observed in the LTE studies in patients with RA who were treated with XELJANZ2
    • In the 6 phase 3 studies, 2 cases of lymphoma were reported in patients receiving XELJANZ 5 mg twice daily (incidence rate 0.12 per 100 pt-yrs)1
    • As of January 2016, in the pooled LTE studies, 4 cases of lymphoma were reported in patients receiving XELJANZ 5 mg twice daily (incidence rate 0.07 per 100 pt-yrs)1
  • As of January 2016, in the pooled LTE studies, 58 malignancies were reported in 1525 patients for XELJANZ 5 mg twice daily (incidence rate of 1.03 per 100 pt-yrs)1
  • NMSCs have been reported in patients treated with XELJANZ. Periodic skin examinations are recommended for patients who are at increased risk for skin cancer2

Some patients are ineligible to enroll in LTEs due to prior events, such as serious infections or malignancies, and some patients discontinue for a range of possible reasons. Based on these factors, this limits the interpretation of long-term safety data. Rates are subject to change. Please see full safety analysis.


  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily2

INCIDENCE RATES OF HERPES ZOSTER (NONSERIOUS AND SERIOUS) ACROSS DOSE GROUPS1

Studies were conducted with XELJANZ 5 mg BID dosing.1,2


gIn Oral Start only.2

  • There were herpes zoster events in the XELJANZ phase 2, phase 3, and LTE studies, and these events occurred more frequently in the XELJANZ groups compared with the placebo groups1
    • In the 6 phase 3 studies, there were 143 cases of HZ (all doses); 11 cases were considered serious1
    • As of January 2016, in the pooled LTE studies, 190 cases were reported in patients receiving XELJANZ 5 mg twice daily (incidence rate 3.69 per 100 pt-yrs)1
    • A serious infection was defined as an infection that required hospitalization or parenteral antimicrobial therapy or met other criteria that required it to be classified as a serious AE1
      • Serious HZ was reported in 14 patients who received XELJANZ 5 mg twice daily (incidence rate 0.25 per 100 pt-yrs), in pooled LTE studies as of January 20161

Some patients are ineligible to enroll in LTEs due to prior events, such as serious infections or malignancies, and some patients discontinue for a range of possible reasons. Based on these factors, this limits the interpretation of long-term safety data. Rates are subject to change. Please see full safety analysis.


  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily2

RATES OF HERPES ZOSTER (NONSERIOUS AND SERIOUS) BY REGION1

Studies were conducted with XELJANZ 5 mg BID dosing.1,2


  • The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan2
  • Data from 2 phase 1, 9 phase 2, 6 phase 3, and 2 LTE studies as of January 2016. Data include serious and nonserious events1
  • The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown2
  • 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/XELJANZ XR2

The phase 2/3 RA controlled studies were not designed to determine similarities or differences in HZ rates by regions. A nonprespecified (post hoc) analysis was performed to identify potential risk factors of HZ infection associated with XELJANZ in the global RA clinical development program. Crude incidence rates (patients with events per 100 pt-yrs) were calculated by region to examine if differences exist. Based on these analyses, the risk of HZ is increased in patients treated with XELJANZ/XELJANZ XR extended release and appears to be higher in patients treated with XELJANZ in Japan.


  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily2

GASTROINTESTINAL (GI) PERFORATION RATES ACROSS TREATMENT GROUPS1

Studies were conducted with XELJANZ 5 mg BID dosing.1,2



hIn Oral Start only.2

iBar indicates 95% confidence limits; incidence rate of patients per 100 pt-yrs.1

  • In the 6 phase 3 clinical trials, 2 adjudicated events of GI perforation were reported in patients receiving XELJANZ 10 mg BID (the recommended dose of XELJANZ is 5 mg twice daily and the recommended dose of XELJANZ XR is 11 mg once daily)1
    • GI perforation events occurred most often in patients taking concomitant nonsteroidal anti-inflammatory drugs, corticosteroids, or MTX2
    • The role of Janus kinase inhibition in these events is not known2
  • As of January 2016, in the pooled LTE studies, 3 cases were reported in 1525 patients for XELJANZ 5 mg twice daily (incidence rate of 0.05 per 100 pt-yrs)1

Some patients are ineligible to enroll in LTEs due to prior events, such as serious infections or malignancies, and some patients discontinue for a range of possible reasons. Based on these factors, this limits the interpretation of long-term safety data. Rates are subject to change. Please see full safety analysis.


  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily2

LAB ABNORMALITIES2

Lymphopenia

Confirmed decreases in lymphocyte counts (<500 cells/mm3) occurred in 0.04% of patients treated with XELJANZ 5 mg in the first 3 months of exposure.2

Neutropenia

Confirmed decreases in absolute neutrophil count (<1000 cells/mm3) occurred in 0.07% of patients treated with XELJANZ in the first 3 months of exposure.2

Anemia

Treatment with XELJANZ should be interrupted in patients who develop Hb levels <8 g/dL or whose Hb levels drop >2 g/dL on treatment. Avoid initiation of treatment in patients with low hemoglobin level (<9 g/dl).2

Liver Enzyme Elevations

Confirmed increases in liver enzymes levels >3 times the upper limit of normal were observed in patients treated with XELJANZ.2

Lipid Elevations

One month after initiation of XELJANZ, elevations were observed in levels of total cholesterol, LDL, HDL, and triglycerides and remained stable thereafter.2

See Lab Monitoring Information

MOST COMMON ADVERSE REACTIONS (0-3 MONTHS)2

Studies were conducted with XELJANZ (tofacitinib citrate) 5 mg BID dosing.2

Adverse Reactions Occurring in ≥2% of Patients on 5 mg Twice-Daily XELJANZ With or Without DMARD (0-3 months) and ≥1% Greater Than That Observed in Patients on Placebo2


XELJANZ or placebo may be +/- nonbiologic DMARDs.2

  • The most commonly reported adverse reactions during the first 3 months in controlled clinical trials (occurring in ≥2% of patients treated with XELJANZ monotherapy or in combination with nonbiologic DMARDs) were upper respiratory tract infections, headache, diarrhea, and nasopharyngitis2
  • XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily2

RA=rheumatoid arthritis; LTE=long-term extension; BID=twice daily; CI=confidence interval; MTX=methotrexate; AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; DMARD=disease-modifying antirheumatic drug; XR=extended release; NMSC=non-melanoma skin cancer; HZ=herpes zoster; GI=gastrointestinal; ANC=absolute neutrophil count; Hb=hemoglobin; LDL=low-density lipoprotein; HDL=high-density lipoprotein; AUC=area under the curve; TDD=total daily dose; IR=incidence rate.