1.1 Rheumatoid Arthritis

• XELJANZ (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 in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

2.1 Dosage in Rheumatoid Arthritis

• XELJANZ may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). The recommended dose of XELJANZ is 5 mg twice daily.
• XELJANZ is given orally with or without food.

2.2 Dosage Modifications due to Serious Infections and Cytopenias

(See Tables 1, 2, and 3 below.)

• It is recommended that XELJANZ not be initiated in patients with an absolute lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3 or who have hemoglobin levels less than 9 g/dL.
• Dose interruption is recommended for management of lymphopenia, neutropenia and anemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
• Avoid use of XELJANZ if a patient develops a serious infection until the infection is controlled.

2.3 Dosage Modifications due to Drug Interactions

• XELJANZ dosage should be reduced to 5 mg once daily in patients:
  • receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole).
  • receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
• Coadministration of potent inducers of CYP3A4 (e.g., rifampin) with XELJANZ may result in loss of or reduced clinical response to XELJANZ. Coadministration of potent inducers of CYP3A4 with XELJANZ is not recommended.

2.4 Dosage Modifications in Patients with Renal or Hepatic Impairment

• XELJANZ dosage should be reduced to 5 mg once daily in patients:
  • with moderate or severe renal insufficiency.
  • with moderate hepatic impairment.
• Use of XELJANZ in patients with severe hepatic impairment is not recommended.

5.1 Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus 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.

Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis).

Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients:

• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

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.

5.2 Malignancy and Lymphoproliferative Disorders

Consider the risks and benefits of XELJANZ 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 in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ [see Adverse Reactions (6.1)].

In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one 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.

5.3 Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events 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 eva luated promptly for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].